Oligonucleotides containing a ligand at a nucleobase, 2' position, or 3' position

Abstract

The present disclosure provides oligonucleotides comprising at least one radical of a central nervous system receptor ligand at a nucleobase, the 2' position of a nucleoside, or the 3' position of a nucleoside. The present disclosure also provides pharmaceutical compositions and kits comprising said oligonucleotides, methods of delivering said oligonucleotides, methods of modulating the activity of a protein using such oligonucleotides, and methods of treating, preventing, or diagnosing diseases (e.g., central nervous system diseases, neurodegenerative diseases, and neurocognitive diseases) in a. subject in need thereof using said oligonucleotides or pharmaceutical compositions thereof. The present disclosure also provides oligonucleosides that may be useful for making the oligonucleotides.

Description

[0001] OLIGONUCLEOTIDES CONTAINING A LIGAND AT A NUCLEOBASE, 2′ 2 POSITION, OR 3′ POSITION 4 RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, 6 U.S.S.N.63 / 520,093, filed August 17, 2023, the contents of which are incorporated by reference herein. 8 BACKGROUND 10 In the use of compounds (e.g., oligonucleotides) in therapeutic, prophylactic, or diagnostic applications, it is often desirable that the compounds be delivered to a specific 12 location (for example, to desired cell(s), to a desired organ or tissue, or to a particular location in a subject) to enhance the therapeutic or prophylactic effect or to be advantageous for diagnostic 14 purposes. This is frequently the case when attempting to deliver a therapeutic compound in vivo. Further, being able to efficiently deliver a compound to a specific location can limit or potentially 16 eliminate unintended consequences (such as off-target effects) that may be caused by administration of the compound. One strategy to facilitate delivery of a compound, such as a 18 therapeutic, prophylactic, or diagnostic compound, to a desired location in vivo, is by linking or attaching the compound to a targeting ligand. 20 One class of compounds that can be targeted using targeting ligands are oligomeric compounds, such as, for example, proteins, peptides, antibodies, and oligonucleotides. 22 Oligomeric compounds that include nucleotide sequences (e.g., oligonucleotides) at least partially complementary to a target nucleic acid have been shown to alter the function and 24 activity of the target both in vitro and in vivo. When delivered to a cell containing a target nucleic acid (such as mRNA or pre-mRNA), oligonucleotides have been shown to modulate the 26 expression or activity of the target nucleic acid. In certain instances, the oligonucleotide can reduce the expression of the gene by inhibiting translation of the nucleic acid target and / or 28 triggering the degradation of the target nucleic acid. If the target nucleic acid is mRNA, one mechanism by which an oligonucleotide can 30 modulate the expression of the mRNA target is through RNA interference. RNA interference is a biological process by which RNA or RNA-like compounds (such as chemically modified RNA 32 compounds) are able to silence gene expression, at least in part, through the RNA-induced silencing complex (RISC) pathway. Additionally, oligonucleotides can modulate the expression 34 of a target nucleic acid, such as a target mRNA, through an RNase recruitment mechanism, microRNA mechanisms, occupancy-based mechanisms, and editing mechanisms. 2 Oligonucleotides may be single-stranded or double-stranded. Oligonucleotides may comprise DNA, RNA, and RNA-like compounds, which can also include modified nucleosides including 4 one or more modified sugars, modified nucleobases, and modified internucleoside linkages. There is a need for new compounds for delivering to subjects pharmaceutical agents (e.g., 6 therapeutic, prophylactic, and diagnostic agents). 8 SUMMARY In one aspect, the present disclosure provides oligonucleotides comprising at least one 10 radical of a central nervous system receptor ligand at a nucleobase, the 2′ position of a nucleoside, or the 3′ position of a nucleoside. 12 In another aspect, the present disclosure is directed to oligonucleotides comprising a modified oligonucleotide strand comprising s1 instances of modified nucleosides independently 14 comprising a moiety of Formula I: 16 (I); and v1 instances of the internucleosidic linkers of the modified oligonucleotide strand are 18 independently repla ; wherein: 20 s1 is 1, 2, 3, 4, 5, or 6; each instance of N1is independently a radical of a nucleobase or a bond; 22 each instance of t1 is independently 1, 2, or 3; each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least 24 one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; each instance of A1, A2, and A3, if present, is independently a radical of a ligand or a 26 lipid, provided that at least one instance of A1, A2, and A3is a radical of a central nervous system receptor ligand; when y1 of an instance of is 0, L1thereof is hydrogen, halogen, 2 substituted or unsubstituted alky nsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 4 heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, 6 substituted or unsubstituted heteroaryl, –CN, –ORb, –SCN, –SRb, –SSRb, –N3, –NO, –N(Rb)2, – NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –S(=O)ORb, –S(=O)SRb, – 8 S(=O)N(Rb)2, –S(=O)2Rb, –S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –OC(=O)Rb, – OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, –10 OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, – SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, –12 NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, – NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, –NRbS(=O)2N(Rb)2, –14 Si(Rb)3, –Si(Rb)2ORb, –Si(Rb)(ORb)2, –Si(ORb)3, –OSi(Rb)3, –OSi(Rb)2ORb, –OSi(Rb)(ORb)2, or – OSi(ORb)3; or when y1 of an instance of is 1, 2, 3, 4, 5, or 6, L1thereof is a 16 linker; each instance of Rbis independe t y yd oge , substituted or unsubstituted alkyl, 18 substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted 20 heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting 22 group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached 24 to the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; 26 when y2 of an instance of is 0, L2thereof is –OH, –ORh, halogen, –CN, or –N3; or when y2 of an instance of is 1, 2, 3, 4, 5, or 6, L2thereof is a linker; 28 each instance of Rhis inde pendently substituted or unsubstituted, C1-6alkyl, or an oxygen protecting group; when the moiety of Formula I is part of an instance of the modified nucleoside at the 5’ 2 end or an internal position of the modified oligonucleotide strand: y3 thereof is 0, and L3thereof is an internucleosidic linker; or 4 when the moiety of Formula I is part of an instance of the modified nucleoside at the 3’ end of the modified oligonucleotide strand: 6 when y3 thereof is 0: L3thereof is –OH, –ORd, halogen, –CN, or –N3, and each instance of Rdis independently substituted or unsubstituted, C1-6alkyl, or an oxygen 8 protecting group; or when y3 thereof is 1, 2, 3, 4, 5, or 6, L3thereof is a linker; 10 v1 is 0, 1, 2, 3, 4, 5, or 6; each instance of LAand L4, when present, is independently a linker; 12 each instance of y4, when present, is independently 1, 2, 3, 4, 5, or 6; and each instance of A4, when present, is independently a radical of a ligand or lipid. 14 In another aspect, the present disclosure is directed to oligonucleotides comprising a modified oligonucleotide strand comprising s1 instances of modified nucleosides independently 16 comprising a moiety of Formula I: 18 (I); and v1 instances of the internucleosidic linkers of the modified oligonucleotide strand are 20 independently repla ; wherein: 22 s1 is 1, 2, 3, 4, 5, or 6; each instance of N1is independently a radical of a nucleobase or a bond; 24 each instance of t1 is independently 1, 2, or 3; each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least 26 one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; each instance of A1, A2, and A3, if present, is independently radical of a central nervous 2 system receptor ligand or a lipid, provided that at least one instance of A1, A2, and A3is a radical of a central nervous system receptor ligand; 4 when y1 of an instance o is 0, L1thereof is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or 6 unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted 8 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –CN, –ORb, –SCN, –SRb, –SSRb, –N3, –NO, –N(Rb)2, –10 NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –S(=O)ORb, –S(=O)SRb, – S(=O)N(Rb)2, –S(=O)2Rb, –S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –OC(=O)Rb, – 12 OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, – OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, –14 SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, – NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, –16 NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, –NRbS(=O)2N(Rb)2, – Si(Rb)3, –Si(Rb)2ORb, –Si(Rb)(ORb)2, –Si(ORb)3, –OSi(Rb)3, –OSi(Rb)2ORb, –OSi(Rb)(ORb)2, or – 18 OSi(ORb)3; or when y1 of an instance is 1, 2, 3, 4, 5, or 6, L1thereof is a linker; 20 each instance of Rbis independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or 22 unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, 24 substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen 26 atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to the same intervening atom are joined together with the intervening atom to form an substituted 28 or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; when y2 of an instanc e o is 0, L2thereof is –OH, –ORh, halogen, –CN, or 2 –N3; or when y2 of an instance of is 1, 2, 3, 4, 5, or 6, L2thereof is a linker; each instance of Rhis independently substituted or unsubstituted, C1-6alkyl, or an oxygen 4 protecting group; when the moiety of Formula I is part of an instance of the modified nucleoside at the 5’ 6 end or an internal position of the modified oligonucleotide strand: y3 thereof is 0, and L3thereof is an internucleosidic linker; or 8 when the moiety of Formula I is part of an instance of the modified nucleoside at the 3’ end of the modified oligonucleotide strand: 10 when y3 thereof is 0: L3thereof is –OH, –ORd, halogen, –CN, or –N3, and each instance of Rdis independently substituted or unsubstituted, C1-6alkyl, or an oxygen 12 protecting group; or when y3 thereof is 1, 2, 3, 4, 5, or 6, L3thereof is a linker; 14 v1 is 0, 1, 2, 3, 4, 5, or 6; each instance of LAand L4, when present, is independently a linker; 16 each instance of y4, when present, is independently 1, 2, 3, 4, 5, or 6; and each instance of A4, when present, is independently a radical of a ligand or lipid. 18 The oligonucleotides may be useful for delivering pharmaceutical agents to a subject (e.g., a human). In some embodiments, at least one instance of the pharmaceutical agents is the 20 oligonucleotide strand. In some embodiments, the ligands are capable of selectively targeting a location within a subject (e.g., the brain of a subject, or a region of the brain of a subject). In 22 some embodiments, the ligands are capable of selectively targeting a particular type of cell (e.g., a cell of the central nervous system, such as a neuron). In some embodiments, the ligands are 24 capable of selectively binding to or otherwise selectively recognizing one or more receptors. In some embodiments, the oligonucleotides are capable of selectively targeting the oligonucleotide 26 strand to a location within a subject (e.g., the brain of a subject, or a region of the brain of a subject). In some embodiments, the oligonucleotides are capable of selectively delivering the 28 oligonucleotide strand to a cell (e.g., a cell of the central nervous system, such as a neuron). In certain embodiments, the oligonucleotides are capable of selectively binding to or otherwise 30 selectively recognizing one or more receptors. The oligonucleotides may be useful in treating, preventing, or diagnosing a disease. The oligonucleotides may be advantageous over the pharmaceutical agents and certain known oligonucleotides (e.g., certain known oligonucleotides 2 that do not comprise at least one radical of a central nervous system receptor ligand at a nucleobase, the 2′ position of a nucleoside, or the 3′ position of a nucleoside) because the former 4 may show higher potency, efficacy, bioavailability, safety, and / or subject compliance; wider therapeutic window; fewer and / or less severe side effects; and / or lower toxicity and / or resistance 6 to treatment than the latter. One or more of the advantages may be at least in part because the oligonucleotides comprise at least one radical of a central nervous system receptor ligand at a 8 nucleobase, the 2′ position of a nucleoside, or the 3′ position of a nucleoside. The present disclosure also provides pharmaceutical compositions and kits, each of which 10 comprise the oligonucleotides disclosed herein. The present disclosure also provides methods of using such oligonucleotides, pharmaceutical compositions, and kits. 12 In another aspect, the present disclosure provides methods for delivering any of the oligonucleotides or pharmaceutical compositions provided herein to a subject. 14 In another aspect, the present disclosure provides any of the oligonucleotides or pharmaceutical compositions provided herein for the manufacture of a medicament for delivering 16 any of the oligonucleotides or pharmaceutical compositions to a subject. In another aspect, the present disclosure provides any of the oligonucleotides or 18 pharmaceutical compositions provided herein for use in delivering any of the oligonucleotides or pharmaceutical compositions to a subject. 20 In another aspect, the present disclosure provides methods for treating a disease in a subject in need thereof using any of the oligonucleotides or pharmaceutical compositions 22 provided herein. In another aspect, the present disclosure provides uses of any of the oligonucleotides or 24 pharmaceutical compositions provided herein for the manufacture of a medicament for treating a disease in a subject in need thereof. 26 In another aspect, the present disclosure provides any of the oligonucleotides or pharmaceutical compositions provided herein for use in treating a disease in a subject in need 28 thereof. In another aspect, the present disclosure provides methods of preventing a disease in a 30 subject in need thereof using any of the oligonucleotides or pharmaceutical compositions provided herein. 32 In another aspect, the present disclosure provides uses of any of the oligonucleotides or pharmaceutical compositions provided herein for the manufacture of a medicament for 34 preventing a disease in a subject in need thereof. In another aspect, the present disclosure provides any of the oligonucleotides or 2 pharmaceutical compositions provided herein for use in preventing a disease in a subject in need thereof. 4 In another aspect, the present disclosure provides nucleosides comprising a moiety of the formula: 6 , wherein: 8 N1is a radical of a nucleobase or a bond; t1 is 1, 2, or 3; 10 each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; 12 each instance of A1, A2, and A3, if present, is independently a radical of a ligand or a lipid, provided that at least one instance of A1, A2, and A3is a radical of a central nervous system 14 receptor ligand; when y1 of an instance is 0, L1thereof is hydrogen, halogen, 16 substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 18 heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl,20 substituted or unsubstituted heteroaryl, –CN, –ORb, –SCN, –SRb, –SSRb, –N3, –NO, –N(Rb)2, – NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –S(=O)ORb, –S(=O)SRb, –22 S(=O)N(Rb)2, –S(=O)2Rb, –S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –OC(=O)Rb, – OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, –24 OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, – SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, –26 NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, – NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, –NRbS(=O)2N(Rb)2, –28 Si(Rb)3, –Si(Rb)2ORb, –Si(Rb)(ORb)2, –Si(ORb)3, –OSi(Rb)3, –OSi(Rb)2ORb, –OSi(Rb)(ORb)2, or – OSi(ORb)3; or when y1 of an instance is 1, 2, 3, 4, 5, or 6, L1 thereof is a 2 linker; each instance of Rbis independently hydrogen, substituted or unsubstituted alkyl, 4 substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted 6 heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting 8 group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached 10 to the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; 12 when y2 is 0, L2is –OH, –ORh, halogen, –CN, or –N3; or when y2 is 1, 2, 3, 4, 5, or 6, L2is a linker; 14 Rhis substituted or unsubstituted, C1-6alkyl, or an oxygen protecting group; when y3 is 0, L3is –OH, –ORd, halogen, –CN, or –N3; or when y3 is 1, 2, 3, 4, 5, or 6, L316 is a linker; and Rdis substituted or unsubstituted, C1-6alkyl, or an oxygen protecting group. 18 In another aspect, the present disclosure provides nucleosides comprising a moiety of the formula: 20 , wherein: 22 N1is a radical of a nucleobase or a bond; t1 is 1, 2, or 3; 24 each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; 26 each instance of A1, A2, and A3, if present, is independently radical of a central nervous system receptor ligand or a lipid, provided that at least one instance of A1, A2, and A3is a radical 28 of a central nervous system receptor ligand; when y1 of an instance o is 0, L1thereof is hydrogen, halogen, 2 substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 4 heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, 6 substituted or unsubstituted heteroaryl, –CN, –ORb, –SCN, –SRb, –SSRb, –N3, –NO, –N(Rb)2, – NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –S(=O)ORb, –S(=O)SRb, – 8 S(=O)N(Rb)2, –S(=O)2Rb, –S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –OC(=O)Rb, – OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, –10 OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, – SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, –12 NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, – NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, –NRbS(=O)2N(Rb)2, –14 Si(Rb)3, –Si(Rb)2ORb, –Si(Rb)(ORb)2, –Si(ORb)3, –OSi(Rb)3, –OSi(Rb)2ORb, –OSi(Rb)(ORb)2, or – OSi(ORb)3; or when y1 of an instan 1thereof is a 16 linker; each instance of Rbis independently hydrogen, substituted or unsubstituted alkyl, 18 substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted 20 heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting 22 group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached 24 to the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; 26 when y2 is 0, L2is –OH, –ORh, halogen, –CN, or –N3; or when y2 is 1, 2, 3, 4, 5, or 6, L2is a linker; 28 Rhis substituted or unsubstituted, C1-6alkyl, or an oxygen protecting group; when y3 is 0, L3is –OH, –ORd, halogen, –CN, or –N3; or when y3 is 1, 2, 3, 4, 5, or 6, L330 is a linker; and Rdis substituted or unsubstituted, C1-6alkyl, or an oxygen protecting group. 32 The nucleosides described herein may be useful for making the oligonucleotides described herein It is understood that the embodiments provided herein with respect to preferred variable 2 selections can be taken alone or in combination with one or more embodiments, or other preferred variable selections provided herein, as if each combination were explicitly listed herein. 4 It should be appreciated that the foregoing concepts, and additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in 6 this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments. 8 DEFINITIONS 10 Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the 12 Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of 14 organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, 16 March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New 18 York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987. 20 Compounds (e.g., oligonucleotides) described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or 22 diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of 24 stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including 26 chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, 28 Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds 30 (McGraw–Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present 32 disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. Unless otherwise provided, formulae and structures depicted herein include compounds 2 that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the 4 replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such 6 compounds are useful, for example, as analytical tools or probes in biological assays. When a range of values (“range”) is listed, it encompasses each value and sub-range 8 within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “C1-6alkyl” encompasses, C1, C2, C3, C4, C5, C6,C1-6, C1–5, C1–4, C1–3, 10 C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl. The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon 12 group having from 1 to 100 carbon atoms (“C1–100alkyl”). In some embodiments, an alkyl group has 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 12 14 carbon atoms (“C1–12alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In 16 some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 18 1 to 6 carbon atoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“ C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In 20 some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“ C1–2alkyl”). In some embodiments, an alkyl group has 22 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1-6alkyl groups include methyl ( C1), ethyl ( C2), propyl ( C3) (e.g., n-24 propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n- pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl ( C6) (e.g., n- 26 hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently 28 unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as fluorine). In certain embodiments, the alkyl group is an 30 unsubstituted C1–12alkyl (such as unsubstituted C1-6alkyl, e.g., −CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)),32 unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t- Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1–12alkyl (such as substituted C1–6alkyl, e.g., 2 –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)). The term “heteroalkyl” refers to an alkyl group, which further includes at least one 4 heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or 6 more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 100 carbon atoms and 1 or more heteroatoms within the 8 parent chain (“heteroC1–100alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent 10 chain (“heteroC1–20alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain 12 (“heteroC1–12alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–11alkyl”). In 14 some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–10alkyl”). In some embodiments, a 16 heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–9alkyl”). In some embodiments, a heteroalkyl group is a 18 saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–8alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 20 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–7alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more 22 heteroatoms within the parent chain (“heteroC1–6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent 24 chain (“heteroC1–5alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC1–4alkyl”). In some 26 embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–3alkyl”). In some embodiments, a heteroalkyl 28 group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 30 carbon atom and 1 heteroatom (“heteroC1alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain 32 (“heteroC2–6alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted 34 heteroalkyl”) with one or more substituents (e.g., oxo, substituted or unsubstituted C1-6alkyl (e.g., –CH3)). In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1–12alkyl. 2 In certain embodiments, the heteroalkyl group is a substituted heteroC1–12alkyl. In some embodiments, unsubstituted heteroC1alkyl is –OCH3or –CH2OH. In some embodiments, 4 substituted heteroC1alkyl is –C(=O)NH2. In some embodiments, unsubstituted heteroC2alkyl is –OCH2CH3, –CH2OCH3, or –CH2CH2OH. The terms “heteroCz1-z2alkyl” and “Cz1-z2heteroalkyl” 6 are used interchangeably, wherein each of z1 and z2 is independently an integer. The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group 8 having from 1 to 100 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 100 carbon atoms (“C1-10010 alkenyl”). In some embodiments, an alkenyl group has at least 2 carbon atoms. In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1–20alkenyl”). In some 12 embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1–12alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C1–11alkenyl”). In some 14 embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1–10alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1–9alkenyl”). In some embodiments, 16 an alkenyl group has 1 to 8 carbon atoms (“C1–8alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1–7alkenyl”). In some embodiments, an alkenyl group has 1 to 18 6 carbon atoms (“C1–6alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1–5alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1–420 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1–3alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1–2alkenyl”). In some 22 embodiments, an alkenyl group has 1 carbon atom (“C1alkenyl”). In certain embodiments, an alkenyl group is C2–3alkenyl, C2–4alkenyl, C2–5alkenyl, C2–6alkenyl, C2–7alkenyl, C2–8alkenyl, 24 C2–9alkenyl, C2–10alkenyl, C2–12alkenyl, C2–16alkenyl, C2–20alkenyl, C2–30alkenyl, C2–40alkenyl, C2–50alkenyl, C2–60alkenyl, C2–70alkenyl, C2–80alkenyl, C2–90alkenyl, or C2–100alkenyl. 26 The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C1–4alkenyl groups include methylidenyl (C1), ethenyl (C2), 28 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C1-6alkenyl groups include the aforementioned C2–4alkenyl groups as well as 30 pentenyl ( C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, 32 each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the 34 alkenyl group is an unsubstituted C1–20alkenyl. In certain embodiments, the alkenyl group is a substituted C1-20alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry 2 is not specified (e.g., −CH=CHCH3or ) may be in the (E)- or (Z)-configuration. The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one 4 heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or 6 more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 100 carbon atoms, at least one double bond, and 1 or more 8 heteroatoms within the parent chain (“heteroC1–100 alkenyl”). In some embodiments, a heteroalkenyl group has at least 2 carbon atoms. In certain embodiments, a heteroalkenyl group 10 refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20alkenyl”). In certain embodiments, a 12 heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–12alkenyl”). In certain 14 embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–11alkenyl”). In 16 certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–1018 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–9alkenyl”). In some 20 embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–8alkenyl”). In some embodiments, a 22 heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–7alkenyl”). In some embodiments, a 24 heteroalkenyl group has 1to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1-6alkenyl”). In some embodiments, a heteroalkenyl group has 26 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–5alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at 28 least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–4alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 30 1 heteroatom within the parent chain (“heteroC1–3alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within 32 the parent chain (“heteroC1–2alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain 34 (“heteroC1–6alkenyl”). In certain embodiments, a heteroalkenyl group is C2–3heteroalkenyl, C2–4 heteroalkenyl, C2–5heteroalkenyl, C2–6heteroalkenyl, C2–7heteroalkenyl, C2–8heteroalkenyl, C2–92 heteroalkenyl, C2–10heteroalkenyl, C2–12heteroalkenyl, C2–16heteroalkenyl, C2–20heteroalkenyl, C2–30heteroalkenyl, C2–40heteroalkenyl, C2–50heteroalkenyl, C2–60heteroalkenyl, C2–704 heteroalkenyl, C2–80heteroalkenyl, C2–90heteroalkenyl, or C2–100heteroalkenyl. Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an 6 “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents (e.g., oxo, substituted or unsubstituted C1-6alkyl (e.g., –CH3)). In certain 8 embodiments, the heteroalkenyl group is an unsubstituted heteroC1–20alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC1–20alkenyl. In some embodiments, 10 unsubstituted heteroC1alkenyl is –CH=NH or =N–CH3. The terms “heteroCz1-z2alkenyl” and “Cz1-z2heteroalkenyl” are used interchangeably, wherein each of z1 and z2 is independently an 12 integer. The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group 14 having from 1 to 100 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-100alkynyl”). In some embodiments, an alkynyl group has 1 to 20 carbon 16 atoms (“C1-20alkynyl”). In some embodiments, an alkynyl group has at least 2 carbon atoms. In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“C1-10alkynyl”). In some 18 embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8alkynyl”). In some embodiments, an alkynyl 20 group has 1 to 7 carbon atoms (“C1-7alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms 22 (“C1-5alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C1-4alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1–3alkynyl”). In 24 some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“C1alkynyl”). In certain embodiments, an 26 alkynyl group is C2–3alkynyl, C2–4alkynyl, C2–5alkynyl, C2–6alkynyl, C2–7alkynyl, C2–8alkynyl, C2–9alkynyl, C2–10alkynyl, C2–12alkynyl, C2–16alkynyl, C2–20alkynyl, C2–30alkynyl, C2–4028 alkynyl, C2–50alkynyl, C2–60alkynyl, C2–70alkynyl, C2–80alkynyl, C2–90alkynyl, or C2–100 alkynyl. The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or 30 terminal (such as in 1-butynyl). Examples of C1–4alkynyl groups include, without limitation, methylidynyl (C1), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl 32 (C4), and the like. Examples of C1-6alkenyl groups include the aforementioned C2–4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl 34 include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a 2 “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C1-20alkynyl. In certain embodiments, the alkynyl group is a substituted C1-204 alkynyl. The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one 6 heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or 8 more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 100 carbon atoms, at least one triple bond, and 1 or more 10 heteroatoms within the parent chain (“heteroC1–100alkynyl”). In some embodiments, a heteroalkynyl group has at least 2 carbon atoms. In certain embodiments, a heteroalkynyl group 12 refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20alkynyl”). In certain embodiments, a 14 heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–10alkynyl”). In some 16 embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–9alkynyl”). In some embodiments, a 18 heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–8alkynyl”). In some embodiments, a heteroalkynyl group has 20 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–7alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at 22 least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–6alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, 24 and 1 or 2 heteroatoms within the parent chain (“heteroC1–5alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms 26 within the parent chain (“heteroC1–4alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain 28 (“heteroC1–3alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1–2alkynyl”). In some 30 embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–6alkynyl”). In certain embodiments, a 32 heteroalkynyl group is C2–3heteroalkynyl, C2–4heteroalkynyl, C2–5heteroalkynyl, C2–6heteroalkynyl, C2–7heteroalkynyl, C2–8heteroalkynyl, C2–9heteroalkynyl, C2–10heteroalkynyl, 34 C2–12heteroalkynyl, C2–16 heteroalkynyl, C2–20heteroalkynyl, C2–30heteroalkynyl, C2–40 heteroalkynyl, C2–50heteroalkynyl, C2–60heteroalkynyl, C2–70heteroalkynyl, C2–80heteroalkynyl, 2 C2–90heteroalkynyl, or C2–100heteroalkynyl. Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or 4 substituted (a “substituted heteroalkynyl”) with one or more substituents (e.g., oxo, substituted or unsubstituted C1-6alkyl (e.g., –CH3)). In certain embodiments, the heteroalkynyl group is an 6 unsubstituted heteroC1–20alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC1–20alkynyl. In some embodiments, unsubstituted heteroC1alkynyl is –C≡N. 8 The terms “heteroCz1-z2alkynyl” and “Cz1-z2heteroalkynyl” are used interchangeably, wherein each of z1 and z2 is independently an integer. 10 The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero 12 heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 14 13 ring carbon atoms (“C3-13carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 16 11 ring carbon atoms (“C3-11carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 18 ring carbon atoms (“C3–8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 20 ring carbon atoms (“C3–6carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4–6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 22 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3–6carbocyclyl groups include cyclopropyl 24 (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3–826 carbocyclyl groups include the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), 28 cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include the aforementioned C3–8carbocyclyl groups as well30 as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H- indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3–832 carbocyclyl groups include the aforementioned C3-10carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), 34 cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or 2 polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can 4 contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or 6 heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic 8 ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with 10 one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14carbocyclyl. 12 In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14cycloalkyl”). In some embodiments, a cycloalkyl group 14 has 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3–8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 16 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4–6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring 18 carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5–6cycloalkyl groups include cyclopentyl (C5) 20 and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3–8cycloalkyl 22 groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently 24 unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-1426 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic 28 ring system, as valency permits. The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- 30 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered 32 heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either 34 be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic 2 heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both 4 rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the 6 carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the 8 heterocyclyl ring, and in such instances, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each 10 instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, 12 the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3–14 membered heterocyclyl. In certain embodiments, the 14 heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as 16 valency permits. In some embodiments, a heterocyclyl group is a 5–10 membered non-aromatic ring 18 system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In 20 some embodiments, a heterocyclyl group is a 5–8 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected 22 from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 24 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered 26 heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, 28 oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. 30 Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom 32 include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,34 dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and 2 dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups 4 containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, 6 morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 8 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic 10 heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, 12 tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, 14 octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-16 b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3- dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-18 pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2- b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like. 20 The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic 22 array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., 24 phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon 26 atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical 28 or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise 30 specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the 32 aryl group is an unsubstituted C6-14aryl. In certain embodiments, the aryl group is a substituted C6-14aryl. The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic 2 (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring 4 system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the 6 point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes 8 ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such 10 instances, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as 12 defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the 14 number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, 16 carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In 18 certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are 20 independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the 22 heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system 24 having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 26 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring 28 system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered 30 aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, 32 and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 34 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, 2 oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted 4 heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a 6 substituted 5-14 membered heteroaryl. Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, 8 furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5- 10 membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include 12 tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, 14 pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl16 groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, 18 isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, 20 and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary 22 tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl. 24 The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I). 26 The term “alkoxy” refers to an -O-alkyl substituent. Affixing the suffix “-ene” to a group indicates the resulting group is a polyvalent (e.g., 28 divalent, trivalent, or tetravalent) moiety. For example, alkylene is a polyvalent moiety of alkyl, alkenylene is a polyvalent moiety of alkenyl, alkynylene is a polyvalent moiety of alkynyl, 30 heteroalkylene is a polyvalent moiety of heteroalkyl, heteroalkenylene is a polyvalent moiety of heteroalkenyl, heteroalkynylene is a polyvalent moiety of heteroalkynyl, carbocyclylene is a 32 polyvalent moiety of carbocyclyl, heterocyclylene is a polyvalent moiety of heterocyclyl, arylene is a polyvalent moiety of aryl, and heteroarylene is a polyvalent moiety of heteroaryl. In some 34 embodiments, unsubstituted C1heteroalkylene is –OCH2– or –CH2O–. In some embodiments, substituted C1heteroalkylene is –NHC(=O)– or –C(=O)NH–. In some embodiments, 2 unsubstituted C2heteroalkylene is –OCH2CH2– or –CH2CH2O–. In some embodiments, unsubstituted C4heteroalkylene is –(OCH2CH2)2– or –(CH2CH2O)2–. In some embodiments, 4 unsubstituted C6heteroalkylene is –(OCH2CH2)3– or –(CH2CH2O)3–. In some embodiments, unsubstituted C8heteroalkylene is –(OCH2CH2)4– or –(CH2CH2O)4–. In some embodiments, 6 unsubstituted C10 heteroalkylene is –(OCH2CH2)5– or –(CH2CH2O)5–. In some embodiments, unsubstituted C12heteroalkylene is –(OCH2CH2)6– or –(CH2CH2O)6–. 8 A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, 10 alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which 12 is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or 14 “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or 16 “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one 18 hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously 20 undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable 22 positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated 24 to include substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that results in the formation of a stable compound. The 26 present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen 28 substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any 30 manner by the exemplary substituents described herein. Exemplary carbon atom substituents include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, 32 −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)2, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, 34 −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, 2 −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −OSi(Raa)3−C(=S)N(Rbb)2, −C(=O)SRaa, 4 −C(=S)SRaa, −SC(=S)SRaa, −SC(=O)SRaa, −OC(=O)SRaa, −SC(=O)ORaa, −SC(=O)Raa, −P(=O)(Raa)2, −P(=O)(ORcc)2, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, −P(=O)(N(Rbb)2)2, 6 −OP(=O)(N(Rbb)2)2, −NRbbP(=O)(Raa)2, −NRbbP(=O)(ORcc)2, −NRbbP(=O)(N(Rbb)2)2, −P(Rcc)2, −P(ORcc)2, −P(Rcc)3+X−, −P(ORcc)3+X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3+X−, 8 −OP(ORcc)2, −OP(ORcc)3+X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, 10 heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, 12 heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; 14 or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; 16 each instance of Raais, independently, selected from C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-1018 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, 20 wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 22 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, 24 −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, 26 −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 28 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, 30 alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; 32 each instance of Rccis, independently, selected from hydrogen, C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–2034 alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 2 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 4 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, 6 −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, 8 −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, 10 −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, 12 −OP(=O)(ORee)2, C1–10alkyl, C1–10perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-1014 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 16 substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =O or =S; wherein X−is a counterion; 18 each instance of Reeis, independently, selected from C1–10alkyl, C1–10perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-1020 carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, 22 aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1–10alkyl, C1–1024 perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, and 5-10 membered 26 heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, 28 carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; 30 each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1–6alkyl, −ON(C1–6alkyl)2, −N(C1–6alkyl)2, −N(C1–6alkyl)3+X−, −NH(C1–6alkyl)2+X−, 32 −NH2(C1-6alkyl)+X−, −NH3+X−, −N(OC1-6alkyl)(C1-6alkyl), −N(OH)(C1-6alkyl), −NH(OH), −SH, −SC1–6alkyl, −SS(C1–6alkyl), −C(=O)(C1–6alkyl), −CO2H, −CO2(C1–6alkyl), 34 −OC(=O)(C1-6alkyl), −OCO2(C1-6alkyl), −C(=O)NH2, −C(=O)N(C1-6alkyl)2, −OC(=O)NH(C1–6alkyl), −NHC(=O)( C1–6alkyl), −N(C1–6alkyl)C(=O)( C1–6alkyl), −NHCO2(C1–6alkyl), 2 −NHC(=O)N(C1-6alkyl)2, −NHC(=O)NH(C1-6alkyl), −NHC(=O)NH2, −C(=NH)O(C1-6alkyl), −OC(=NH)(C1–6alkyl), −OC(=NH)OC1–6alkyl, −C(=NH)N(C1–6alkyl)2, −C(=NH)NH(C1–64 alkyl), −C(=NH)NH2, −OC(=NH)N(C1-6alkyl)2, −OC(NH)NH(C1-6alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6alkyl), −SO2N(C1–6alkyl)2, 6 −SO2NH(C1-6alkyl), −SO2NH2, −SO2C1-6alkyl, −SO2OC1-6alkyl, −OSO2C1-6alkyl, −SOC1-6alkyl, −Si(C1-6alkyl)3, −OSi(C1-6alkyl)3−C(=S)N(C1-6alkyl)2, C(=S)NH(C1-6alkyl), 8 C(=S)NH2, −C(=O)S(C1–6alkyl), −C(=S)SC1–6alkyl, −SC(=S)SC1–6alkyl, −P(=O)(OC1–6alkyl)2, −P(=O)(C1-6alkyl)2, −OP(=O)(C1-6alkyl)2, −OP(=O)(OC1-6alkyl)2, C1–10alkyl, C1–1010 perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; 12 or two geminal Rggsubstituents can be joined to form =O or =S; and each X−is a counterion. 14 In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −ORaa, −SRaa, 16 −N(Rbb)2, –CN, –SCN, –NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2. In certain 18 embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, 20 –SCN, –NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted 22 (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, 24 pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) 26 when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, or a nitrogen protecting group 28 (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., 30 substituted with one or more halogen) or unsubstituted C1-6alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2. In certain embodiments, each carbon atom substituent is independently halogen, 32 substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1–10alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2, wherein Raais hydrogen, substituted (e.g., 34 substituted with one or more halogen) or unsubstituted C1–10alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or 2 benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a 4 sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, 6 Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., 8 substituted with one or more halogen) or unsubstituted C1-6alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom 10 substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group, 12 wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis 14 independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom 16 substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl or a nitrogen protecting group. 18 In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting 20 groups include −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, 22 −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1–10alkyl (e.g., aralkyl, heteroaralkyl), C1–20alkenyl, C1–20alkynyl, hetero C1–20alkyl, hetero C1–20alkenyl, hetero C1–20alkynyl, C3-10carbocyclyl, 3-14 24 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, 26 aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rcc, and Rddare as defined herein. Nitrogen protecting groups are well known in the art 28 and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999. 30 For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., 32 −C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is 34 independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- 2 pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o- nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’- 4 dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- 6 phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o- 8 (benzoyloxymethyl)benzamide. In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., 10 a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, 12 together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-14 fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10- 16 tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl 18 carbamate (hZ), 1–(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-20 trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di- t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2¢- and 4¢-pyridyl)ethyl carbamate22 (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1- adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl 24 carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-26 methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz),28 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2- methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl 30 carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate32 (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- 34 chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl 2 carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- 4 decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl 6 carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl 8 carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-10 dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1- phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- 12 (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate. 14 In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., 16 −S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is 18 independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- 20 trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 22 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-24 trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4¢,8¢- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, 26 trifluoromethylsulfonamide, and phenacylsulfonamide. In certain embodiments, each nitrogen protecting group, together with the nitrogen atom 28 to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, 30 N’-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3- 32 diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-34 dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N- allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1- 2 isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N- di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- 4 [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N’- 6 oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, 8 N-(N’,N’-dimethylaminomethylene)amine, N-p-nitrobenzylideneamine, N-salicylideneamine, N- 5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-10 cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N- diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N- 12 copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide 14 (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, 16 pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two 18 instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine. 20 In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts. 22 In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, −C(=O)Raa, −CO2Raa, 24 −C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or 26 unsubstituted C1-6alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted 28 C1-10alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted 30 C1-10alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-632 alkyl or an oxygen protecting group. In certain embodiments, the substituent present on an oxygen atom is an oxygen 34 protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, 2 −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb)2)2, 4 wherein X−, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. 6 Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999. In certain embodiments, each oxygen protecting group, together with the oxygen atom to 8 which the oxygen protecting group is attached, is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, 10 (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl 12 (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl14 (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-16 methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin- 4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a- 18 octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 20 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-22 dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p- cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl,24 p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, 4,4′-dimethoxytrityl (4,4′- dimethoxytriphenylmethyl or DMT), α-naphthyldiphenylmethyl, p-26 methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p- methoxyphenyl)methyl, 4-(4’-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-28 dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"‘-[N-(imidazolylmethyl) ]trityl Ether (IDTr-30 OR), 4,4’-Dimethoxy-3"‘-[N-(imidazolylethyl)carbamoyl]trityl Ether (IETr-OR), 1,1-bis(4- methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- 32 oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), 34 diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl 2 (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, 4 phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- 6 methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate 8 (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl10 carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p- methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p- 12 nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- 14 (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-16 dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4- bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate,18 (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, 20 alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). 22 In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl. 24 In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, −C(=O)Raa, −CO2Raa, 26 −C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or 28 unsubstituted C1-10alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted 30 C1-10alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted 32 C1-10alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-634 alkyl or a sulfur protecting group. In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting 2 group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of −Raa, −N(Rbb)2, −C(=O)SRaa, 4 −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, 6 −P(=O)(ORcc)2, and −P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting 8 Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999. 10 In certain embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a 12 substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, 14 hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or 16 iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond 18 donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors. “Click chemistry” is a chemical approach first introduced by K. Barry Sharpless in 2001 20 and tailored to generate substances quickly and reliably by joining small units together through coupling reactions. See, e.g., Kolb, Finn and Sharpless Angewandte Chemie International Edition 22 (2001) 40: 2004–2021; Evans, Australian Journal of Chemistry (2007) 60: 384–395). Exemplary coupling reactions include, but are not limited to, formation of esters, thioesters, amides (e.g., 24 peptide coupling) from activated acids or acyl halides; nucleophilic displacement reactions (e.g., nucleophilic displacement of a halide or ring opening of strained ring systems); azide–alkyne 26 Huisgen cycloaddition; thiol–yne addition; imine formation; Michael additions (e.g., maleimide addition); and Diels–Alder reactions (e.g., tetrazine [4 + 2] cycloaddition). 28 As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the 30 neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically 32 neutral (without a net charge). Salts of the compounds of this the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of 34 an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, 2 oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, 4 aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, 6 glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, 8 malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, 10 propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, 12 alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts 14 include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl 16 sulfonate. The term “pharmaceutically acceptable salt” refers to those salts which are, within the 18 scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are 20 commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in 22 J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and 24 bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, 26 phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other 28 methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, 30 camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, 32 heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, 34 nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, 2 undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4salts. Representative alkali or 4 alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, 6 quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. 8 The term “prodrug” refers to a compound that may be converted under physiological conditions or by solvolysis to an oligonucleotide described herein. The prodrug may be a 10 precursor of the oligonucleotide and may be pharmaceutically acceptable. The prodrug may be inactive when administered to a subject, but at least one of the converted products, e.g., the 12 oligonucleotide, may be active. Compared to the oligonucleotide, the prodrug may offer advantages, such as higher solubility, higher permeability, higher absorption, improved 14 distribution, improved metabolism, improved excretion, higher exposure, higher tissue compatibility, slower delivery, more sustained delivery, lower toxicity, and / or wider therapeutic 16 window (see, e.g., Bundgard, H., DESIGN OF PRODRUGS (1985), pp.7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel 18 Delivery Systems,” A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. 20 The prodrug may be a compound wherein a hydrogen atom of –OH, –NH2, –SH, –C(=O)OH, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O– of the 22 oligonucleotide is replaced with a protecting group (“PG,” e.g., a carbon-bound moiety, such as substituted or unsubstituted alkyl or substituted or unsubstituted phenyl). The prodrug that 24 comprises –OPG, –NPG2, –SPG, –C(=O)OPG, –OP(=O)(OPG)O–, –SP(=O)(OPG)O–, –OP(=O)(OPG)S–, or –OP(=O)(SPG)O– may be converted under physiological conditions or by 26 solvolysis to form –OH, –NH2, –SH, –C(=O)OH, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. Examples of prodrugs include, but are not limited to 28 glutathione, acyloxy, thioacyloxy, 2-carboalkoxyethyl, disulfide, thiaminal, and enol ester derivatives of a phosphorus atom-modified nucleic acid. Phosphonate and phosphate prodrugs 30 can be found, for example, in Wiener et al., “Prodrugs or phosphonates and phosphates: crossing the membrane” Top. Curr. Chem., 2015, 360:115-160. In certain embodiments, the prodrug is a 32 prodrug of any of the formulae described herein. A “subject” to which administration is contemplated refers to a human (e.g., male or 34 female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain 2 embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), 4 or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may 6 be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of 8 treatment of a disease. The term “administer,” “administering,” or “administration” refers to implanting, 10 absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a pharmaceutical composition thereof, in or on a subject. 12 The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, 14 treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the 16 absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or 18 in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. 20 The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was 22 with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of 24 regression of the disease than an average healthy member of a population of subjects. The terms “condition,” “disease,” and “disorder” are used interchangeably. 26 An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may 28 vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular 30 compound , the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain 32 embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is 34 the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In 2 certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every 4 four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, 6 fourteen, or more administrations). A “therapeutically effective amount” of a compound is an amount sufficient to provide a 8 therapeutic benefit in the treatment of a condition or to delay or minimize one or more signs and / or symptoms associated with the condition. In certain embodiments, the therapeutically 10 effective amount is an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. 12 A “prophylactically effective amount” of a compound is an amount sufficient to prevent a condition, or one or more signs and / or symptoms associated with the condition or prevent its 14 recurrence. In certain embodiments, the prophylactically effective amount is an amount that improves overall prophylaxis and / or enhances the prophylactic efficacy of another prophylactic 16 agent. The term “composition” means a mixture of substances. The term “pharmaceutical 18 composition” means a composition suitable for administering to a subject. The symbol “ ” denotes the point of attachment of a chemical moiety to the 20 remainder of a compound or chemical formula. The term “small molecule” refers to molecules, whether naturally-occurring or artificially 22 created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon). The small molecule may 24 contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight 26 of a small molecule is not more than 2,000 g / mol. In certain embodiments, the molecular weight of a small molecule is not more than 1,500 g / mol. In certain embodiments, the molecular weight 28 of a small molecule is not more than 1,000 g / mol, not more than 900 g / mol, not more than 800 g / mol, not more than 700 g / mol, not more than 600 g / mol, not more than 500 g / mol, not more 30 than 400 g / mol, not more than 300 g / mol, not more than 200 g / mol, or not more than 100 g / mol. In certain embodiments, the molecular weight of a small molecule is at least 100 g / mol, at least 32 200 g / mol, at least 300 g / mol, at least 400 g / mol, at least 500 g / mol, at least 600 g / mol, at least 700 g / mol, at least 800 g / mol, or at least 900 g / mol, or at least 1,000 g / mol. Combinations of the 34 above ranges (e.g., at least 200 g / mol and not more than 500 g / mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a 2 molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms 4 and / or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce 6 a biological effect in animals, preferably mammals, more preferably humans. Small molecules include radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. 8 Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory 10 body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460; drugs for veterinary use are listed by the FDA 12 under 21 C.F.R. §§ 500 through 589. All listed drugs are considered acceptable for use in accordance with the present disclosure. 14 The term “peptide,” “polypeptide,” or “protein” refers to an oligomer or polymer of amino acid residues covalently connected together by peptide bonds. A peptide, polypeptide, or 16 protein may be of any size, structure, and function, and may be an individual peptide, polypeptide, or protein, or a collection (e.g., a complex) of peptides, polypeptides, and proteins, 18 and optionally small molecules and / or metal ions. In certain embodiments, a peptide comprises between 2 and 10, between 11 and 20, between 21 and 30, between 31 and 40, or between 41 and 20 50, inclusive, amino acid residues. In certain embodiments, a polypeptide or protein comprises between 51 and 100, between 101 and 200, between 201 and 300, between 301 and 500, between 22 501 and 1,000, between 1,001 and 3,000, between 3,001 and 10,000, or between 10,001 and 30,000, inclusive, amino acid residues. A peptide, polypeptide, or protein may contain only 24 natural amino acids but no non-natural amino acids; only non-natural amino acids but no natural amino acids; or both natural and non-natural amino acids. A peptide, polypeptide, or protein may 26 contain amino acid analogs only or in addition to natural and / or non-natural amino acids. In certain embodiments, the amino acid residues of a peptide, polypeptide, or protein are residues of 28 alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, 30 tyrosine, and / or valine, in D and / or L form (e.g., in L form). One or more of the amino acid residues in a peptide, polypeptide, or protein may be alpha amino acid residues or homologs 32 thereof (e.g., beta amino acid residues). One or more of the amino acid residues in a peptide, polypeptide, or protein may be protected or unprotected. One or more (e.g., two) of the termini of 34 a peptide, polypeptide, or protein may be protected (e.g., to form an ester or amide) or unprotected (e.g., as –NH2, –NH3+, –C(=O)OH, or –C(=O)O–). One or more of the amino acid 2 residues in a peptide, polypeptide, or protein may be modified or unmodified. A modification to an amino acid residue in a peptide, polypeptide, or protein may be an addition of a carbohydrate 4 group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, or a linker for conjugation or functionalization. A peptide, polypeptide, or protein may be 6 naturally occurring, recombinant, synthetic, or a combination thereof. A peptide, polypeptide, or protein may be a fragment of a naturally occurring peptide, polypeptide, or protein. 8 The term “nucleic acid” refers to compounds composed of linked monomeric nucleotides or nucleosides. A nucleic acid includes, but is not limited to, ribonucleic acids (RNA), 10 deoxyribonucleic acids (DNA), single-stranded nucleic acids, and double-stranded nucleic acids. The term “oligomeric compound” or “oligomer” means a compound that consists of a 12 small number of linked (e.g., covalently linked) subunits. With reference to a protein, peptide, polypeptide, or antibody, “subunit” refers to an amino acid (e.g., protected or unprotected amino 14 acid) or peptide bond. With reference to an oligonucleotide, “subunit” refers to a nucleotide, nucleoside, nucleobase, internucleosidic linker, or sugar, or a modified nucleotide, nucleoside, 16 nucleobase, internucleosidic linker, or sugar, or a combination thereof (e.g., a combination of nucleobase, internucleosidic linker, or sugar, each of which may be modified or unmodified). 18 The small number may be between 6 and 100, inclusive. In some embodiments, the small number is between 6 and 9, between 10 and 13, between 14 and 18, between 19 and 23, between 24 and 20 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, or between 81 and 100, inclusive. 22 The term “oligonucleotide” means an oligomer of linked (e.g., covalently linked) nucleotides and / or nucleosides (e.g., nucleic acid, oligomer of nucleotides), each of which can be 24 modified or unmodified, independent from one another. Without limitation, an oligonucleotide may be comprised of ribonucleic acids (e.g., comprised of ribonucleosides), deoxyribonucleic 26 acids (e.g., comprised of deoxyribonucleosides), modified nucleic acids (e.g., comprised of modified nucleobases, sugars, and / or phosphate groups), or a combination thereof. 28 Oligonucleotides may comprise one or more loops in their structure (e.g., a stem loop, hairpin loop, or internal loop in the structure of an RNA). Oligonucleotides may be single-stranded or 30 double-stranded and may be RNA, DNA, or a hybrid thereof. Oligonucleotides may include single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), plasmid DNA (pDNA), 32 genomic DNA (gDNA), complementary DNA (cDNA), chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), 34 provirus, lysogen, repetitive DNA, satellite DNA, viral DNA, single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), messenger RNA (mRNA), precursor messenger RNA (pre- 2 mRNA), transfer RNA (tRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or lncRNA), satellite RNA, viral satellite 4 RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, 6 flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, antisense oligonucleotides (e.g., antisense DNA and antisense RNA), interfering RNA compounds (RNAi 8 compounds), circular RNA (circRNA) compounds, microRNA (miRNA) targeting oligonucleotides, miRNA mimics, occupancy-based compounds (e.g., mRNA processing or 10 translation blocking compounds and splicing compounds) and editing compounds (e.g., ADAR recruiting compounds, ADAR targeting compounds, single-stranded guide nucleic acids, or a12 combination thereof). RNAi compounds include double-stranded compounds (e.g., short- interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds 14 (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics). RNAi compounds work at least in part through the RNA- 16 induced silencing complex (RISC) pathway resulting in sequence specific degradation and / or sequestration of a target nucleic acid through a process known as RNA interference (RNAi). The 18 term “RNAi compound” is meant to be equivalent to other terms used to describe nucleic acid compounds that are capable of mediating sequence-specific RNA interference, for example, 20 interfering RNA (iRNA), iRNA agent, RNAi agent, small interfering RNA, short interfering RNA, short interfering oligonucleotide, short interfering nucleic acid, short interfering modified 22 oligonucleotide, chemically modified siRNA, and others. Additionally, the term “RNAi” is meant to be equivalent to other terms used to describe sequence-specific RNA interference. In 24 some embodiments, an oligonucleotide comprises 6-100 nucleotides and nucleosides. In some embodiments, an oligonucleotide comprises 10-50 nucleotides and nucleosides. In some 26 embodiments, an oligonucleotide comprises 14-30 nucleotides and nucleosides. In some embodiments, an oligonucleotide comprises 20-23 nucleotides and nucleosides. In certain 28 embodiments, an oligonucleotide comprises 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides and nucleosides. 30 A double-stranded oligonucleotide may comprise “blunt ends” or “overhangs.” In a blunt- ended oligonucleotide, both strands of the oligonucleotide are of equal length and end at the same 32 base position, leaving no unpaired bases on either end. An oligonucleotide with overhangs (or “sticky ends”), in contrast, comprises unpaired nucleotides at each end. In some embodiments, an 34 oligonucleotide has blunt ends at both ends. In some embodiments, an oligonucleotide has overhangs at each end. In some embodiments, an oligonucleotide has a blunt end at one end and 2 an overhang at the other end. In certain embodiments, the oligonucleotide comprises between 6 and 8, between 9 and 11, between 12 and 14, between 15 and 17, between 18 and 20, between 21 4 and 24, between 25 and 28, between 29 and 32, between 33 and 36, or between 37 and 40, inclusive, paired base pairs. 6 The term “nucleobase” refers to a nitrogen-containing moiety at the 1′ position of a nucleoside. Nucleobases may include purine bases and pyrimidine bases. Five nucleobases— 8 adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U)—are referred to as primary or canonical nucleobases. Nucleobases may include unmodified and modified nucleobases. When 10 a nucleobase is listed in a formula definition, it refers to that moiety covalently bonded to the recited formula. 12 The term “nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage. 14 The term “nucleoside” means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. The 16 nucleoside may an unmodified or modified nucleoside. “Modified nucleoside” means a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified18 nucleosides include abasic nucleosides, which lack a nucleobase and optionally include a non- nucleobase moiety at the corresponding position (e.g., 1¢ position). 20 The terms “internucleoside linkage,” “internucleoside linker,” “internucleosidic linkage,” and “internucleosidic linker” are used interchangeably. 22 The term “target nucleic acid,” “target RNA,” and “nucleic acid target” all mean a nucleic acid capable of being targeted by oligonucleotides (e.g., a radical of a ligand included in the 24 oligonucleotides) described herein. “Target region” means a portion of a target nucleic acid to which one or more 26 oligonucleotides (e.g., a radical of a ligand included in the oligonucleotides) is targeted. “Terminal group” means a chemical group or group of atoms that is covalently linked to a 28 terminus of an oligonucleotide. The term “sense oligonucleotide,” “sense oligonucleotide strand,” or “sense strand” 30 means the strand of a double-stranded oligonucleotide that includes a region that is substantially complementary to a region of the antisense strand of the double-stranded oligonucleotide. The 32 sense strand may carry a translatable code in the 5′ to 3′ direction. The term “antisense oligonucleotide,” “antisense oligonucleotide strand,” or “antisense 34 strand” means an oligonucleotide which includes a region that is complementary, or at least partially complementary, to a target nucleic acid or sense strand of a nucleic acid. In some 2 embodiments, the antisense strand does not carry a translatable code in the 5′ to 3′ direction. In some embodiments, the antisense strand and the sense strand or target nucleic acid are at least 4 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% complementary to one another. In certain embodiments, the 6 antisense strand and the sense strand or target nucleic acid are completely complementary (100% complementary) to one another. 8 The terms “microRNA” and “miRNA,” as may be used interchangeably herein, refer to short (e.g., about 20 to about 24 nucleotides in length) non-coding ribonucleic acids (RNAs) that 10 are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA 12 polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha 14 ribonuclease III enzyme to produce a stem-loop precursor miRNA (pre-miRNA) approximately 70 nucleotides in length, which is further processed in the RNAi pathway. As part of this 16 pathway, the pre-miRNA is cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into 18 an RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing (i.e., partial complementarity) with the miRNA and most commonly results in 20 translational inhibition or destabilization of the target mRNA. This mechanism is most often seen through the binding of the miRNA on the 3′ untranslated region (UTR) of the target mRNA, 22 which can decrease gene expression by either inhibiting translation (for example, by blocking the access of ribosomes for translation) or directly causing degradation of the transcript. The term 24 (i.e., miRNA) may be used herein to refer to any form of the subject miRNA (e.g., precursor, primary, and / or mature miRNA). 26 The terms “small interfering RNA,” “short interfering RNA,” and “siRNA,” as may be used interchangeably herein, refer to RNA compounds that present as non-coding single-stranded 28 RNA or double-stranded RNA (dsRNA) compounds having a strand or strands of about 20 to about 24 nucleotides in length and are useful in RNA interference (RNAi). siRNAs are often30 found with phosphorylated 5′ ends and hydroxylated 3′ ends, which 3′ ends typically have a 2- nucleotide overhang beyond the 5′ end of the anti-parallel strand (e.g., complementary strand of 32 the dsRNA compound). siRNAs can interfere with the expression of specific genes through binding of target sequences (e.g., target nucleic acid sequences) to which they are complementary 34 and promoting (e.g., facilitating, triggering, initiating) degradation of the mRNA, thereby preventing (e.g., inhibiting, silencing, interfering with) translation. RNAi act, at least in part, 2 through an RNA-induced silencing complex (RISC) pathway or Ago2, but not through RNaseΗ, to modulate a target nucleic acid and / or protein encoded by a target nucleic acid. After 4 integration and separation into the RISC complex, siRNAs base-pair (e.g., full complementarity) to their target mRNA and cleave it, thereby preventing it from being used as a translation 6 template. As discussed herein above, also part of the RNAi pathway, a miRNA-loaded RISC complex scans cytoplasmic mRNAs for potential complementarity (e.g., partial 8 complementarity). The term “circular RNA” (“circRNA”) refers to an RNA that is covalently closed (i.e., 10 the 5′ and 3′ ends have been joined together) to form a continuous loop. CircRNAs are resistant to exonuclease degradation and are often much more stable than a corresponding linear RNA of 12 the same sequence. CircRNAs therefore typically have longer half-lives than linear RNAs. They have many different biological functions and are known to act, for example, as transcriptional 14 regulators, microRNA sponges, and protein templates. CircRNAs are also known to interact with proteins, e.g., by mediating or altering protein-protein interactions, sequestering proteins, 16 recruiting proteins to chromatin, and facilitating protein translocation. A “short hairpin RNA” (“shRNA”) refers to an RNA compound with a tight hairpin turn 18 that can be used, for example, to silence target gene expression via RNAi. shRNA often have lower rates of degradation and turnover relative to other RNAi agents due to the presence of the 20 hairpin structure. The term “mRNA” or “mRNA molecule” refers to messenger RNA, or the RNA that 22 serves as a template for protein synthesis in a cell. The sequence of a strand of mRNA is based on the sequence of a complementary strand of DNA comprising a sequence coding for the 24 protein to be synthesized. The term “ADAR recruiting compound,” as may be used herein, refers to a nucleic acid 26 that is configured to increase the concentration of Adenosine Deaminase Acting on Ribonucleic Acid (ADAR) enzyme in a location around the nucleic acid. In some embodiments, an increased 28 concentration is relative to the concentration in a given location absent the ADAR recruiting compound. In some embodiments, an ADAR recruiting compound comprises a double-stranded 30 RNA duplex. The term “ADAR targeting compound,” as may be used herein, refers to a nucleic acid 32 that is configured to direct an ADAR compound to a desirable location (e.g., location). As used herein, the term “direct” refers to increasing the concentration of ADAR in the desirable location 34 as compared to the concentration absent the ADAR targeting compound. In some embodiments, the ADAR targeting compound can be configured to control the desirable location by altering the 2 sequence and / or properties of the nucleic acid (e.g., by modifications to the nucleobase, sugar, internucleoside linkage, or other component). In some embodiments, an ADAR targeting 4 compound comprises an ADAR recruiting compound and a single-stranded guide nucleic acid. In some embodiments, an ADAR targeting compound comprises a double-stranded RNA duplex 6 and a single-stranded guide nucleic acid. The term “single-stranded guide nucleic acid” or “guide RNA,” as may be used herein, 8 refers to a nucleic acid of a single strand, which comprises a specific sequence that is at least partially complementary to a target sequence. In some embodiments, the target sequence is at, 10 adjacent to, or in proximity to, a location where it is desirable to modulate ADAR concentration. In some embodiments, the level of complementarity is sufficient to facilitate binding (e.g., 12 annealing) of the single-stranded guide nucleic acid to the target sequence. “Modified oligonucleotide” means an oligonucleotide, wherein at least one sugar, 14 nucleobase, or internucleoside linkage is modified. “Nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or 16 oligonucleotide independent of any sugar or internucleoside linkage. The term “oligomeric duplex” means a duplex formed by two oligomeric compounds 18 having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may be referred to as a “duplexed oligomeric compound.” The oligonucleotides of each 20 oligomeric compound of an oligomeric duplex may include non-complementary overhanging nucleosides. “Phosphorothioate,” “phosphorothioate linkage,” or “phosphorothioate linker” 22 means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced with a sulfur atom. 24 “Phosphorothiolate,” “phosphorothiolate linkage,” or “phosphorothiolate linker” means a modified phosphate linkage in which one or each of the bridging oxygen atoms is replaced with a 26 sulfur atom. A “linker” refers to a polyvalent (e.g., divalent, trivalent, or tetravalent) chemical moiety 28 (e.g., a combination of atoms having appropriate valency according to known chemistry principles) that covalently connects two or more (e.g., three or four) components of a compound 30 (e.g., oligonucleotide) provided herein. The term “ligand” refers to a substance that binds to or otherwise interacts with a protein, 32 nucleic acid, or other biological molecule. In some embodiments, a ligand is selected from the group consisting of small molecules; saccharines; oligosaccharides; polysaccharides; biological 34 macromolecules, e.g., peptides, proteins, and peptide analogs and derivatives; peptidomimetics; antibodies and antigen binding fragments thereof; nucleic acids; nucleic acid analogs and 2 derivatives; an extract made from biological materials such as bacteria, plants, fungi, or animal cells; animal tissues; and naturally occurring or synthetic compositions. In some embodiments, a 4 ligand is a small molecule. In some embodiments, a ligand binds to a protein (e.g., a receptor). In certain embodiments, a ligand binds to tropomyosin receptor kinase B (TrkB), cannabinoid 6 receptor type 1 (CB1), α4β1 / 7integrin receptor, or N-methyl-D-aspartate (NMDA) receptor. In some embodiments, a ligand is capable of selectively targeting an oligonucleotide (e.g., an 8 oligonucleotide strand thereof) to a region of the body, or to a cell. In some embodiments, a ligand is capable of targeting an oligonucleotide (e.g., an oligonucleotide strand thereof) to the 10 brain of a subject (e.g., to the striatum, cerebellum, brain stem, hippocampus, frontal cortex, or spinal cord of the subject). In some embodiments, a ligand is capable of targeting an 12 oligonucleotide (e.g., an oligonucleotide strand thereof) to a central nervous system (CNS) cell (e.g., a neuron). In some embodiments, a ligand is not a lipid. 14 The term “internal position” of an oligonucleotide strand refers to a position of the oligonucleotide strand other than the 5′ or 3′ nucleoside. In some embodiments, the internal 16 position is at an internucleoside linkage (e.g., the internucleoside linkage between the 5′ nucleoside and the second nucleoside counted from the 5′ end; the internucleoside linkage 18 between the 3′ nucleoside and the second nucleoside counted from the 3′ end; the internucleoside linkage between the first n and n+1 nucleosides counted from the 5′ end, wherein n is an integer 20 between 2 and 20, inclusive, as the number of nucleosides of the oligonucleotide strand permits). In some embodiments, the internal position is at a position on an “internal nucleoside” (a 22 nucleoside that is not the 5′ or 3′ nucleoside). An oligonucleotide comprising a modification (e.g., conjugation of a radical of a ligand) at an internal position may be referred to as an “internally- 24 modified oligonucleotide.” The term “lipid” or “lipophilic moiety” refers to organic compounds that are substantially 26 insoluble in water at ambient temperature and pressure. A lipid may be a lipid recited in the LIPID MAPS®Structure Database (LMSD). A lipid may be a fatty acyl, glycerolipid, 28 glycerophospholipid, sphingolipid, saccharolipid, polyketide, sterol lipid, or prenol lipid. A fatty acyl may be a fatty acid or conjugate, octadecanoid, eicosanoid, docosanoid, fatty alcohol, fatty 30 aldehyde, fatty ester, fatty amide, fatty nitrile, fatty ether, hydrocarbon, oxygenated hydrocarbon, or fatty acyl glycoside. A glycerolipid may be a monoradylglycerol, 32 diradylglycerol, triradylglycerol, glycosylmonoradylglycerol, glycosyldiradylglycerol, betaine monoradylglycerol, or betaine diradylglycerol. A glycerophospholipid may be a 34 glycerophosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoglycerol, glycerophosphoglycerophosphate, glycerophosphoinositol, 2 glycerophosphoinositol monophosphate, glycerophosphoinositol bisphosphate, glycerophosphoinositol trisphosphate, glycerophosphate, glyceropyrophosphate, 4 glycerophosphoglycerophosphoglycerol, CDP-glycerol, glycosylglycerophospholipid, glycerophosphoinositolglycan, glycerophosphonocholine, glycerophosphonoethanolamine, di- 6 glycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphoethanolamine glycan, dihydroxyacetonephosphate, 8 glycerophosphoethanol, glycerophosphothreonine, or cyclic glycerophosphatidic acid. A sphingolipid may be a sphingoid base, ceramide, phosphosphingolipid, phosphonosphingolipid, 10 neutral glycosphingolipid, acidic glycosphingolipid, basic glycosphingolipid, amphoteric glycosphingolipid, or arsenosphingolipid. A saccharolipid may be an acylaminosugar, 12 acylaminosugar glycan, acyltrehalose, or acyltrehalose glycan. A polyketide may be a linear polyketide, halogenated acetogenin, annonaceae acetogenin, macrolide, lactone polyketide, 14 ansamycin, polyene, linear tetracycline, angucycline, polyether antibiotic, aflatoxin, cytochalasin, flavonoid, aromatic polyketide, non-ribosomal peptide / polyketide hybrid, or phenolic lipid. A 16 sterol lipid may be a sterol, steroid, secosteroid, bile acid or a derivative thereof, or steroid conjugate. A prenol lipid may be an isoprenoid, quinone, hydroquinone, polyprenol, or hopanoid. 18 The term lipid includes, e.g., cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1- pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyanol, 20 hexadecylglycerol, borneol, menthol, 1,3- propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, 22 dimethoxytrityl, or phenoxazine. A lipid may be a hydrocarbon (e.g., substituted or unsubstituted, saturated or unsaturated, branched or unbranched hydrocarbon). A hydrocarbon may be an 24 alkane, alkene, or alkyne. The size of an unsubstituted hydrocarbon may be C7-C36(that is, the unsubstituted hydrocarbon contains totally 7-36 carbon atoms in the backbone and, if present, the 26 branches). A substituted hydrocarbon may be a hydrocarbon substituted at least with one or more halogen (e.g., F) atoms, as valency permits. In certain embodiments, each substituent of a 28 substituted hydrocarbon is not another hydrocarbon. The size of a substituted hydrocarbon may be C7-C36(that is, the substituted hydrocarbon contains totally 7-36 carbon atoms in the 30 backbone and, if present, the branches, excluding the atoms in the substituents). The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least 32 one double or triple bond. The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., 34 the moiety only contains single bonds. 2 DETAILED DESCRIPTION In one aspect, the present disclosure provides oligonucleotides comprising at least one 4 radical of a central nervous system receptor ligand at a nucleobase, the 2′ position of a nucleoside, or the 3′ position of a nucleoside. The present disclosure also provides 6 pharmaceutical compositions and kits comprising any of the oligonucleotides disclosed herein. The present disclosure also provides methods of delivering any of the oligonucleotides disclosed 8 herein to a subject, methods of treating a disease in a subject in need thereof using any of the oligonucleotides disclosed herein, methods of preventing a disease in a subject in need thereof 10 using any of the oligonucleotides disclosed herein, and methods of modulating the activity of a protein in a subject, cell, tissue, or biological sample. In certain embodiments, the disease is a 12 CNS disease, neurodegenerative disease, or neurocognitive disorder. 14 Oligonucleotides In another aspect, the present disclosure provides oligonucleotides comprising a modified 16 oligonucleotide strand comprising s1 instances of modified nucleosides independently comprising a moiety of Formula I: 18 d v1 instances of the internucleosidic linkers of the modified oligonucleotide strand are 20 independently repla ; wherein: 22 s1 is 1, 2, 3, 4, 5, or 6; each instance of N1is independently a radical of a nucleobase or a bond; 24 each instance of t1 is independently 1, 2, or 3; each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least 26 one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; each instance of A1, A2, and A3, if present, is independently a radical of a ligand or a 2 lipid, provided that at least one instance of A1, A2, and A3is a radical of a central nervous system receptor ligand; 4 when y1 of an instance o is 0, L1thereof is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or 6 unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted 8 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –CN, –ORb, –SCN, –SRb, –SSRb, –N3, –NO, –N(Rb)2, –10 NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –S(=O)ORb, –S(=O)SRb, – S(=O)N(Rb)2, –S(=O)2Rb, –S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –OC(=O)Rb, – 12 OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, – OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, –14 SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, – NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, –16 NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, –NRbS(=O)2N(Rb)2, – Si(Rb)3, –Si(Rb)2ORb, –Si(Rb)(ORb)2, –Si(ORb)3, –OSi(Rb)3, –OSi(Rb)2ORb, –OSi(Rb)(ORb)2, or – 18 OSi(ORb)3; or when y1 of an instan 1thereof is a linker; 20 each instance of Rbis independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or 22 unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, 24 substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen 26 atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to the same intervening atom are joined together with the intervening atom to form an substituted 28 or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; when y2 of an instance is 0, L2thereof is –OH, –ORh, halogen, –CN, or 30 –N3; or when y2 of an instance is 1, 2, 3, 4, 5, or 6, L2thereof is a linker; each instance of Rhis independently substituted or unsubstituted, C1-6alkyl, or an oxygen 2 protecting group; when the moiety of Formula I is part of an instance of the modified nucleoside at the 5’ 4 end or an internal position of the modified oligonucleotide strand: y3 thereof is 0, and L3thereof is an internucleosidic linker; or 6 when the moiety of Formula I is part of an instance of the modified nucleoside at the 3’ end of the modified oligonucleotide strand: 8 when y3 thereof is 0: L3thereof is –OH, –ORd, halogen, –CN, or –N3, and each instance of Rdis independently substituted or unsubstituted, C1-6alkyl, or an oxygen 10 protecting group; or when y3 thereof is 1, 2, 3, 4, 5, or 6, L3thereof is a linker; 12 v1 is 0, 1, 2, 3, 4, 5, or 6; each instance of LAand L4, when present, is independently a linker; 14 each instance of y4, when present, is independently 1, 2, 3, 4, 5, or 6; and each instance of A4, when present, is independently a radical of a ligand or lipid. 16 In some embodiments, each instance of A1, A2, and A3, if present, is independently a radical of a central nervous system receptor ligand or a lipid, provided that at least one instance 18 of A1, A2, and A3is a radical of a central nervous system receptor ligand. In one aspect, the present disclosure provides oligonucleotides comprising a modified 20 oligonucleotide strand comprising s1 instances of modified nucleosides independently comprising a moiety of Formula I: 22 d v1 instances of the internucleosidic linkers of the modified oligonucleotide strand are 24 independently repla ; wherein: 26 s1 is 1, 2, 3, 4, 5, or 6; each instance of N1is independently a radical of a nucleobase or a bond; each instance of t1 is independently 1, 2, or 3; 2 each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; 4 each instance of A1, A2, and A3, if present, is independently radical of a central nervous system receptor ligand or a lipid, provided that at least one instance of A1, A2, and A3is a radical 6 of a central nervous system receptor ligand; when y1 of an instance o is 0, L1thereof is hydrogen, halogen, 8 substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 10 heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl,12 substituted or unsubstituted heteroaryl, –CN, –ORb, –SCN, –SRb, –SSRb, –N3, –NO, –N(Rb)2, – NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –S(=O)ORb, –S(=O)SRb, –14 S(=O)N(Rb)2, –S(=O)2Rb, –S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –OC(=O)Rb, – OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, –16 OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, – SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, –18 NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, – NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, –NRbS(=O)2N(Rb)2, –20 Si(Rb)3, –Si(Rb)2ORb, –Si(Rb)(ORb)2, –Si(ORb)3, –OSi(Rb)3, –OSi(Rb)2ORb, –OSi(Rb)(ORb)2, or – OSi(ORb)3; or when y1 of an instan 1thereof is a 22 linker; each instance of Rbis independently hydrogen, substituted or unsubstituted alkyl, 24 substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted 26 heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting 28 group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached 30 to the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; when y2 of an instance o is 0, L2thereof is –OH, –ORh, halogen, –CN, or 2 –N3; or when y2 of an instance o is 1, 2, 3, 4, 5, or 6, L2thereof is a linker; each instance of Rhis independently substituted or unsubstituted, C1-6alkyl, or an oxygen 4 protecting group; when the moiety of Formula I is part of an instance of the modified nucleoside at the 5’ 6 end or an internal position of the modified oligonucleotide strand: y3 thereof is 0, and L3thereof is an internucleosidic linker; or 8 when the moiety of Formula I is part of an instance of the modified nucleoside at the 3’ end of the modified oligonucleotide strand: 10 when y3 thereof is 0: L3thereof is –OH, –ORd, halogen, –CN, or –N3, and each instance of Rdis independently substituted or unsubstituted, C1-6alkyl, or an oxygen 12 protecting group; or when y3 thereof is 1, 2, 3, 4, 5, or 6, L3thereof is a linker; 14 v1 is 0, 1, 2, 3, 4, 5, or 6; each instance of LAand L4, when present, is independently a linker; 16 each instance of y4, when present, is independently 1, 2, 3, 4, 5, or 6; and each instance of A4, when present, is independently a radical of a ligand or lipid. 18 In some embodiments, s1 is 1, and the modified nucleoside is at the 5’ end of the modified oligonucleotide strand. In some embodiments, s1 is 1, and the modified nucleoside is at 20 an internal position of the modified oligonucleotide strand. In some embodiments, s1 is 1, and the modified nucleoside is at the 3’ end of the modified oligonucleotide strand. 22 In certain embodiments, s1 is 2; one instance of the modified nucleoside is at the 5’ end of the modified oligonucleotide strand; and the other instance of the modified nucleoside is at an 24 internal position of the modified oligonucleotide strand. In certain embodiments, s1 is 2; one instance of the modified nucleoside is at the 3’ end of the modified oligonucleotide strand; and 26 the other instance of the modified nucleoside is at an internal position of the modified oligonucleotide strand. In certain embodiments, s1 is 2; and each instance of the modified 28 nucleoside is at an internal position of the modified oligonucleotide strand. In certain embodiments, s1 is 3, 4, 5, or 6. 30 In certain embodiments, at least one instance of the internal position is the first n nucleoside of the modified oligonucleotide strand counted from the 5’ end; and n is an integer between 2 and 20, inclusive, as the number of nucleosides of the modified oligonucleotide strand 2 permits. In certain embodiments, at least one instance of the internal position is the first n nucleoside of the modified oligonucleotide strand counted from the 3’ end; and n is an integer 4 between 2 and 20, inclusive, as the number of nucleosides of the modified oligonucleotide strand permits. 6 In some embodiments, at least one instance of N1is a radical of a nucleobase. In certain embodiments, at least one instance of N1is a radical of adenine, cytosine, guanine, or uracil. In 8 some embodiments, at least one instance of N1is a bond. In certain embodiments, at least one instance of t1 is 1. In certain embodiments, v1 is 0. 10 In certain embodiments, v1 is 1. In certain embodiments, v1 is 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of y1 is 0. In certain embodiments, at least one instance of y1 12 is 1. In certain embodiments, at least one instance of y1 is 2. In certain embodiments, at least one instance of y1 is 3, 4, 5, or 6. In certain embodiments, at least one instance of y2 is 0. In certain 14 embodiments, at least one instance of y2 is 1. In certain embodiments, at least one instance of y2 is 2. In certain embodiments, at least one instance of y2 is 3, 4, 5, or 6. In certain embodiments, 16 at least one instance of y3 is 0. In certain embodiments, at least one instance of y3 is 1. In certain embodiments, at least one instance of y3 is 2. In certain embodiments, at least one instance of y3 18 is 3, 4, 5, or 6. In certain embodiments, at least one instance of y4, when present, is 1. In certain embodiments, at least one instance of y4, when present, is 2, 3, 4, 5, or 6. 20 In certain embodiments, in at least one instance of the moiety of Formula I: each instance of y1 is 0; y2 is 0; and y3 is 1. In certain embodiments, in at least one instance of the moiety of 22 Formula I: each instance of y1 is 0; y2 is 0; and y3 is 2. In certain embodiments, in at least one instance of the moiety of Formula I: t1 is 1; y1 is 1; y2 is 0; and y3 is 1. In certain embodiments, 24 in at least one instance of the moiety of Formula I: each instance of y1 is 0; y2 is 1; and y3 is 1. In certain embodiments, in at least one instance of the moiety of Formula I, each of t1, y1, y2, 26 and y3 is 1. In certain embodiments, in at least one instance of the moiety of Formula I: y1 is 0; y2 is 2; and y3 is 1. 28 In certain embodiments, Formula I comprises:

[0002] 2 , ,

[0003] , , 2 ,

[0004] ,

[0005] . 2 In certain embodiments, an oligonucleotide strand has a nucleobase sequence that is at least partially complementary to a target nucleic acid sequence (e.g., an expressed target nucleic 4 acid within a cell). In some embodiments, the oligonucleotide, upon delivery to a cell expressing a target nucleic acid, is able to modify the expression of the underlying gene. In some 6 embodiments, the oligonucleotide, upon delivery to a cell expressing a target nucleic acid, is able to inhibit the expression of the underlying gene. The gene expression can be modified or 8 inhibited in vitro or in vivo. In certain embodiments, an oligonucleotide comprises one or more ribonucleic acids (e.g., one or more ribonucleosides), deoxyribonucleic acids (e.g., one or more 10 deoxyribonucleosides), modified nucleic acids (e.g., one or more modified nucleobases, sugars, and / or internucleoside linkages), or a combination thereof. In some embodiments, an 12 oligonucleotide comprises a ribonucleic acid (RNA). In some embodiments, an oligonucleotide comprises a deoxyribonucleic acid (DNA). In some embodiments, an oligonucleotide comprises 14 a modification (e.g., modified nucleobase, modified sugar, or modified internucleoside linkage). In some embodiments, an oligonucleotide is double-stranded (e.g., comprised of two 16 single-stranded nucleic acids). In some embodiments, a double-stranded oligonucleotide comprises a first oligonucleotide strand having a region complementary to a target nucleic acid 18 and a second oligonucleotide strand having a region complementary to the first oligonucleotide strand. The first and second oligonucleotide strands can be independently modified. In certain 20 embodiments, the first oligonucleotide strand is linked to one or more radicals of ligands (e.g., TrkB, CB1, α4β1 / 7integrin, and / or NMDA receptor ligands). In certain embodiments, the second 22 oligonucleotide strand is linked to one or more radicals of ligands (e.g., TrkB, CB1, α4β1 / 7 integrin, and / or NMDA receptor ligands). In certain embodiments, an oligonucleotide comprises 2 one or more radicals of ligands at one or more internal positions. In certain embodiments, an oligonucleotide comprises one or more radicals of ligands at one or more internal positions. In 4 certain embodiments, an oligonucleotide comprises one or more radicals of ligands at a nucleobase. In certain embodiments, an oligonucleotide comprises one or more radicals of 6 ligands at the 2′ position of a nucleoside. In certain embodiments, an oligonucleotide comprises one or more radicals of ligands at the 3′ position of a nucleoside. 8 In some embodiments, an oligonucleotide strand is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 10 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 12 95, 96, 97, 98, 99, or 100 nucleotides in length. In some embodiments, an oligonucleotide strand is 6-10, 11-15, 16-20, 21-25, 26-30, 31-14 35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96- 100, inclusive, nucleotides in length. In some embodiments, an oligonucleotide strand is about 6 16 nucleotides in length to about 100 nucleotides in length, inclusive. In some embodiments, an oligonucleotide strand is about 20 nucleotides in length to about 90 nucleotides in length, 18 inclusive. In some embodiments, an oligonucleotide strand is about 30 nucleotides in length to about 80 nucleotides in length, inclusive. In some embodiments, an oligonucleotide strand is 20 about 40 nucleotides in length to about 70 nucleotides in length, inclusive. In some embodiments, an oligonucleotide strand is about 50 nucleotides in length to about 60 nucleotides in length, 22 inclusive. In certain embodiments, an oligonucleotide strand is about 14 nucleotides in length to 24 about 23 nucleotides in length. In some embodiments, an oligonucleotide is a therapeutic oligonucleotide. A therapeutic 26 oligonucleotide may comprise, for example, without limitation, an RNA (e.g., a small interfering RNA (siRNA), a microRNA (miRNA) antagonist, a miRNA mimic, an ADAR recruiting 28 compound, an ADAR targeting compound, a guide RNA, an antisense oligonucleotide, a short hairpin RNA (shRNA), a circular RNA (circRNA)) or combinations thereof. 30 In certain embodiments, a miRNA is a precursor, primary, and / or mature miRNA. In certain embodiments, an oligonucleotide comprises an antisense oligonucleotide 32 strand. In certain embodiments, an antisense oligonucleotide strand is complementary to a sense oligonucleotide strand (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at 34 least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary). In certain embodiments, an antisense oligonucleotide strand is complementary to a pre-mRNA. In 2 certain embodiments, an antisense oligonucleotide strand blocks translation and promotes degradation of the mRNA transcript. In certain embodiments, the antisense oligonucleotide 4 (alone or together with a complementary sense oligonucleotide) is able to silence gene expression through the RNA-induced silencing complex (RISC) pathway. In certain embodiments, an 6 antisense oligonucleotide strand recruits RNase H and promotes degradation of the mRNA transcript. In certain embodiments, an antisense oligonucleotide strand targets miRNA, inhibiting 8 the miRNA from modulating mRNA expression and promoting degradation of the miRNA. In certain embodiments, an oligonucleotide comprises or recruits an editing complex to edit RNA. 10 Certain oligonucleotides of the present disclosure can exist in an unsolvated forms as well as solvated forms, including hydrated forms. Certain oligonucleotides of the present disclosure 12 may exist in crystalline or amorphous forms. In certain embodiments, an oligonucleotide comprises an oligonucleotide strand having at 14 least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to a gene (e.g., human gene) with which a disease (e.g., CNS disease) is 16 associated, or a portion thereof (e.g., 10 nucleotides thereof, 11 nucleotides thereof, 12 nucleotides thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 18 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 nucleotides thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 20 nucleotides thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 nucleotides thereof, 29 nucleotides thereof, or 30 nucleotides thereof). In certain embodiments, 22 the disease is associated with the overexpression of the gene. In certain embodiments, “associated with” refers to “caused at least in part by.” 24 In certain embodiments, an oligonucleotide comprises an oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or 26 complementarity to a microtubule-associated protein tau (MAPT) gene (e.g., human MAPT gene), or a portion thereof (e.g., 10 nucleotides thereof, 11 nucleotides thereof, 12 nucleotides 28 thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 nucleotides 30 thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 nucleotides thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 nucleotides 32 thereof, 29 nucleotides thereof, or 30 nucleotides thereof). Exemplary nucleotide sequences of the human MAPT gene can be found, for example, at GenBank Accession No. NM_001377265.1 34 (incorporated herein as SEQ ID NO: 1), and nucleotides 2624000 to 2761000 of NT_010783.14 (incorporated herein as SEQ ID NO: 2). Additional examples of MAPT sequences are readily 2 available through publicly available databases, e.g., GenBank, UniProt, and OMIM. Further information on MAPT can be found, for example, at www.ncbi.nlm.nih.gov / gene / ?term=MAPT. 4 MAPT, as used herein, also refers to variations of the MAPT gene including variants provided in the SNP database. Numerous sequence variations within the MAPT gene have been identified 6 and may be found at, for example, NCBI dbSNP and UniProt (see, e.g., www.ncbi.nlm.nih.gov / snp / ?term=MAPT). In certain embodiments, the oligonucleotide inhibits 8 the expression, translation, or activity of MAPT in a subject, cell, tissue, or biological sample. In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of10 MAPT in a subject, cell, tissue, or biological sample by 3-10%, 10-20%, 20-40%, 40-60%, 60- 90%, or 90-99% relative to the expression, translation, or activity in a negative control (e.g., as 12 measured by an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq)). 14 In certain embodiments, an oligonucleotide comprises a sense oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% 16 identity or complementarity to a superoxide dismutase type 1 (SOD1) gene (e.g., a human SOD1 gene), or a portion thereof (e.g., 10 nucleotides thereof, 11 nucleotides thereof, 12 nucleotides 18 thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 nucleotides 20 thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 nucleotides thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 nucleotides 22 thereof, 29 nucleotides thereof, or 30 nucleotides thereof). Exemplary nucleotide sequences of the human SOD1 gene can be found, for example, at nucleotides 5092 to 138872 of 24 NG_007398.2 (incorporated herein as SEQ ID NO: 3), and GenBank Accession No NM_016835.5 (incorporated herein as SEQ ID NO: 4). Additional examples of SOD1 sequences 26 are readily available through publicly available databases, e.g., GenBank, UniProt, and OMIM. Further information on SOD1 can be found, for example, at 28 www.ncbi.nlm.nih.gov / gene / ?term=SOD1. SOD1, as used herein, also refers to variations of the SOD1 gene including variants provided in the SNP database. Numerous sequence variations 30 within the SOD1 gene have been identified and may be found at, for example, NCBI dbSNP and UniProt (see, e.g., www.ncbi.nlm.nih.gov / snp / ?term=SOD1). In certain embodiments, the 32 oligonucleotide inhibits the expression, translation, or activity of SOD1 in a subject, cell, tissue, or biological sample. In certain embodiments, the oligonucleotide inhibits the expression, 34 translation, or activity of SOD1 in a subject, cell, tissue, or biological sample by 3-10%, 10-20%, 20-40%, 40-60%, 60-90%, or 90-99% relative to the expression, translation, or activity in a 2 negative control (e.g., as measured by an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq)). 4 In certain embodiments, an oligonucleotide comprises a sense oligonucleotide strand having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% 6 identity or complementarity to an leucine-rich repeat kinase 2 (LRRK2) gene (e.g., a human LRRK2 gene), or a portion thereof (e.g., 10 nucleotides thereof, 11 nucleotides thereof, 12 8 nucleotides thereof, 13 nucleotides thereof, 14 nucleotides thereof, 15 nucleotides thereof, 16 nucleotides thereof, 17 nucleotides thereof, 18 nucleotides thereof, 19 nucleotides thereof, 20 10 nucleotides thereof, 21 nucleotides thereof, 22 nucleotides thereof, 23 nucleotides thereof, 24 nucleotides thereof, 25 nucleotides thereof, 26 nucleotides thereof, 27 nucleotides thereof, 28 12 nucleotides thereof, 29 nucleotides thereof, or 30 nucleotides thereof). Exemplary nucleotide sequences of the human LRRK2 gene can be found, for example, at GenBank Accession No. 14 NM_198578.4 (incorporated herein as SEQ ID NO: 5), and nucleotides 5002 to 149290 of NG_011709.2 (incorporated herein as SEQ ID NO: 6). Additional examples of LRRK2 16 sequences are readily available through publicly available databases, e.g., GenBank, UniProt, and OMIM. Further information on LRRK2 can be found, for example, at 18 www.ncbi.nlm.nih.gov / gene / ?term=LRRK2. LRRK2, as used herein, also refers to variations of the LRRK2 gene including variants provided in the SNP database. Numerous sequence variations 20 within the LRRK2 gene have been identified and may be found at, for example, NCBI dbSNP and UniProt (see, e.g., www.ncbi.nlm.nih.gov / snp / ?term=LRRK2). In certain embodiments, the 22 oligonucleotide inhibits the expression, translation, or activity of LRRK2 in a subject, cell, tissue, or biological sample. In certain embodiments, the oligonucleotide inhibits the expression,24 translation, or activity of LRRK2 in a subject, cell, tissue, or biological sample by 3-10%, 10- 20%, 20-40%, 40-60%, 60-90%, or 90-99% relative to the expression, translation, or activity in a 26 negative control (e.g., as measured by an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq)). 28 Linkers 30 In some embodiments, the oligonucleotides provided herein comprise one or more linkers (e.g., L1, L2, L3, LA, and L4). 32 In certain embodiments, a linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units or combination of such repeating units. In certain embodiments, 34 a linker comprises 1-5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, or 46-50, inclusive, repeating units. In certain embodiments, the repeating unit is –CH2–. In certain 2 embodiments, the repeating unit is –CH2CH2O– or –OCH2CH2–. In certain embodiments, a linker is 1-5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 4 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100, inclusive, atoms long, between any two of the attachment points. 6 In certain embodiments, a linker contains in the backbone thereof carbon atoms (e.g., 1-5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 8 76-80, 81-85, 86-90, 91-95, or 96-100, inclusive, carbon atoms). In certain embodiments, a linker contains in the backbone thereof heteroatoms (e.g., nitrogen, oxygen, sulfur, phosphorous) (e.g., 10 1-3, 4-6, 7-9, 10-12, 13-15, 16-18, 19-21, 22-24, 25-27, 28-30, 31-33, 34-36, or 37-40, inclusive, heteroatoms). In certain embodiments, a linker comprises in the backbone thereof amide, ester, 12 disulfide, or a combination thereof. In certain embodiments, a linker comprises in the backbone thereof hydrazone, oxime, imine, guanidine, urea, carbamate, alkyl, sulfonamide, heterocyclic, or 14 a combination thereof. In certain embodiments, a linker comprises in the backbone thereof one or more groups independently selected from alkyl, amino, οxο, amide, disulfide, polyethylene 16 glycol, ether, thioether, and hydroxylamino. In certain embodiments, a linker comprises in the backbone thereof at least one phosphorus atom. In certain embodiments, a linker includes at least 18 one non-polar linking group. In certain embodiments, a linker includes at least one polar linking group. In certain embodiments, a linker includes at least one linking group formed by a click- 20 chemistry reaction of a first and second click-chemistry reactive moieties. In certain embodiments, a linker is substituted. In certain embodiments, a linker is substituted with alkyl, 22 alkenyl, alkynyl, amino, alkylamino, dialkylamino, trialkylamino, hydroxyl, alkoxy, carbonyl, halogen, aryl, heterocyclic, aromatic heterocyclic, cyano, amide, carbamoyl, carboxylic acid, 24 ester, thioether, alkylthioether, thiol, ureido, or a combination thereof. As would be appreciated by one of skill in this art, each of these groups may in turn be substituted. In some embodiments, 26 a linker is substituted with one, two, three, four, five, six, seven, eight, nine, ten, or more than ten substituents. 28 In some embodiments, a linker is a bond (e.g., a single bond). In some embodiments, a linker is optionally substituted alkylene. In some embodiments, a 30 terminal backbone carbon atom of alkylene is an attachment point. In some embodiments, an internal backbone carbon atom of alkylene is an attachment point. In some embodiments, a linker 32 is optionally substituted alkenylene. In some embodiments, a linker is optionally substituted alkynylene. In some embodiments, a linker is substituted or unsubstituted, C1-100alkylene, 34 substituted or unsubstituted, C2-100alkenylene, or substituted or unsubstituted, C2-100alkynylene. In certain embodiments, one or more (e.g., two, three, or four) backbone atoms of the C1-1002 alkylene, C2-100alkenylene, or C2-100alkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or 4 unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. In some embodiments, a linker is substituted or unsubstituted, C7-70alkylene, substituted or unsubstituted, 6 C7-70alkenylene, or substituted or unsubstituted, C7-70alkynylene. In certain embodiments, one or more (e.g., two, three, or four) backbone atoms of the C7-70alkylene, C7-70alkenylene, or C7-708 alkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted 10 or unsubstituted heteroarylene, as valency permits. In certain embodiments, one or two backbone atoms of the C7-70alkylene, C7-70alkenylene, or C7-70alkynylene are independently replaced with 12 substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency 14 permits. In some embodiments, a linker is substituted or unsubstituted, C1-6, C7-12, C13-18, C19-24, C25–30, C31–36, C37–44, C45-52, C53–60, or C61-70alkylene, substituted or unsubstituted, C2–6, C7-12, C13- 1618, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or C61-70alkenylene, or substituted or unsubstituted, C2–6, C7-12, C13-18, C19-24, C25–30, C31–36, C37–-44, C45-52, C53–60, or C61-70alkynylene. In certain18 embodiments, one or more (e.g., two, three, or four) backbone atoms of the C1-6, C7-12, C13-18, C19-24, C25–30, C31–36, C37–44, C45-52, C53–60, or C61-70alkylene, C2–6, C7-12, C13-18, C19-24, C25–30, C31–36, 20 C37-44, C45-52, C53-60, or C61-70alkenylene, or C2-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53–60, or C61-70alkynylene are independently replaced with substituted or unsubstituted 22 carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. 24 In some embodiments, a linker is optionally substituted alkenylene comprising one, two, three, four, five, six, seven, eight, nine, ten, or more than ten double bonds. In some 26 embodiments, a linker is optionally substituted alkynylene comprising one, two, three, four, five, six, seven, eight, nine, ten, or more than ten triple bonds. In some embodiments, a linker is 28 optionally substituted, alkylene, alkenylene, or alkynylene and comprises one or more (e.g., two, three, four, five) branch points. In certain embodiments, the linker comprises two, three, four, or 30 five branch points. In some embodiments, a linker is optionally substituted heteroalkylene. In some 32 embodiments, a terminal backbone atom of heteroalkylene is an attachment point. In some embodiments, an internal backbone atom of heteroalkylene is an attachment point). In some 34 embodiments, a linker is optionally substituted heteroalkenylene. In some embodiments, a linker is optionally substituted heteroalkynylene. In some embodiments, a linker is substituted or 2 unsubstituted, C1-100heteroalkylene, substituted or unsubstituted, C2-100heteroalkenylene, or substituted or unsubstituted, C2-100heteroalkynylene. In certain embodiments, one or more (e.g., 4 two, three, or four) backbone atoms of the C1-100heteroalkylene, C2-100heteroalkenylene, or C2-100heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, 6 substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. In some embodiments, a linker is substituted 8 or unsubstituted, C7-70heteroalkylene, substituted or unsubstituted, C7-70heteroalkenylene, or substituted or unsubstituted, C7-70heteroalkynylene. In certain embodiments, one or more (e.g., 10 two, three, or four) backbone atoms of the C7-70heteroalkylene, C7-70heteroalkenylene, or C7-70heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, 12 substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. In certain embodiments, one or two backbone 14 atoms of the C7-70heteroalkylene, C7-70heteroalkenylene, or C7-70heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or 16 unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. In some embodiments, a linker is substituted or 18 unsubstituted, C1-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or C61-70heteroalkylene, substituted or unsubstituted, C1-6, C7-12, C13-18, C19-24, C25–30, C31–36, C37–44, C45-52, C53–60, or C61-7020 heteroalkenylene, or substituted or unsubstituted, C2-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53–60, or C61-70heteroalkynylene. In certain embodiments, one or more (e.g., two, three, or 22 four) backbone atoms of the C1-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or C61-70heteroalkylene, C1-6, C7-12, C13-18, C19-24, C25–30, C31–36, C37–44, C45-52, C53–60, or C61-7024 heteroalkenylene, or C2-6, C7-12, C13-18, C19-24, C25-30, C31-36, C37-44, C45-52, C53-60, or C61-70heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, 26 substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. 28 In some embodiments, the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroarylene. 30 In some embodiments, the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl fused 32 with substituted or unsubstituted, 7- to 9-membered, monocyclic carbocyclyl. In some embodiments, the substituted or unsubstituted heteroarylene that replaces one of the backbone 34 atoms is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl fused with substituted or unsubstituted, 7- to 9-membered, monocyclic heterocyclyl. In some embodiments, 2 the substituted or unsubstituted heteroarylene that replaces one of the backbone atoms is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl fused with substituted or 4 unsubstituted, 7- to 9-membered, monocyclic heterocyclyl fused with one or two substituted or unsubstituted phenyl. In some embodiments, the substituted or unsubstituted heteroarylene or 6 substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms is substituted or unsubstituted, 5- or 6-membered, monocyclic heterocyclylene. In some 8 embodiments, the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms is a moiety formed by a click-chemistry 10 reaction of a first and second click-chemistry reactive moieties. In some embodiments, the substituted or unsubstituted heteroarylene or substituted or 12 unsubstituted heterocyclylene that replaces one of the backbone atoms is of the formula: 14 16 k21 is 0, 1, 2, 3, or 4; 18 each instance of Rd, if present, is independently halogen, substituted or unsubstituted, C1-6alkyl, or –O–(substituted or unsubstituted, C1-6alkyl); k22 is 0, 1, 2, 3, or 4; 2 each instance of Re, if present, is independently halogen, substituted or unsubstituted, C1-6alkyl, or –O–(substituted or unsubstituted, C1-6alkyl); 4 k23 is an integer between 0 and 11, inclusive; each instance of Rf, if present, is independently halogen, substituted or unsubstituted, C1-66 alkyl, or –O–(substituted or unsubstituted, C1-6alkyl); and Rgis hydrogen, halogen, substituted or unsubstituted, C1-6alkyl, or –O–(substituted or 8 unsubstituted, C1-6alkyl). The substituted or unsubstituted heteroarylene or substituted or unsubstituted 10 heterocyclylene that replaces one of the backbone atoms may be attached at either direction. In certain embodiments, the substituted or unsubstituted heteroarylene that replaces one 12 of the backbone atoms is of the formula: 14 16 The substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms may be attached at any orientation. 18 In some embodiments, a linker is optionally substituted heteroalkenylene comprising one, two, three, four, five, six, seven, eight, nine, ten, or more than ten double bonds. In some 20 embodiments, a linker is optionally substituted heteroalkynylene comprising one, two, three, four, five, six, seven, eight, nine, ten, or more than ten triple bonds. In some embodiments, a linker is optionally substituted heteroalkylene, heteroalkenylene, or heteroalkynylene and 2 comprises one or more (e.g., two, three, four, or five) branch point. In certain embodiments, the linker comprises two, three, four, or five branch points. 4 In some embodiments, optionally substituted heteroalkylene is optionally substituted polyethylene glycol (optionally substituted PEG). In some embodiments, a terminal backbone 6 atom of the PEG is an attachment point. In some embodiments, an internal backbone atom of the PEG is an attachment point. In some embodiments, a linker comprises one or more PEG 8 repeating units (–OCH2CH2– or –CH2CH2O–). In certain embodiments, a linker comprises 2-3, 4-5, 6-7, 8-9, 10-11, 12-13, or 14-15 PEG repeating units. In certain embodiments, a linker 10 comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 PEG repeating units. In some embodiments, a linker comprises one or more (e.g., two, three, or four) PEG. 12 In some embodiments, a linker comprises a moiety formed by a Michael addition reaction of a Michael donor and a Michael acceptor. In some embodiments, the Michael donor is an 14 enolate. In some embodiments, the Michael acceptor is a moiety comprising α,β-unsaturated- carbonyl. In some embodiments, the Michael donor is –SH. In some embodiments, the Michael 16 accep . In some embodiments, a linker is a combination of –CH2 , , , –O–, 18 –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, , provided that: 20 the number of backbone atoms of the linker is between 2 and 6, between 7 and 12, between 13 and 20, between 21 and 30, between 31 and 40, between 41 and 50, between 51 and 22 60, between 61 and 80, between 81 and 100, inclusive; and the linker does not comprise O–O, O–N, N–O, or N–N. , , 4 the number of backbone atoms of the linker is between 7 and 70, inclusive; and the linker does not comprise O–O, O–N, N–O, or N–N. 6 In some embodiments, a linker is a combination of –CH2–, provided 8 that: the number of backbone atoms of the linker is between 2 and 6, between 7 and 12, 10 between 13 and 20, between 21 and 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, or between 81 and 100, inclusive; 12 the linker does not comprise O–O, O–N, N–O, or N–N; and the combined number of –C(=O)NH–, –NHC(=O) , , of the 14 linker is between 0 and 4, inclusive. In some embodiments, a linker is a combination of –CH2–, , , –O–, , provided that: 18 the number of backbone atoms of the linker is between 7 and 70, inclusive; the linker does not comprise O–O, O–N, N–O, or N–N; and the combined number of –C(=O)NH–, –NHC(=O) of the 2 linker is between 0 and 4, inclusive. In some embodiments, a linker is –CH2 , , , –O–, 4 –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, , or a combination of two or more instances of each one of the 6 foregoing, or a combination of two or more of the foregoing, provided that: the number of backbone atoms of the linker is between 2 and 6, between 7 and 12, 8 between 13 and 20, between 21 and 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, between 81 and 100, inclusive; and 10 the linker does not comprise O–O, O–N, N–O, or N–N. In some embodiments, a linker is –CH2 , –O–, 12 –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, , o , or a combination of two or more instances of each one of the 14 foregoing, or a combination of two or more of the foregoing, provided that: the number of backbone atoms of the linker is between 7 and 70, inclusive; and 16 the linker does not comprise O–O, O–N, N–O, or N–N. In some embodiments, a linker is –CH2, 18 –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O) , , , or a combination of two or more instances of each one of the foregoing, or a combination of two or 20 more of the foregoing, provided that: the number of backbone atoms of the linker is between 2 and 6, between 7 and 12, 2 between 13 and 20, between 21 and 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, or between 81 and 100, inclusive; 4 the linker does not comprise O–O, O–N, N–O, or N–N; and the combined number of –C(=O)NH–, –NHC(=O)– , , of the 6 linker is between 0 and 4, inclusive. In some embodiments, a linker is –CH2– 8 –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC (=O)–, , or , or a combination of two or more instances of each one of the foregoing, or a combination of two or 10 more of the foregoing, provided that: the number of backbone atoms of the linker is between 7 and 70, inclusive; 12 the linker does not comprise O–O, O–N, N–O, or N–N; and the combined number of –C(=O)NH–, –NHC(=O)– of the 14 linker is between 0 and 4, inclusive. In some embodiments, a linker includes –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, 16 –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, or –N(CH3)C(=O)–. In some embodiments, a linker is a combination of any two or more (e.g., three, four, five, six, seven, eight, nine, or ten) of 18 –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, and –N(CH3)C(=O)–, provided that the number of backbone atoms of the instance of the linker is 20 between 7 and 70, inclusive; and the instance of the linker does not comprise O–O, O–N, N–O, or N–N. 22 In certain embodiments, a linker comprises a cleavable bond or moiety. In certain embodiments, a linker does not comprise a cleavable bond or moiety. In certain embodiments, a 24 linker comprises a covalent attachment to a solid support. In certain embodiments, a linker includes multiple positions for attachment of radicals of ligands. In certain embodiments, the linker comprises a peptide in the backbone of the linker. In 2 certain embodiments, the peptide comprises 1-5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, or 36- 40, inclusive, amino acids. 4 In certain embodiments, a linker includes pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), 6- 6 aminohexanoic acid (ΑΗΕΧ or AHA), or a combination thereof. In some embodiments, y1 of an instance is 0, and L1thereof is 8 hydrogen, halogen, substituted or unsubstituted, C1-6alkyl, substituted or unsubstituted, C2-6alkenyl, substituted or unsubstituted, C2–6heteroalkyl, substituted or unsubstituted, monocyclic 10 carbocyclyl, substituted or unsubstituted, monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted, monocyclic heteroaryl, –CN, –ORb, –SCN, –SRb, –SSRb, –12 N3, –NO, –N(Rb)2, –NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, – S(=O)ORb, –S(=O)SRb, –S(=O)N(Rb)2, –S(=O)2Rb, –S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –14 OC(=O)Rb, –OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, – OS(=O)SRb, –OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –16 ON(Rb)2, –SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, – NRbC(=O)ORb, –NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –18 NRbS(=O)SRb, –NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, or – NRbS(=O)2N(Rb)2. 20 In some embodiments,y1 of an instance is 0, and L1thereof is hydrogen, halogen, substituted or unsubstituted, C1-6alkyl, substituted or unsubstituted, C2–622 alkenyl, substituted or unsubstituted, C2-6heteroalkyl, –CN, –ORb, –SCN, –SRb, –SSRb, –N3, – NO, –N(Rb)2, –NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –24 S(=O)ORb, –S(=O)SRb, –S(=O)N(Rb)2, –S(=O)2Rb, –S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, – OC(=O)Rb, –OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –26 OS(=O)SRb, –OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, – ON(Rb)2, –SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, – 28 NRbC(=O)ORb, –NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, – NRbS(=O)SRb, –NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, or – 30 NRbS(=O)2N(Rb)2. In certain embodiments, y1 of an instance o is 0, and L1thereof is 32 hydrogen halogen substituted or unsubstituted C1-6alkyl –ORbor –N(Rb)2In certain embodiments, y1 of an instance o is 0, and L1thereof is hydrogen, halogen, 2 or substituted or unsubstituted, C1-6alkyl. In certain embodiments, y1 of an instance of is 0, and L1thereof is hydrogen. In some embodiments, each instance of Rbis 4 independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, each instance of Rbis independently hydrogen. In certain 6 embodiments, each instance of Rbis independently unsubstituted alkyl. In certain embodiments, each instance of Rbis independently CH3, CH2CH3, or CH2CH2CH3. 8 In some embodiments, at least one instance o , if present, is of the formula: 10 ; each of –L1A1–L1A2–, –L1A3–L1A4–, –L1A5–L1A6–, and –L1A7–L1A8– is independently a12 single bond, –O–, –S–, –S–S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, – C(=O)NRa–, –C(=NRa)NRa–, –S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–,14 –OS(=O)2–, –NRaC(=O)–, –NRaC(=NRa)–, –NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, – OC(=NRa)O–, –OS(=O)O–, –OS(=O)2O–, –NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, –16 NRaS(=O)2O–, –OC(=O)NRa–, –OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, – NRaC(=O)NRa–, –NRaC(=NRa)NRa–, –NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, –18 C(=NRa)–, –S(=O)–, –S(=O)2–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or – OP(=O)(SRa)O–; 20 each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when 22 attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted 24 or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L1B1and L1B2is independently a single bond, substituted or unsubstituted, C1-10026 alkylene, or substituted or unsubstituted, C1-100heteroalkylene; L1C1is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the 28 backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; and 30 bond C1Ais attached to A1. In some embodiments, each of –L1A1–L1A2–, –L1A3–L1A4–, –L1A5–L1A6–, and –L1A7–L1A8– 2 is independently a single bond, –O–, –NRa–, –C(=O)NRa–, or –NRaC(=O)–. In some embodiments, each of –L1A1–L1A2–, –L1A3–L1A4–, –L1A5–L1A6–, and –L1A7–L1A8– is 4 independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In certain embodiments, each of –L1A1–L1A2–, –L1A3–L1A4–, –L1A5–L1A6–, and –L1A7–L1A8– is independently a single bond, 6 –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L1A1–L1A2–, –L1A3–L1A4–, – L1A5–L1A6–, and –L1A7–L1A8– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In 8 some embodiments, at least one of –L1A1–L1A2–, –L1A3–L1A4–, –L1A5–L1A6–, and –L1A7–L1A8– is independently –C(=O)O–, –OC(=O)–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–,10 or –OP(=O)(SRa)O–. In some embodiments, at least one of –L1A1–L1A2–, –L1A3–L1A4–, –L1A5– L1A6–, and –L1A7–L1A8– is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, – 12 SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Rais independently hydrogen or 14 substituted or unsubstituted, C1-6alkyl. In some embodiments, each instance of Rais independently hydrogen or substituted or unsubstituted, C1-6alkyl. In certain embodiments, each 16 instance of Rais independently hydrogen or unsubstituted C1-6alkyl. In some embodiments, each of L1B1and L1B2is independently a single bond, substituted 18 or unsubstituted, C1-20alkylene or substituted or unsubstituted, C1-20heteroalkylene. In some embodiments, each of L1B1and L1B2is independently substituted or unsubstituted, C1-10alkylene 20 or substituted or unsubstituted, C1-10heteroalkylene. In certain embodiments, each of L1B1and L1B2is independently unsubstituted C1-10alkylene. In certain embodiments, each of L1B1and L1B222 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, L1C1is a single bond. In certain embodiments, L1C1is substituted 24 or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, (which may be attached at either direction). 26 In some embodiments, L1thereof is of the formula: . 28 In certain embodiments, at least one instance of –L1A7–L1A8– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L1A7–L1A8– is –NH–C(=O)– or 30 –C(=O)–NH–. In certain embodiments, at least one instance of –L1A7–L1A8– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L1A7–L1A8– is –O–. In certain 2 embodiments, at least one instance of –L1A7–L1A8– is –NH–. In certain embodiments, at least one instance of –L1A7–L1A8– is –C(=O)–. In certain embodiments, at least one instance of –L1A7– 4 L1A8– is a single bond. In certain embodiments, L1thereof is of the formula: . In certain embodiments, y1 of an instance o is 1, 2, 3, 4, 5, or 6, and L18 thereof is substituted or unsubstituted, C7-70heteroalkylene. In some embodiments, at least one instance o is of the formula: 10 ; each of –L2A1–L2A2–, –L2A3–L2A4–, –L2A5–L2A6–, and –L2A7–L2A8– is independently a12 single bond, –O–, –S–, –S–S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, – C(=O)NRa–, –C(=NRa)NRa–, –S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–,14 –OS(=O)2–, –NRaC(=O)–, –NRaC(=NRa)–, –NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, – OC(=NRa)O–, –OS(=O)O–, –OS(=O)2O–, –NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, –16 NRaS(=O)2O–, –OC(=O)NRa–, –OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, – NRaC(=O)NRa–, –NRaC(=NRa)NRa–, –NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, –18 C(=NRa)–, –S(=O)–, –S(=O)2–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or – OP(=O)(SRa)O–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a 2 nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two 4 instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; 6 each of L2B1and L2B2is independently a single bond, substituted or unsubstituted, C1-100alkylene, or substituted or unsubstituted, C1-100heteroalkylene; 8 L2C1is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone 10 atoms; and bond C2Ais attached to A2. 12 In some embodiments, each of –L2A1–L2A2–, –L2A3–L2A4–, –L2A5–L2A6–, and –L2A7–L2A8– is independently a single bond, –O–, –NRa–, –C(=O)NRa–, or –NRaC(=O)–. In some 14 embodiments, each of –L2A1–L2A2–, –L2A3–L2A4–, –L2A5–L2A6–, and –L2A7–L2A8– is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In certain embodiments, 16 each of –L2A1–L2A2–, –L2A3–L2A4–, –L2A5–L2A6–, and –L2A7–L2A8– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L2A1–L2A2–, –L2A3–L2A4–, – 18 L2A5–L2A6–, and –L2A7–L2A8– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –L2A1–L2A2–, –L2A3–L2A4–, –L2A5–L2A6–, and –L2A7–L2A8– is 20 independently –C(=O)O–, –OC(=O)–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–. In some embodiments, at least one of –L2A1–L2A2–, –L2A3–L2A4–, –L2A5–22 L2A6–, and –L2A7–L2A8– is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, – SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. 24 In some embodiments, at least one instance of Rais independently hydrogen or substituted or unsubstituted, C1-6alkyl. In some embodiments, each instance of Rais 26 independently hydrogen or substituted or unsubstituted, C1-6alkyl. In certain embodiments, each instance of Rais independently hydrogen or unsubstituted C1-6alkyl. 28 In some embodiments, each of L2B1and L2B2is independently a single bond, substituted or unsubstituted, C1–20alkylene or substituted or unsubstituted, C1–20heteroalkylene. In some 30 embodiments, each of L2B1and L2B2is independently substituted or unsubstituted, C1-10alkylene or substituted or unsubstituted, C1-10heteroalkylene. In certain embodiments, each of L2B1and 32 L2B2is independently unsubstituted C1-10alkylene. In certain embodiments, each of L2B1and L2B2independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, L2C1is a single bond. In certain embodiments, L2C1is substituted 2 or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, L2 s (which may be attached at either direction). 4 In some embodiments, at least one instance o is of the formula: . 6 In certain embodiments, at least one instance of –L2A7–L2A8– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L2A7–L2A8– is –NH–C(=O)– or 8 –C(=O)–NH–. In certain embodiments, at least one instance of –L2A7–L2A8– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L2A7–L2A8– is –O–. In certain 10 embodiments, at least one instance of –L2A7–L2A8– is –NH–. In certain embodiments, at least one instance of –L2A7–L2A8– is –C(=O)–. In certain embodiments, at least one instance of –L2A7– 12 L2A8– is a single bond. In certain embodiments, at least one instance of is of the formula: 14 . In certain embodiments, at least one instance of is of the form . 16 In certain embodiments, at least one instance o is of the formula:

[0006] . 2 In some embodiments, at least one instanc of the formula: ; 4 each of –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, –L2A15–L2A16–, –L2A17–L2A18–, – L2A19–L2A20–, –L2A21–L2A22–, and –L2A23–L2A24– is independently a single bond, –O–, –S–, –S– 6 S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, –C(=O)NRa–, –C(=NRa)NRa–, – S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–, –OS(=O)2–, –NRaC(=O)–, – 8 NRaC(=NRa)–, –NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, –OC(=NRa)O–, –OS(=O)O–, – OS(=O)2O–, –NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, –NRaS(=O)2O–, –OC(=O)NRa–,10 –OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, –NRaC(=O)NRa–, –NRaC(=NRa)NRa–, – NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, –C(=NRa)–, –S(=O)–, –S(=O)2–, – 12 OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a 14 nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted 2 or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L2B3, L2B4, L2B5, L2B6, L2B7, and L2B8is independently a single bond, substituted or 4 unsubstituted, C1-100alkylene, or substituted or unsubstituted, C1-100heteroalkylene; each of L2C2and L2C3is independently a single bond, substituted or unsubstituted 6 heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; 8 bond C2Bis attached to a first instance of A2; and bond C2Cis attached to a second instance of A2. 10 In some embodiments, each of –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, –L2A15– L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, and –L2A23–L2A24– is independently a12 single bond, –O–, –NRa–, –C(=O)NRa–, or –NRaC(=O)–. In some embodiments, each of –L2A9– L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, –L2A15–L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, –L2A21–14 L2A22–, and –L2A23–L2A24– is independently a single bond, –O–, –NH–, –C(=O)NH–, or – NHC(=O)–. In certain embodiments, each of –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, – 16 L2A15–L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, and –L2A23–L2A24– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L2A9–L2A10–, –18 L2A11–L2A12–, –L2A13–L2A14–, –L2A15–L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, and – L2A23–L2A24– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some 20 embodiments, at least one of –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, –L2A15–L2A16–, – L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, and –L2A23–L2A24– is independently –C(=O)O–, – 22 OC(=O)–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–. In some embodiments, at least one of –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, –L2A15–L2A16–, –24 L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, and –L2A23–L2A24– is independently –C(=O)O–, – OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. 26 In some embodiments, at least one instance of Rais independently hydrogen or substituted or unsubstituted, C1-6alkyl. In some embodiments, each instance of Rais 28 independently hydrogen or substituted or unsubstituted, C1-6alkyl. In certain embodiments, each instance of Rais independently hydrogen or unsubstituted C1-6alkyl. 30 In some embodiments, each of L2B3, L2B4, L2B5, L2B6, L2B7, and L2B8is independently a single bond, substituted or unsubstituted, C1-20alkylene or substituted or unsubstituted, C1-2032 heteroalkylene. In some embodiments, each of L2B3, L2B4, L2B5, L2B6, L2B7, and L2B8is independently substituted or unsubstituted, C1-10alkylene or substituted or unsubstituted, C1-1034 heteroalkylene. In certain embodiments, each of L2B3, L2B4, L2B5, L2B6, L2B7, and L2B8is independently unsubstituted C1-10alkylene. In certain embodiments, each of L2B3, L2B4, L2B5, 2 L2B6, L2B7, and L2B8independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. 4 In certain embodiments, each of L2C2and L2C3is independently a single bond. In certain embodiments, each of L2C2and L2C3is independently substituted or unsubstituted heteroarylene 6 that replaces one of the backbone atoms. In certain embodiments, each of L2C2and L2C3is independe n y (which may be attached at either direction). 8 In some embodiments, at least one instanc of the formula: . 10 In certain embodiments, at least one instance of –L2A17–L2A18– is –NRa–C(=O)– or –C(=O)–NRa–. In certain embodiments, at least one instance of –L2A17–L2A18– is –NH–C(=O)– or 12 –C(=O)–NH–. In certain embodiments, at least one instance of –L2A17–L2A18– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L2A17–L2A18– is –O–. In certain 14 embodiments, at least one instance of –L2A17–L2A18– is –NH–. In certain embodiments, at least one instance of –L2A17–L2A18– is –C(=O)–. In certain embodiments, at least one instance of – 16 L2A17–L2A18– is a single bond. In certain embodiments, at least one instance of –L2A23–L2A24– is –NRa–C(=O)– or 18 –C(=O)–NRa–. In certain embodiments, at least one instance of –L2A23–L2A24– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L2A23–L2A24– is –O–C(=O)– or –C(=O)–O–. In certain embodiments, at least one instance of –L2A23–L2A24– is –O–. In certain 2 embodiments, at least one instance of –L2A23–L2A24– is –NH–. In certain embodiments, at least one instance of –L2A23–L2A24– is –C(=O)–. In certain embodiments, at least one instance of – 4 L2A23–L2A24– is a single bond. In certain embodiments, at least one instanc of the formula: . In certain embodiments, y2 of an instance o is 1, 2, 3, 4, 5, or 6, and L28 thereof is substituted or unsubstituted, C7-70heteroalkylene. In some embodiments, the moiety of Formula I is part of an instance of the modified 10 nucleoside at the 5’ end or an internal position of the modified oligonucleotide strand; y3 thereof is 0; and L3thereof is an internucleosidic linker, e.g., phosphate internucleosidic linker, 12 phosphorothioate internucleosidic linker, or methylphosphonate internucleosidic linker. In some embodiments, the moiety of Formula I is part of an instance of the modified nucleoside at the 3’14 end of the modified oligonucleotide strand; y3 thereof is 0; L3thereof is –OH, –ORd, halogen, – CN, or –N3; and each instance of Rdis independently substituted or unsubstituted, C1-6alkyl, or 16 an oxygen protecting group. In certain embodiments, L3is –OH, –OCH3, or F. In some embodiments, the moiety of Formula I is part of an instance of the modified nucleoside at the 3’ 18 end of the modified oligonucleotide strand; y3 thereof is 1, 2, 3, 4, 5, or 6; and L3thereof is a linker. In some embodiments, at least one instance of is of the formula: 2 . In some embodiments, at least one instance of is of the formula: . 4 In some embodiments, at least one instance o is of the formula: ; 6 each of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, and –L3A7–L3A8– is independently a single bond, –O–, –S–, –S–S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, – 8 C(=O)NRa–, –C(=NRa)NRa–, –S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–, –OS(=O)2–, –NRaC(=O)–, –NRaC(=NRa)–, –NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, –10 OC(=NRa)O–, –OS(=O)O–, –OS(=O)2O–, –NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, – NRaS(=O)2O–, –OC(=O)NRa–, –OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, – 12 NRaC(=O)NRa–, –NRaC(=NRa)NRa–, –NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, – C(=NRa)–, –S(=O)–, –S(=O)2–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or – 14 OP(=O)(SRa)O–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a 16 nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two 18 instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; 20 each of L3B1and L3B2is independently a single bond, substituted or unsubstituted, C1-100alkylene, or substituted or unsubstituted, C1-100heteroalkylene; 22 L3C1is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone 24 atoms; and bond C3Ais attached to A3. 26 In some embodiments, each of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, and –L3A7–L3A8– is independently a single bond, –O–, –NRa–, –C(=O)NRa–, or –NRaC(=O)–. In some 28 embodiments, each of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, and –L3A7–L3A8– is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In certain embodiments, 2 each of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, and –L3A7–L3A8– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L3A1–L3A2–, –L3A3–L3A4–, – 4 L3A5–L3A6–, and –L3A7–L3A8– is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, and –L3A7–L3A8– is 6 independently –C(=O)O–, –OC(=O)–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–. In some embodiments, at least one of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5– 8 L3A6–, and –L3A7–L3A8– is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, – SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. 10 In some embodiments, at least one instance of Rais independently hydrogen or substituted or unsubstituted, C1-6alkyl. In some embodiments, each instance of Rais 12 independently hydrogen or substituted or unsubstituted, C1-6alkyl. In certain embodiments, each instance of Rais independently hydrogen or unsubstituted C1-6alkyl. 14 In some embodiments, each of L3B1and L3B2is independently a single bond, substituted or unsubstituted, C1–20alkylene or substituted or unsubstituted, C1–20heteroalkylene. In some 16 embodiments, each of L3B1and L3B2is independently substituted or unsubstituted, C1-10alkylene or substituted or unsubstituted, C1-10heteroalkylene. In certain embodiments, each L3B1and L3B218 is independently unsubstituted C1-10alkylene. In certain embodiments, each of L3B1and L3B2independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. 20 In certain embodiments, L3C1is a single bond. In certain embodiments, L3C1is substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, 2 (which may be attached at either direction). : 2 . In certain embodiments, at least one instance of –L3A7–L3A8– is –NRa–C(=O)– or 26 –C(=O)–NRa–. In certain embodiments, at least one instance of –L3A7–L3A8– is –NH–C(=O)– or –C(=O)–NH–. In certain embodiments, at least one instance of –L3A7–L3A8– is –O–C(=O)– or 28 –C(=O)–O–. In certain embodiments, at least one instance of –L3A7–L3A8– is –O–. In certain embodiments, at least one instance of –L3A7–L3A8– is –NH–. In certain embodiments, at least one instance of –L3A7–L3A8– is –C(=O)–. In certain embodiments, at least one instance of –L3A7– 2 L3A8– is a single bond. In certain embodiments, at least one instance o is of the formula: . In some embodiments, y3 is 1; an thereof is 6 ; each of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, and –L3A7–L3A8– is independently a 8 single bond, –O–, –S–, –S–S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, – C(=O)NRa–, –C(=NRa)NRa–, –S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–,10 –OS(=O)2–, –NRaC(=O)–, –NRaC(=NRa)–, –NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, – OC(=NRa)O–, –OS(=O)O–, –OS(=O)2O–, –NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, –12 NRaS(=O)2O–, –OC(=O)NRa–, –OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, – NRaC(=O)NRa–, –NRaC(=NRa)NRa–, –NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, –14 C(=NRa)–, –S(=O)–, –S(=O)2–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or – OP(=O)(SRa)O–; 16 each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when 18 attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted 20 or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L3B1and L3B2is independently a single bond, substituted or unsubstituted, C1-1002 alkylene, or substituted or unsubstituted, C1-100heteroalkylene; L3C1is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the 4 backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. 6 In some embodiments, y3 there thereof is ; 8 each of –L3A9–L3A10–, –L3A11–L3A12–, –L3A13–L3A14–, –L3A15–L3A16–, –L3A17–L3A18–, – L3A19–L3A20–, and –L3A21–L3A22– is independently a single bond, –O–, –S–, –S–S–, –NRa–, –10 C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, –C(=O)NRa–, –C(=NRa)NRa–, –S(=O)NRa–, – S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–, –OS(=O)2–, –NRaC(=O)–, –NRaC(=NRa)–, –12 NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, –OC(=NRa)O–, –OS(=O)O–, –OS(=O)2O–, – NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, –NRaS(=O)2O–, –OC(=O)NRa–, – 14 OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, –NRaC(=O)NRa–, –NRaC(=NRa)NRa–, – NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, –C(=NRa)–, –S(=O)–, –S(=O)2–, – 16 OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a 18 nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two 20 instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; 22 each of L3B3, L3B4, L3B5, L3B6, and L3B7is independently a single bond, substituted or unsubstituted, C1-100alkylene, or substituted or unsubstituted, C1-100heteroalkylene; and 24 each of L3C2and L3C3is independently a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted 26 heteroarylene that replaces one of the backbone atoms. In some embodiments, each of –L3A9–L3A10–, –L3A11–L3A12–, –L3A13–L3A14–, –L3A15–28 L3A16–, –L3A17–L3A18–, –L3A19–L3A20–, and –L3A21–L3A22– is independently a single bond, –O–, – NRa–, –C(=O)NRa–, or –NRaC(=O)–. In some embodiments, each of –L3A9–L3A10–, –L3A11– 2 L3A12–, –L3A13–L3A14–, –L3A15–L3A16–, –L3A17–L3A18–, –L3A19–L3A20–, and –L3A21–L3A22– is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In certain embodiments, 4 each of –L3A9–L3A10–, –L3A11–L3A12–, –L3A13–L3A14–, –L3A15–L3A16–, –L3A17–L3A18–, –L3A19– L3A20–, and –L3A21–L3A22– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In 6 certain embodiments, each of –L3A9–L3A10–, –L3A11–L3A12–, –L3A13–L3A14–, –L3A15–L3A16–, – L3A17–L3A18–, –L3A19–L3A20–, and –L3A21–L3A22– is independently a single bond, –C(=O)NH–, or 8 –NHC(=O)–. In some embodiments, at least one of –L3A9–L3A10–, –L3A11–L3A12–, –L3A13–L3A14–, –L3A15–L3A16–, –L3A17–L3A18–, –L3A19–L3A20–, and –L3A21–L3A22– is independently –C(=O)O–, – 10 OC(=O)–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–. In some embodiments, at least one of –L3A9–L3A10–, –L3A11–L3A12–, –L3A13–L3A14–, –L3A15–L3A16–, –12 L3A17–L3A18–, –L3A19–L3A20–, and –L3A21–L3A22– is independently –C(=O)O–, –OC(=O)–, – OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. 14 In some embodiments, at least one instance of Rais independently hydrogen or substituted or unsubstituted, C1-6alkyl. In some embodiments, each instance of Rais 16 independently hydrogen or substituted or unsubstituted, C1-6alkyl. In certain embodiments, each instance of Rais independently hydrogen or unsubstituted C1-6alkyl. 18 In some embodiments, each of L3B3, L3B4, L3B5, L3B6, and L3B7is independently a single bond, substituted or unsubstituted, C1–20alkylene or substituted or unsubstituted, C1–2020 heteroalkylene. In some embodiments, each of L3B3, L3B4, L3B5, L3B6, and L3B7is independently substituted or unsubstituted, C1-10alkylene or substituted or unsubstituted, C1-10heteroalkylene. In 22 certain embodiments, each L3B3, L3B4, L3B5, L3B6, and L3B7is independently unsubstituted C1-10alkylene. In certain embodiments, each of L3B3, L3B4, L3B5, L3B6, and L3B7independently consists 24 of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L3C2and L3C3is independently a single bond. In certain 26 embodiments, each of L3C2and L3C3is independently substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, each of L3C2and L3C3is 28 independe (which may be attached at either direction). In certain embodiments, y3 is 2; and thereof is , . In some embodiments, at least once instanc , when present, is between the 6 first and second nucleosides of the modified oligonucleotide strand counted from the 5’ end. In certain embodiments, at least one instan , when present, is between the first n 8 and n+1 nucleosides of the modified oligonucleotide strand counted from the 5’ end; and n is an integer between 2 and 20, inclusive, as the number of nucleosides of the modified 10 oligonucleotide strand permits. In some embodiments, at least one instance of LA, when present, is of the formula: 1 ; each instance of ZA1and ZA2is independently a single bond, substituted or unsubstituted, 2 C1-6alkylene, or substituted or unsubstituted, C2–6alkenylene; each instance of WAis independently a radical, as valency permits, of substituted or 4 unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, 6 substituted or unsubstituted heteroarylene, -O-, -OP(=O)(ORc)O-, -N(Rc)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRc-, -NRcC(=O)-, -C(=O)Rc-, -NRcC(=O)O-, -NRcC(=O)NRc-, -OC(=O)-, 8 -OC(=O)O-, -OC(=O)N(Rc)-, -S(=O)2NRc-, -NRcS(=O)2-, or a combination thereof; each instance of Rcis independently hydrogen, substituted or unsubstituted acyl, 10 substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 12 heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, 14 substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two instances of RC16 are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and 18 bond C4Ais attached to L4. In some embodiments, at least one instance of ZA1is substituted or unsubstituted, C1-620 alkylene. In some embodiments, at least one instance of ZA1is substituted or unsubstituted, C1-3alkylene. In certain embodiments, at least one instance of ZA1is unsubstituted C1–3alkylene. In 22 some embodiments, at least one instance of ZA2is substituted or unsubstituted, C1-6alkylene. In some embodiments, at least one instance of ZA2is substituted or unsubstituted, C1–3alkylene. In 24 certain embodiments, at least one instance of ZA2is unsubstituted C1-3alkylene. In some embodiments, WAis -N(Rc)-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRc-, or 26 -NRcC(=O)-. In certain embodiments, WAis -N(Rc)-, -C(=O)NRc-, or -NRcC(=O)-. In some embodiments, each instance of Rcis independently hydrogen, substituted or 28 unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In some embodiments, at least one instance of LA, when present, is of the formula when present, is of the formula . 4 In certain embodiments, at least one instance of LA, when present, is of the formula ; each of –L4A1–L4A2–, –L4A3–L4A4–, –L4A5–L4A6–, –L4A7–L4A8–, –L4A17–L4A18–, and – 10 L4A19–L4A20– is independently a single bond, –O–, –S–, –S–S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, –C(=O)NRa–, –C(=NRa)NRa–, –S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–,12 –OC(=NRa)–, –OS(=O)–, –OS(=O)2–, –NRaC(=O)–, –NRaC(=NRa)–, –NRaS(=O)–, – NRaS(=O)2–, –OC(=O)O–, –OC(=NRa)O–, –OS(=O)O–, –OS(=O)2O–, –NRaC(=O)O–, –14 NRaC(=NRa)O–, –NRaS(=O)O–, –NRaS(=O)2O–, –OC(=O)NRa–, –OC(=NRa)NRa–, – OS(=O)NRa–, –OS(=O)2NRa–, –NRaC(=O)NRa–, –NRaC(=NRa)NRa–, –NRaS(=O)NRa–, –16 NRaS(=O)2NRa–, –C(=O)–, –C(=NRa)–, –S(=O)–, –S(=O)2–, –OP(=O)(ORa)O–, – SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–; 18 each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when 20 attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted 22 or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L4B1, L4B2, and L4B3is independently a single bond, substituted or unsubstituted, 2 C1-100alkylene, or substituted or unsubstituted, C1-100heteroalkylene; each of L4C1and L4C2is a single bond, substituted or unsubstituted heterocyclylene that 4 replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; and 6 bond C4Ais attached to A4. In some embodiments, each of –L4A1–L4A2–, –L4A3–L4A4–, –L4A5–L4A6–, –L4A7–L4A8–, – 8 L4A17–L4A18–, and –L4A19–L4A20– is independently a single bond, –O–, –NRa–, –C(=O)NRa–, or – NRaC(=O)–. In some embodiments, each of –L4A1–L4A2–, –L4A3–L4A4–, –L4A5–L4A6–, –L4A7–10 L4A8–, –L4A17–L4A18–, and –L4A19–L4A20– is independently a single bond, –O–, –NH–, – C(=O)NH–, or –NHC(=O)–. In certain embodiments, each of –L4A1–L4A2–, –L4A3–L4A4–, –L4A5–12 L4A6–, –L4A7–L4A8–, –L4A17–L4A18–, and –L4A19–L4A20– is independently a single bond, – C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L4A1–L4A2–, –L4A3–L4A4–, –L4A5–14 L4A6–, –L4A7–L4A8–, –L4A17–L4A18–, and –L4A19–L4A20– is independently a single bond, – C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –L4A1–L4A2–, –L4A3–L4A4–, –16 L4A5–L4A6–, –L4A7–L4A8–, –L4A17–L4A18–, and –L4A19–L4A20– is independently –C(=O)O–, – OC(=O)–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–. In18 some embodiments, at least one of –L4A1–L4A2–, –L4A3–L4A4–, –L4A5–L4A6–, –L4A7–L4A8–, – L4A17–L4A18–, and –L4A19–L4A20– is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, – 20 SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O–. In some embodiments, at least one instance of Rais independently hydrogen or 22 substituted or unsubstituted, C1-6alkyl. In some embodiments, each instance of Rais independently hydrogen or substituted or unsubstituted, C1-6alkyl. In certain embodiments, each 24 instance of Rais independently hydrogen or unsubstituted C1-6alkyl. In some embodiments, each of L4B1, L4B2, and L4B3is independently a single bond, 26 substituted or unsubstituted, C1–20alkylene or substituted or unsubstituted, C1–20heteroalkylene. In some embodiments, each of L4B1, L4B2, and L4B3is independently substituted or unsubstituted, C1- 28 10 alkylene or substituted or unsubstituted, C1-10heteroalkylene. In certain embodiments, each of L4B1, L4B2, and L4B3is independently unsubstituted C1-10alkylene. In certain embodiments, each 30 of L4B1, L4B2, and L4B3independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. 32 In certain embodiments, each of L4C1and L4C2is independently a single bond. In certain embodiments, each of L4C1and L4C2is independently substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. In certain embodiments, each of L4C1and L4C2is 2 independe n y (which may be attached at either direction). In some embodiments, at least one instance of y4 is 2; and thereof is ; each of –L4A21–L4A22–, –L4A23–L4A24–, –L4A25–L4A26–, –L4A27–L4A28–, –L4A29–L4A30–, – 6 L4A31–L4A32–, –L4A33–L4A34–, –L4A35–L4A36–, –L4A37–L4A38–, –L4A39–L4A40–, –L4A41–L4A42–, – L4A43–L4A44–, –L4A45–L4A46–, –L4A47–L4A48–, and –L4A49–L4A50– is independently a single bond, – 8 O–, –S–, –S–S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, –C(=O)NRa–, – C(=NRa)NRa–, –S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–, –OS(=O)2–, –10 NRaC(=O)–, –NRaC(=NRa)–, –NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, –OC(=NRa)O–, – OS(=O)O–, –OS(=O)2O–, –NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, –NRaS(=O)2O–, –12 OC(=O)NRa–, –OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, –NRaC(=O)NRa–, – NRaC(=NRa)NRa–, –NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, –C(=NRa)–, –S(=O)–, – 14 S(=O)2–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a 16 nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two 18 instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; 20 each of L4B4, L4B5, L4B6, L4B7, L4B8, L4B9, L4B10, L4B11, and L4B12is independently a single bond, substituted or unsubstitute -100alkylene, or substituted or unsubstituted, C1-10022 heteroalkylene; each of L4C3, L4C4, L4C5, L4C6, L4C7, and L4C8is a single bond, substituted or unsubstituted 2 heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; 4 bond C4Bis attached to a first instance of A4; and bond C4Cis attached to a second instance of A4. 6 In some embodiments, each of –L4A21–L4A22–, –L4A23–L4A24–, –L4A25–L4A26–, –L4A27– L4A28–, –L4A29–L4A30–, –L4A31–L4A32–, –L4A33–L4A34–, –L4A35–L4A36–, –L4A37–L4A38–, –L4A39– 8 L4A40–, –L4A41–L4A42–, –L4A43–L4A44–, –L4A45–L4A46–, –L4A47–L4A48–, and –L4A49–L4A50– is independently a single bond, –O–, –NRa–, –C(=O)NRa–, or –NRaC(=O)–. In some embodiments,10 each of –L4A21–L4A22–, –L4A23–L4A24–, –L4A25–L4A26–, –L4A27–L4A28–, –L4A29–L4A30–, –L4A31– L4A32–, –L4A33–L4A34–, –L4A35–L4A36–, –L4A37–L4A38–, –L4A39–L4A40–, –L4A41–L4A42–, –L4A43–12 L4A44–, –L4A45–L4A46–, –L4A47–L4A48–, and –L4A49–L4A50– is independently a single bond, –O–, – NH–, –C(=O)NH–, or –NHC(=O)–. In certain embodiments, each of –L4A21–L4A22–, –L4A23–14 L4A24–, –L4A25–L4A26–, –L4A27–L4A28–, –L4A29–L4A30–, –L4A31–L4A32–, –L4A33–L4A34–, –L4A35– L4A36–, –L4A37–L4A38–, –L4A39–L4A40–, –L4A41–L4A42–, –L4A43–L4A44–, –L4A45–L4A46–, –L4A47– 16 L4A48–, and –L4A49–L4A50– is independently a single bond, –C(=O)NRa–, or –NRaC(=O)–. In certain embodiments, each of –L4A21–L4A22–, –L4A23–L4A24–, –L4A25–L4A26–, –L4A27–L4A28–, –18 L4A29–L4A30–, –L4A31–L4A32–, –L4A33–L4A34–, –L4A35–L4A36–, –L4A37–L4A38–, –L4A39–L4A40–, – L4A41–L4A42–, –L4A43–L4A44–, –L4A45–L4A46–, –L4A47–L4A48–, and –L4A49–L4A50– is independently20 a single bond, –C(=O)NH–, or –NHC(=O)–. In some embodiments, at least one of –L4A21– L4A22–, –L4A23–L4A24–, –L4A25–L4A26–, –L4A27–L4A28–, –L4A29–L4A30–, –L4A31–L4A32–, –L4A33–22 L4A34–, –L4A35–L4A36–, –L4A37–L4A38–, –L4A39–L4A40–, –L4A41–L4A42–, –L4A43–L4A44–, –L4A45– L4A46–, –L4A47–L4A48–, and –L4A49–L4A50– is independently –C(=O)O–, –OC(=O)–, – 24 OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–. In some embodiments, at least one of –L4A21–L4A22–, –L4A23–L4A24–, –L4A25–L4A26–, –L4A27–L4A28–, –26 L4A29–L4A30–, –L4A31–L4A32–, –L4A33–L4A34–, –L4A35–L4A36–, –L4A37–L4A38–, –L4A39–L4A40–, – L4A41–L4A42–, –L4A43–L4A44–, –L4A45–L4A46–, –L4A47–L4A48–, and –L4A49–L4A50– is independently28 –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or – OP(=O)(SH)O–. 30 In some embodiments, at least one instance of Rais independently hydrogen or substituted or unsubstituted, C1-6alkyl. In some embodiments, each instance of Rais 32 independently hydrogen or substituted or unsubstituted, C1-6alkyl. In certain embodiments, each instance of Rais independently hydrogen or unsubstituted C1-6alkyl. In some embodiments, each of L4B4, L4B5, L4B6, L4B7, L4B8, L4B9, L4B10, L4B11, and L4B12is 2 independently a single bond, substituted or unsubstituted, C1–20alkylene or substituted or unsubstituted, C1-20heteroalkylene. In some embodiments, each of L4B4, L4B5, L4B6, L4B7, L4B8, 4 L4B9, L4B10, L4B11, and L4B12is independently substituted or unsubstituted, C1-10alkylene or substituted or unsubstituted, C1-10heteroalkylene. In certain embodiments, each of L4B4, L4B5, 6 L4B6, L4B7, L4B8, L4B9, L4B10, L4B11, and L4B12is independently unsubstituted C1-10alkylene. In certain embodiments, each of L4B4, L4B5, L4B6, L4B7, L4B8, L4B9, L4B10, L4B11, and L4B128 independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, each of L4C3, L4C4, L4C5, L4C6, L4C7, and L4C8is independently a 10 single bond. In certain embodiments, each of L4C3, L4C4, L4C5, L4C6, L4C7, and L4C8is independently substituted or unsubstituted heteroarylene that replaces one of the backbone atoms. 12 In certain embodiments, each of L4C3, L4C4, L4C5, L4C6, L4C7, and L4C8is independently (which may be attached at either direction). 14 In certain embodiments, a linker is a linker described in the following references: U.S. 5,994,517; U.S.6,300,319; U.S.6,660,720; U.S.6,906,182; U.S.7,262,177; U.S.7,491,805; U.S. 16 8,106,022; U.S.7,723,509; U.S.9,127,276; U.S.2006 / 0148740; U.S.2011 / 0123520; WO 2013 / 033230; WO 2012 / 037254, Biessen et al., J. Med. Chem.1995, 38, 1846-1852; Lee et al., 18 Bioorganic & Medicinal Chemistry 2011,19, 2494-2500; Rensen et al., J. Biol. Chem.2001, 276, 37577-37584; Rensen et al., J. Med. Chem.2004, 47, 5798-5808; Sliedregt et al., J. Med. Chem. 20 1999, 42, 609-618; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Lee, Carbohydr. Res.1978, 67, 509-514; Connolly et al., J. Biol. Chem.1982, 257, 939-945; Pavia et al., Int. J. Pep. Protein 22 Res.1983, 22, 539-548; Lee et al., Biochem.1984, 23, 4255-4261; Lee et al., Glycoconjugate J. 1987, 4, 317-328; Toyokuni et al., Tetrahedron Lett.1990, 31, 2673-2676; Biessen et al., J. Med. 24 Chem.1995, 38, 1538-1546; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Kim et al., Tetrahedron Lett.1997, 38, 3487-3490; Lee et al., Bioconjug. Chem.1997, 8, 762-765; Kato et 26 al., Glycobiol.2001, 11, 821-829; Rensen et al., J. Biol. Chem.2001, 276, 37577-37584; Lee et al., Methods Enzymol.2003, 362, 38-43; Westerlind et al., Glycoconj. J.2004, 21, 227-241; Lee 28 et al., Bioorg. Med. Chem. Lett.2006, 16(19), 5132-5135; Maierhofer et al., Bioorg. Med. Chem. 2007, 15, 7661-7676; Khorev et al., Bioorg. Med. Chem.2008, 16, 5216-5231; Lee et al., 30 Bioorg. Med. Chem.2011, 19, 2494-2500; Kornilova et al., Analyt. Biochem.2012, 425, 43-46; Pujol et al., Angew. Chemie Int. Ed. Engl.2012, 51, 7445-7448; Biessen et al., J. Med. Chem. 32 1995, 38, 1846-1852; Sliedregt et al., J. Med. Chem.1999, 42, 609-618; Rensen et al., J. Med. Chem.2004, 47, 5798-5808; Rensen et al., Arterioscler. Thromh. Vase. Biol.2006, 26, 169-175; van Rossenberg et al., Gene Ther.2004, 11, 457-464; Sato et al., J. Am. Chem. Soc.2004, 126, 2 14013-14022; Lee et al., J. Org. Chem.2012, 77, 7564-7571; Biessen et al., FASEB J.2000, 14, 1784-1792; Rajur et al., Bioconjug. Chem.1997, 8, 935-940; Duff et al., Methods Enzymol. 4 2000, 313, 297-321; Maier et al., Bioconjug. Chem.2003, 14, 18-29; Jayaprakash et al., Org. Lett.2010, 12, 5410-5413; Manoharan, Antisense Nucleic Acid Drug Dev.2002, 12, 103-128; 6 Merwin et al., Bioconjug. Chem.1994, 5, 612-620; Tomiya et al., Bioorg. Med. Chem., 2013, 21, 5275-5281; International Applications WO 1998 / 013381; WO 2011 / 038356; WO 1997 / 046098; 8 WO 2008 / 098788; WO 2004 / 101619; WO 2012 / 037254; WO 2011 / 120053; WO 2011 / 100131; WO 2011 / 163121; WO 2012 / 177947; WO 2013 / 033230; WO 2013 / 075035; WO 2012 / 083185; 10 WO 2012 / 083046; WO 2009 / 082607; WO 2009 / 134487; WO 2010 / 144740; WO 2010 / 148013; WO 1997 / 020563; WO 2010 / 088537; WO 2002 / 043771; WO 2010 / 129709; WO 2012 / 068187; 12 WO 2009 / 126933; WO 2004 / 024757; WO 2010 / 054406; WO 2012 / 089352; WO 2012 / 089602; WO 2013 / 166121; WO 2013 / 165816; U.S. Patent Nos.4,751,219; 7,582,744; 8,552,163; 14 8,137,695; 6,908,903; 6,383,812; 7,262,177; 6,525,031; 5,994,517; 6,660,720; 6,300,319; 7,723,509; 8,106,022; 7,491,805; 7,491,805; 8,541,548; 8,344,125; 8,313,772; 8,349,308; 16 8,450,467; 8,501,930; 8,158,601; 7,262,177; 6,906,182; 6,620,916; 8,435,491; 8,404,862; 7,851,615; U.S. Patent Application Publications Nos. U.S.2011 / 0097264; U.S.2011 / 0097265; 18 U.S.2013 / 0004427; U.S.2003 / 0119724; U.S.2011 / 0207799; U.S.2012 / 0035115; U.S. 2012 / 0230938; U.S.2005 / 0164235; U.S.2006 / 0183886; U.S.2012 / 0136042; U.S. 20 2012 / 0095075; U.S.2013 / 0109817; U.S.2006 / 0148740; U.S.2008 / 0206869; U.S. 2012 / 0165393; U.S.2012 / 0101148; U.S.2013 / 0121954; U.S.2011 / 0123520; U.S. 22 2003 / 0077829; U.S.2008 / 0108801; and U.S.2009 / 0203132. In certain embodiments, a linker comprises a structure selected from: 2 In certain embodiments, a linker comprises a structure selected from: , , wherein each n is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 2 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, a linker comprises a structure selected from:

[0007] , wherein each L is, independently, a phosphotriester, alkylphosphonate, 6 phosphoramidate, phosphorothioate, phosphorodithioate, or phosphorothiolate; and each n is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. 8 In certain embodiments, a linker comprises a structure selected from: , 1

[0008] each n is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. 4 In certain embodiments, a linker comprises a structure selected from: , wherein each n is, independently, 1, 2, 3, 4, 5, 6, 7, 2 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, a linker comprises a structure selected from: 1 , wherein each n is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 2 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, a linker comprises a structure selected from: , wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. 6 In certain embodiments, a linker comprises a structure selected from: 8 wherein each n is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. 10 In certain embodiments, a linker comprises a structure selected from: 12 each n is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, a linker comprises a structure selected from: 1 , wherein each n is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. 16 In certain embodiments, a linker comprises the structure: In certain embodiments, a linker comprises the structure: , wherein each n is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. 4 Ligands 6 In an oligonucleotide of the present disclosure, each instance of each of A1, A2, A3, and A4, if present, may independently be a radical of a ligand. 8 Two or more ligands may be attached to the same or different positions of the corresponding linker, as valency permits. For example, when y is 2, the two 10 instances of A1may be attached to the same position of L1or two different positions of L1, as valency permits. 12 In some embodiments, at least one instance of A1, if present, is a radical of a ligand. In certain embodiments, at least two instances of A1, if present, are radicals of ligands. In some 14 embodiments, at least one instance of A2, if present, is a radical of a ligand. In certain embodiments, at least two instances of A2, if present, are radicals of ligands. In some 16 embodiments, at least one instance of A3, if present, is a radical of a ligand. In certain embodiments, at least two instances of A3, if present, are radicals of ligands. In some 18 embodiments, at least one instance of A4, if present, is a radical of a ligand. In certain embodiments, at least two instances of A4, if present, are radicals of ligands. In some 20 embodiments, at least one ligand is a central nervous system receptor ligand. In certain embodiments, at least one ligand is a TrkB receptor ligand. In certain embodiments, at least one22 ligand is a selective TrkB modulator. In certain embodiments, at least one ligand is a non- selective TrkB modulator (i.e., a pan TrkABC modulator). In certain embodiments, at least one 24 ligand is a CB1receptor ligand. In certain embodiments, at least one ligand is an α4β1 / 7integrin receptor ligands. In certain embodiments, at least one ligand is an NMDA receptor ligand. In 26 some embodiments, a ligand directs an oligonucleotide to a location in a subject. In some embodiments, a ligand targets a tissue. In some embodiments, the tissue is brain tissue. In some 28 embodiments, the ligand targets an organ. In some embodiments, the organ is a brain. In some embodiments, a ligand targets a cell. 30 In some embodiments, a ligand targets a cell receptor. In certain embodiments, a cell receptor is a TrkB receptor, a CB1 receptor, an α4β1 / 7integrin receptor, or an NMDA receptor. In 32 some embodiments, a receptor is in the brain. In some embodiments, a receptor is in the frontal cortex. In some embodiments, a receptor is in the striatum. In some embodiments, a receptor is in 2 the cerebellum. In some embodiments, a receptor is in the brain stem. In some embodiments, a receptor is in the hippocampus. In some embodiments, a receptor is in the spinal cord. In some 4 embodiments, a ligand is used to target an oligonucleotide to a cell type. In some embodiments, the cell is a central nervous system cell. In certain embodiments, the cell is a neuron. In certain 6 embodiments, the cell is a glial cell. In certain embodiments, the cell is an astrocyte. In certain embodiments, the cell is an oligodendrocyte. In certain embodiments, the cell is an ependymal 8 cell. In certain embodiments, the cell is a microglia. In some embodiments, a ligand is an agonist of a receptor (e.g., a TrkB, CB1, α4β1 / 710 integrin, or NMDA receptor agonist). In some embodiments, a ligand is an antagonist of a receptor (e.g., a TrkB, CB1, α4β1 / 7integrin, or NMDA receptor antagonist). 12 In some embodiments, the oligonucleotides provided herein include at least one TrkB ligand that is a radical of a compound of the formula: 14 16 2 R2is hydrogen, -OR7, -SR8, or -NR9R10; R3is hydrogen, -OR31, -SR32, or -NR33R34; 4 R4is hydrogen, -OR35, -SR36, or -NR37R38; R5is hydrogen, -OR39, -SR40, or -NR41R42; 6 R6is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH2, optionally substituted -NHAc, -SH, or =O; 8 R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, 10 optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 12 Y is CH2, NH, S, or O; Z is optionally substituted aryl or optionally substituted heteroaryl; 14 R11and R13are each independently absent, hydrogen, or optionally substituted alkyl; R12, R14, and R15are each independently hydrogen, optionally substituted alkyl, 16 optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 18 R16is hydrogen, halogen, –CN, –N3, –SOn16R1A, –SOv16NR16BR16C, -NHNR16BR16C, -ONR16BR16C, -NHC(O)NHNR16BR16C, -NHC(O)NR16BR16C, –N(O)m16, –NR16BR16C,20 –C(O)R16D, –C(O)OR16D, –C(O)NR16BR16C, –OR16A, -NR16BSO2R16A, -NR16BC(O)R16D, - NR16BC(O)OR16D, –NR16BOR16D, optionally substituted alkyl, optionally substituted heteroalkyl, 22 optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 24 a are each independently a single bond or a double bond, wherein if is a single bond, t is a double bond, and R13is absent; and further wherein if is a single 26 bond, en is a double bond, and R11is absent; R16A, R16B, R16C, R16Dare each independently hydrogen, halogen, –CF3, –CCl3, –CBr3, 28 –CI3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, 2 substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R16Band R16Csubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or 4 unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R17, R18, and R19are each independently hydrogen, optionally substituted alkyl, 6 optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 8 R20is hydrogen, halogen, –CN, –N3, –SOn20R1A, –SOv20NR20BR20C, -NHNR20BR20C, -ONR20BR20C, -NHC(O)NHNR20BR20C, -NHC(O)NR20BR20C, –N(O)m20, –NR20BR20C, 10 –C(O)R20D, –C(O)OR20D, –C(O)NR20BR20C, –OR20A, -NR20BSO2R20A, -NR20BC(O)R20D, -NR20BC(O)OR20D, –NR20BOR20D, optionally substituted alkyl, optionally substituted heteroalkyl, 12 optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 14 R21is hydrogen, halogen, –CN, –N3, –SOn21R1A, –SOv21NR21BR21C, -NHNR21BR21C, -ONR21BR21C, -NHC(O)NHNR21BR21C, -NHC(O)NR21BR21C, –N(O)m21, –NR21BR21C, 16 –C(O)R21D, –C(O)OR21D, –C(O)NR21BR21C, –OR21A, -NR21BSO2R21A, -NR21BC(O)R21D, -NR21BC(O)OR21D, –NR21BOR21D, optionally substituted alkyl, optionally substituted heteroalkyl, 18 optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 20 R22and R23are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, 22 optionally substituted aryl, or optionally substituted heteroaryl; R24is hydrogen, halogen, –CN, –N3, –SOn24R1A, –SOv24NR24BR24C, -NHNR24BR24C, 24 -ONR24BR24C, -NHC(O)NHNR24BR24C, -NHC(O)NR24BR24C, –N(O)m24, –NR24BR24C, –C(O)R24D, –C(O)OR24D, –C(O)NR24BR24C, –OR24A, -NR24BSO2R24A, -NR24BC(O)R24D, 26 –NR24BC(O)OR24D, –NR24BOR24D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally 28 substituted aryl, or optionally substituted heteroaryl; R20A, R20B, R20C, R20D, R21A, R21B, R21C, R21D, R24A, R24B, R24C, and R24Dare each 30 independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –Cl3,–COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 32 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R20B, R20C, R21B, R21C, R24B, R24C, R24B, and R24C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or 2 unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; n16, n20, n21, n23, n24, z6, and z8 are each independently 0, 1, 2, 3, or 4; 4 v16, v20, v21, m16, m20, m21, and m24 are each independently 1 or 2; z3 is 0, 1, 2, 3, 4, or 5; 6 z4 and z7 are each independently 0, 1, or 2; z5 is 0, 1, 2, or 3; and 8 z6 and z8 are each independently 0, 1, 2, 3, or 4. In some embodiments, R2is hydrogen or -OR7. In certain embodiments, R2is hydrogen. 10 In certain embodiments, R2is -OR7. In certain embodiments, R2is -OH. In certain embodiments, R2is -OCH3. In some embodiments, R3is hydrogen or -OR31. In certain embodiments, R3is 12 hydrogen. In certain embodiments, R3is -OR31. In certain embodiments, R3is -OH. In certain embodiments, R3is -OCH3. In some embodiments, R4is hydrogen or -OR35. In certain 14 embodiments, R4is hydrogen. In certain embodiments, R4is -OR35. In certain embodiments, R4is -OH. In certain embodiments, R4is -OCH3. In some embodiments, R5is hydrogen or -OR39. In 16 certain embodiments, R5is hydrogen. In certain embodiments, R5is -OR39. In certain embodiments, R5is -OH. In certain embodiments, R5is -OCH3. In some embodiments, R6is 18 hydrogen, -OH, or optionally substituted -O-alkyl. In certain embodiments, R6is hydrogen. In some embodiments, R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, 20 and R42are each independently hydrogen or optionally substituted alkyl. In certain embodiments, R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently 22 hydrogen. In certain embodiments, R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently optionally substituted alkyl. In certain embodiments, R7, R8, 24 R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently unsubstituted alkyl. In certain embodiments, R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, 26 R39, R40, R41, and R42are each independently -CH3. In some embodiments, Y is NH or O. In certain embodiments, Y is O. 28 In some embodiments, Z is optionally substituted aryl. In certain embodiments, Z is optionally substituted phenyl. In certain embodiments, Z is unsubstituted phenyl. 30 In certain embodiments, at least one radical of a TrkB ligand is of the formula certain embodiments, at least one radical of a TrkB ligand is of the formula , . 4 In some embodiments, R11and R13are each independently absent or hydrogen. In certain embodiments, R11and R13are each independently absent. In some embodiments, R12, R14, and 6 R15are each independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R12, R14, and R15are each independently hydrogen. In 8 certain embodiments, R12, R14, and R15are each independently optionally substituted alkyl. In certain embodiments, R12, R14, and R15are each independently unsubstituted alkyl. In certain 10 embodiments, R12is –CH3. In some embodiments, R16is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R16is hydrogen,12 halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R16is – NHCH3. 14 In some embodiments, R17, R18, and R19are each independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R17, R18, and R1916 are each independently hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments, R20is hydrogen, halogen, optionally substituted alkyl, or 18 optionally substituted heteroalkyl. In certain embodiments, R20is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R20is hydrogen. In 20 some embodiments, R21is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R21is hydrogen, halogen, unsubstituted alkyl, or 22 unsubstituted heteroalkyl. In certain embodiments, R21is hydrogen. In some embodiments, R22and R23are each independently hydrogen, optionally substituted alkyl, or optionally substituted 24 heteroalkyl. In certain embodiments, R22and R23are each independently hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R22and R23are each independently 2 hydrogen. In some embodiments, R24is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R24is hydrogen, halogen, 4 unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R24is hydrogen. In some embodiments, n16, n20, n21, n23, n24, z6, and z8 are each independently 0, 1, 2. 6 In certain embodiments, n16, n20, n21, n23, n24, z6, and z8 are each independently 0. In certain embodiments, v16, v20, v21, m16, m20, m21, and m24 are each independently 1. In certain 8 embodiments, v16, v20, v21, m16, m20, m21, and m24 are each independently 2. In some embodiments, z3 is 0, 1, 2, or 3. In certain embodiments, z3 is 0. In some embodiments, z4 and 10 z7 are each independently 0 or 1. In certain embodiments, z4 and z7 are each independently 0. In some embodiments, z5 is 0, 1, or 2. In certain embodiments, z5 is 0. In some embodiments, z6 12 and z8 are each independently 0, 1, or 2. In certain embodiments, z6 and z8 are each independently 0. 14 In some embodiments, at least one radical of a TrkB ligand is of the formula 1 , . 2 In some embodiments, at least one radical of a TrkB ligand is of the formula: . 4 In certain embodiments, at least one radical of a TrkB ligand is of the formula: , 6 8 In certain embodiments, at least one TrkB ligand is flavone, tropoflavin, or a derivative thereof. In certain embodiments, at least one TrkB ligand is 3,7-dihydroxyflavone, 3,7,8,2- 10 tetrahydroxyflavone, 7,3 -dihydroxyflavone, 7,8,2-trihydroxyflavone, 7,8,3 -trihydroxyflavone, 7,8,4-trihydroxyflavone, diosmetin (5,7,3 -trihydroxy-4-methoxyflavone), 7-hydroxy-4-12 methoxyflavone, 8-hydroxy-7-methoxyflavone, eutropoflavin (4-dimethylamino-7,8- dihydroxyflavone), norwogonin (5,7,8-trihydroxyflavone), R7, R13, tropoflavin (7,8- dihydroxyflavone), 7,8-dimethoxyflavone, quercetin (3,3',4,5,7-pentahydroxyflavone), apigenin 2 (4',5,7-trihydroxyflavone), isocoumarin, gossypetin (3,5,7,8 ',3',4-hexahydroxyflavone), 2- methyl-8-phenylchromeno[7,8-d]imidazol-6(3H)-one, 8-phenylchromeno[7,8-d]imidazol-6(3H)- 4 one, 4-oxo-2-phenyl-4H-chromene-7,8-diyl diacetate, or ANA-12. In some embodiments, at least one α4β1 / 7integrin ligand is a compound of the formula: , , ,

[0009] ,

[0010] . 4 In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula: 6 R2Zis hydrogen, polyethylene glycol, substituted or unsubstituted heteroalkyl, or substituted or unsubstituted heteroaryl; and 8 each of R3Zand R4Zis independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted –O–alkyl. In some embodiments, R2Zis hydrogen or substituted or unsubstituted heteroalkyl. In 2 certain embodiments, R2Zis hydrogen. In some embodiments, each of R3Zand R4Zis independently hydrogen or halogen. In certain embodiments, each of R3Zand R4Zis 4 independently halogen. In certain embodiments, at least one α4β1 / 7integrin ligand is of the formula: . In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula: 8 R4Zis hydrogen, halogen, polyethylene glycol, optionally substituted alkyl, optionally 10 substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted –O–alkyl, or optionally substituted cycloalkyl; 12 R5Zis optionally substituted heteroalkyl or optionally substituted heterocyclyl; and n1Z is 1, 2, or 3. 14 In some embodiments, R4Zis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R4Zis hydrogen. In some 16 embodiments, R5Zis optionally substituted heteroalkyl. In some embodiments, n1Z is 1 or 2. In certain embodiments, n1Z is 1. 18 In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula: ,

[0011] 2 ; R6Zis hydrogen, –OH, –NH2, –NHR7Z, –OR7Z, or absent; and 4 R7Zis hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. 6 In some embodiments, R6Zis hydrogen, –OH, –NH2, or absent. In certain embodiments, R6Zis hydrogen. In certain embodiments, R6Zis absent. In some embodiments, R7Zis hydrogen 8 or optionally substituted alkyl. In certain embodiments, R7Zis hydrogen or unsubstituted alkyl. In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula: 10 ,

[0012] 2 4 n2Z is 0, 1, 2, or 3. In some embodiments, n2Z is 0 or 1. In certain embodiments, n2Z is 0. 6 In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula: ,

[0013] 2 4 n3Z is 0, 1, 2, or 3. In some embodiments, n3Z is 0 or 1. In certain embodiments, n3Z is 0. 6 In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula: ,

[0014] 2 each of R8Z, R9Z, R10Z, and R11Zis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted –O–alkyl, or substituted or unsubstituted cycloalkyl; 4 each of R12Zand R13Zis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalk , nd R14Zis optionally substituted C1-C5alkyl, optionally substituted C1-C5alkylene-(C3-C6)- 8 cycloalkyl, or optionally substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, each of R8Z, R9Z, R10Z, and R11Zis independently hydrogen, 10 halogen, or optionally substituted alkyl. In certain embodiments, each of R8Z, R9Z, R10Z, and R11Zis independently optionally substituted alkyl. In certain embodiments, each of R8Z, R9Z, R10Z, and 12 R11Zis independently unsubstituted alkyl. In some embodiments, each of R12Zand R13Zis independently hydrogen, , or . In certain embodiments, each of R12Zand 14 R13Zis independently H or . In some embodiments, R14Zis optionally substituted C1- C5alkyl. In certain embodiments, R14Zis optionally substituted C4alkyl. 16 In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula:

[0015] . 2 In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula: 4 r 6 R15Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; 8 each of R16Zand R17Zis independently H, halogen, optionally substituted alkyl, or optionally substituted –O–alkyl; and 10 )2–. In some embodiments, R15Zis H, optionally substituted alkyl, or optionally substituted 2 heteroalkyl. In certain embodiments, R15Zis H. In some embodiments, each of R16Zand R17Zis independently H or optionally substituted alkyl. In certain embodiments, each of R16Zand R17Zis 4 independently H. In certain embodiments, YZis –CH2–. In certain embodiments, YZis –(CH2)2–. In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula: 6 ; 8 R18Zis H, –OH, –NH2, –NHR19Z, –OR19Z, or –CONHR19Z; each instance of R19Zis independently H, polyethylene glycol, optionally substituted 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and 12 n4Z is 1 or 2. In some embodiments, R18Zis H, –OH, or –NH2. In certain embodiments, R18Zis H. In 14 some embodiments, each instance of R19Zis independently H or optionally substituted alkyl. In certain embodiments, each instance of R19Zis independently H or unsubstituted alkyl. In certain 16 embodiments, n4Z is 1. In certain embodiments, n4Z is 2. In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula: 18 or ; R19Zis H, –CH2OR20Z, –(CH2)2OR20Z, –CH2NHCOR20Z, or –OR20Z; and 20 R20Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. 22 In some embodiments, R19Zis H or –CH2NHCOR20Z. In certain embodiments, R19Zis – CH2NHCOR20Z. In some embodiments, R20Zis H or optionally substituted alkyl. In certain 24 embodiments, R20Zis H or unsubstituted alkyl. In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula: 2 r ; 4 R21Zis H, –CONHR22Z, –CH2OR22Z, –(CH2)2OR22Z, –CH2NHCOR22Z, or –OR22Z; R22Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted 6 heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and X1Zis H or halogen. 8 In some embodiments, R21Zis H or –CH2NHCOR22Z. In certain embodiments, R21Zis – CH2NHCOR22Z. In some embodiments, R22Zis H or optionally substituted alkyl. In certain 10 embodiments, R22Zis H or unsubstituted alkyl. In certain embodiments, X1Zis H. In certain embodiments, X1Zis halogen. 12 In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula: r 14 ; R23Zis H, -CONHR24Z, -CH2OR24Z, -(CH2)2OR24Z, -CH2NHCOR24Z, or -OR24Z; 16 R24Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and 18 n5Z is 0, 1, 2, or 3. In some embodiments, R23Zis H or -CONHR24Z. In certain embodiments, R23Zis 2 -CONHR24Z. In some embodiments, R24Zis H or optionally substituted alkyl. In certain embodiments, R24Zis H or unsubstituted alkyl. In some embodiments, n5z is 0, 1, or 2. In certain, 4 embodiments, n5z is 1. In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula: , 6 R25Zis H, –CONHR27Z, –CH2OR27Z, –(CH2)2OR27Z, –CH2NHCOR27Z, or –OR27Z; R26Zis H, optionally substituted alkyl, or optionally substituted cycloalkyl; 8 R27Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and 10 X2Zis optionally substituted CH2or optionally substituted NH. In some embodiments, R25Zis H or –CH2NHCOR27Z. In certain embodiments, R25Zis – 12 CH2NHCOR27Z. In some embodiments, R26Zis H or optionally substituted alkyl. In some embodiments, R26Zis H or unsubstituted alkyl. In certain embodiments, R26Zis H or -CH3. In 14 some embodiments, R27Zis H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R27Zis H, unsubstituted alkyl, or unsubstituted heteroalkyl. In some 16 embodiments, X2Zis optionally substituted NH. In certain embodiments, X2Zis NH. In certain embodiments, at least one radical of an α4β1 / 7integrin ligand is of the formula: 2 4 R30Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; 6 R31Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and 8 n3Z is 1, 2, or 3. In some embodiments, R28Zis H, –CH2NHCOR30Z, or –OR30Z. In certain embodiments, 10 R28Zis –CH2NHCOR30Z. In some embodiments, R29Zis H, –OH, –NH2. In some embodiments, R30Zis H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain 12 embodiments, R30Zis H, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments, R31Zis H, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain 14 embodiments, R31Zis H, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, n3Z is 1. In certain embodiments, n3Z is 2. 16 In some embodiments, at least one CB1 ligand is a compound of the formula: ; 18 X1Yis NR10Yor CR11YR12Y; each of R10Y, R11Y, and R12Yis independently hydrogen, optionally substituted alkyl, 20 optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 22 R19Yis hydrogen, –SOn19YR19YA, –SOv19YNR19YBR19YC, -NHNR19YBR19YC, -ONR19YBR19YC, -NHC(O)NHNR19YBR19YC, -NHC(O)NR19YBR19YC, –NR19YBR19YC, – 24 C(O)R19YD, –C(O)OR19YD, –C(O)NR19YBR19YC, –OR19YA, -NR19YBSO2R19YA, -NR19YBC(O)R19YD, –NR19YBC(O)OR19YD, –NR19YBOR19YD, optionally substituted alkyl, optionally substituted 2 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 4 each of R19YA, R19YB, R19YC, and R19YDis independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted 6 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R19YBand R19YC8 bonded to the same nitrogen atom are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 10 n19Y is 0, 1, 2, 3, or 4; and v19Y is 1 or 2. 12 In some embodiments, X1Y 10Y. In certain embodiments, X1Yis NH. In some embodiments, R10Yis hydrogen, optionally substituted alkyl, or optionally substituted 14 heteroalkyl. In certain embodiments, R10Yis hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R10Yis hydrogen. In some embodiments, R19Yis hydrogen, 16 optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R19Yis hydrogen, unsubstituted alkyl, or unsubstituted heteroalkyl. 18 In certain embodiments, at least one radical of a CB1ligand is of the formula: . In certain embodiments, at least one radical of a CB1 ligand is of the 20 formula: . 22 In certain embodiments at least one CB1 ligand is a compound of the formula: , 2 wherein: R17Yis hydrogen, –SOn17YR17YA, –SOv17YNR17YBR17YC, -NHNR17YBR17YC, 4 -ONR17YBR17YC, -NHC(O)NHNR17YBR17YC, -NHC(O)NR17YBR17YC, –NR17YBR17YC, – C(O)R17YD, –C(O)OR17YD, –C(O)NR17YBR17YC, –OR17YA, –NR17YBSO2R17YA, – 6 NR17YBC(O)R17YD, –NR17YBC(O)OR17YD, –NR17YBOR17YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted 8 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each of R17YA, R17YB, R17YC, and R17YDis independently hydrogen, halogen, –CF3, –CCl3, 10 –CBr3, –Cl3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, 12 substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R17YBand R17YCsubstituents bonded to the same nitrogen atom may optionally be joined to form a 14 substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; n17Y is 0, 1, 2, 3, or 4; and 16 v17Y is 1 or 2. In some embodiments, R17Yis hydrogen, optionally substituted alkyl, optionally 18 substituted heteroalkyl, or –NR17YBR17YC. In certain embodiments, R17Yis –NR17YBR17YC. In certain embodiments, R17Yis –NH2. In some embodiments, each of R17YBand R17YCis 20 independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, each of R17YBand R17YCis independently hydrogen. 22 In certain embodiments, at least one radical of a CB1ligand is of the formula: . In certain embodiments, at least one CB1 ligand is a compound of the formula: 2 . In certain embodiments, at least one radical of a CB1 ligand is of the formula: 4 . In certain embodiments, at least one CB1 ligand is a compound of the formula: 6 , R3Y, R4Y, R5Y, R6Y, and R8Yare each independently hydrogen, halogen, optionally 8 substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 10 R9Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl; or R6Yand R9Ysubstituents may be joined together form an optionally substituted heterocycloalkyl or 12 optionally substituted heteroaryl; R7Yis hydrogen, –SOn7YR7YA, –SOv7YNR7YBR7YC, -NHNR7YBR7YC, -ONR7YBR7YC, 14 -NHC(O)NHNR7YBR7YC, -NHC(O)NR7YBR7YC, –NR7YBR7YC, –C(O)R7YD, –C(O)OR7YD, –C(O)NR7YBR7YC, –OR7YA, –NR7YBSO2R7YA, –NR7YBC(O)R7YD, –NR7YBC(O)OR7YD, 16 –NR7YBOR7YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or 18 optionally substituted heteroaryl; R7YA, R7YB, R7YC, R7YDare each independently hydrogen, halogen, –CF3, –CCl3, –CBr3, 20 –Cl3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 2 wherein R7YBand R7YCsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 4 n7Y is 0, 1, 2, 3, or 4; and v7Y is 1 or 2. 6 In some embodiments, R3Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R3Yis hydrogen. In certain 8 embodiments, R3Yis halogen. In some embodiments, R4Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R4Yis hydrogen. 10 In certain embodiments, R4Yis halogen. In some embodiments, R5Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R5Yis 12 hydrogen. In certain embodiments, R5Yis halogen. In some embodiments, R6Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain 14 embodiments, R6Yis hydrogen. In certain embodiments, R6Yis halogen. In some embodiments, R7Yis hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, or –C(O)R7YD. 16 In certain embodiments, R7Yis –C(O)R7YD. In some embodiments, R7YDis optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, R7YDis optionally substituted 18 aryl. In some embodiments, R8Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R8Yis optionally substituted heteroalkyl. In 20 certain embodiments, R8Yis substituted heteroalkyl. In some embodiments, R9Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R9Yis 22 hydrogen. In certain embodiments, at least one radical of a CB1 ligand is of the formula: 24 ,

[0016] . 2 , 4 R16Yis hydrogen, halogen, –CN, –N3, –NO2, –NR16YBR16YC, –C(O)R16YD, –C(O)OR16YD, –C(O)NR16YBR16YC, –OR16YA, –NR16YBC(O)R16YD, optionally substituted alkyl, optionally 6 substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and 8 R16YA, R16YB, R16YC, and R16YDare each independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted 10 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R16YBand R16YC12 bonded to the same nitrogen atom are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. 14 In some embodiments, R16Yis hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R16Yis hydrogen, halogen, 16 unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, at least one radical of a CB1 ligand is of the formula: 1 . In certain embodiments, at least one CB1 ligand is a compound of the formula:

[0017] . In certain embodiments, at least one radical of an NMDA receptor ligand is of the 2 form . In certain embodiments, at least one radical of an NMDA receptor embodiments, at least one radical of an NMDA receptor ligand is of the formula: . In certain embodiments, at least one radical of an NMDA receptor ligand is of In certain embodiments, at least one radical of an 8 NMDA receptor ligand is of the formul r . In certain embodiments, at least one radical of an NMDA receptor 10 ligand is of the formu In certain embodiments, at least one radical of an NMDA receptor ligand is of the formul . In certain embodiments, at least one 2 radical of an NMDA receptor ligand is of the formula least one radical of an NMDA receptor ligand is of the formula: 6 In some embodiments, a ligand is an antibody (e.g., an anti-TrkB, anti-CB1, anti-α4β1 / 7integrin, or anti-NMDA receptor antibody). In certain embodiments, a ligand is an antibody 8 fragment or an antibody variant. An “an anti-TrkB receptor antibody,” “anti-CB1receptor antibody,” “anti-α4β1 / 7integrin receptor antibody,” or “anti-NMDA receptor antibody” refers to 10 an immune system protein that recognizes, binds to, or otherwise interacts with a TrkB, CB1, α4β1 / 7integrin, or NMDA receptor, respectively. 12 In some embodiments, an oligonucleotide comprises at least two ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 ligands). In some embodiments, an oligonucleotide comprises two ligands. In 14 some embodiments, an oligonucleotide comprises three ligands. In some embodiments, an oligonucleotide comprises at least one ligand conjugated at the 5′-end. In some embodiments, an 16 oligonucleotide comprises at least one ligand conjugated at the 3′-end. In certain embodiments, an oligonucleotide comprises at least one ligand conjugated at the 5′-end and at least one ligand 18 conjugated at the 3′-end. In some embodiments, an oligonucleotide comprises at least two ligands conjugated at the 5′-end. In some embodiments, an oligonucleotide comprises at least two ligands 2 conjugated at the 3′-end. In certain embodiments, an oligonucleotide comprises at least two ligands conjugated at the 5′-end and at least two ligands conjugated at the 3′-end. In some 4 embodiments, an oligonucleotide comprises at least one ligand conjugated at a nucleobase. In some embodiments, an oligonucleotide comprises at least two ligands conjugated at a 6 nucleobase. In some embodiments, an oligonucleotide comprises at least one ligand conjugated at the 2′ position of a nucleoside. In some embodiments, an oligonucleotide comprises at least two 8 ligands conjugated at the 2′ position of a nucleoside. In some embodiments, at least two ligands are of the same ligand type. In some 10 embodiments, each ligand is of the same ligand type. In some embodiments, at least two ligands are the same. In some embodiments, at least two ligands are different ligands of the same ligand 12 type. In some embodiments, at least two ligands are of different ligand types. In some embodiments, none of the ligands are of the same ligand type. In certain embodiments, when 14 ligands are of the same ligand type, they bind the same target. In some embodiments, at least one ligand is a small molecule, peptide, or protein. 16 In some embodiments, each instance of A1is a radical of the same ligand type. In some embodiments, each instance of A1is the same radical of a ligand. In some embodiments, at least 18 two instances of A1are radicals of different ligand types. In some embodiments, at least two instances of A1are radicals of different ligands of the same ligand type. In some embodiments, at 20 least two instances of A1are radicals of different ligands of different ligand types. In some embodiments, each instance of A2is a radical of the same ligand type. In some 22 embodiments, each instance of A2is the same radical of a ligand. In some embodiments, at least two instances of A2are radicals of different ligand types. In some embodiments, at least two 24 instances of A2are radicals of different ligands of the same ligand type. In some embodiments, at least two instances of A2are radicals of different ligands of different ligand types. 26 In some embodiments, each instance of A3is a radical of the same ligand type. In some embodiments, each instance of A3is the same radical of a ligand. In some embodiments, at least 28 two instances of A3are radicals of different ligand types. In some embodiments, at least two instances of A3are radicals of different ligands of the same ligand type. In some embodiments, at 30 least two instances of A3are radicals of different ligands of different ligand types. In some embodiments, each instance of A4is a radical of the same ligand type. In some 32 embodiments, each instance of A4is the same radical of a ligand. In some embodiments, at least two instances of A4are radicals of different ligand types. In some embodiments, at least two instances of A4are radicals of different ligands of the same ligand type. In some embodiments, at 2 least two instances of A4are radicals of different ligands of different ligand types. In some embodiments, at least one instance of A1and at least one instance of A2are 4 radicals of the same ligand type. In some embodiments, at least one instance of A1and at least one instance of A2are the same radical of a ligand. In some embodiments, at least one instance of 6 A1and at least one instance of A2are radicals of different ligand types. In some embodiments, at least one instance of A1and at least one instance of A2are radicals of different ligands of the 8 same ligand type. In some embodiments, at least one instance of A1and at least one instance of A2are radicals of different ligands of different ligand types. In some embodiments, at least one 10 instance of A1and at least one instance of A3are radicals of the same ligand type. In some embodiments, at least one instance of A1and at least one instance of A3are the same radical of a 12 ligand. In some embodiments, at least one instance of A1and at least one instance of A3are radicals of different ligand types. In some embodiments, at least one instance of A1and at least 14 one instance of A3are radicals of different ligands of the same ligand type. In some embodiments, at least one instance of A1and at least one instance of A3are radicals of different 16 ligands of different ligand types. In some embodiments, at least one instance of A1and at least one instance of A4are radicals of the same ligand type. In some embodiments, at least one 18 instance of A1and at least one instance of A4are the same radical of a ligand. In some embodiments, at least one instance of A1and at least one instance of A4are radicals of different 20 ligand types. In some embodiments, at least one instance of A1and at least one instance of A4are radicals of different ligands of the same ligand type. In some embodiments, at least one instance 22 of A1and at least one instance of A4are radicals of different ligands of different ligand types. In some embodiments, at least one instance of A2and at least one instance of A3are radicals of the 24 same ligand type. In some embodiments, at least one instance of A2and at least one instance of A3are the same radical of a ligand. In some embodiments, at least one instance of A2and at least 26 one instance of A3are radicals of different ligand types. In some embodiments, at least one instance of A2and at least one instance of A3are radicals of different ligands of the same ligand 28 type. In some embodiments, at least one instance of A2and at least one instance of A3are radicals of different ligands of different ligand types. In some embodiments, at least one instance 30 of A2and at least one instance of A4are radicals of the same ligand type. In some embodiments, at least one instance of A2and at least one instance of A4are the same radical of a ligand. In 32 some embodiments, at least one instance of A2and at least one instance of A4are radicals of different ligand types. In some embodiments, at least one instance of A2and at least one instance 34 of A4are radicals of different ligands of the same ligand type. In some embodiments, at least one instance of A2and at least one instance of A4are radicals of different ligands of different ligand 2 types. In some embodiments, at least one instance of A3and at least one instance of A4are radicals of the same ligand type. In some embodiments, at least one instance of A3and at least 4 one instance of A4are the same radical of a ligand. In some embodiments, at least one instance of A3and at least one instance of A4are radicals of different ligand types. In some embodiments, at 6 least one instance of A3and at least one instance of A4are radicals of different ligands of the same ligand type. In some embodiments, at least one instance of A3and at least one instance of 8 A4are radicals of different ligands of different ligand types. In some embodiments, each instance of A1, A2, A3, and A4is the same radical of a ligand. 10 In some embodiments, each instance of A1, A2, A3, and A4is a different radical of a ligand compared to any other radical of a ligand in the oligonucleotide. In some embodiments, each 12 instance of A1, A2, A3, and A4is the same radical of a TrkB ligand. In some embodiments, each instance of A1, A2, A3, and A4is the same radical of a CB1 receptor ligand. In some 14 embodiments, each instance of A1, A2, A3, and A4is the same radical of an α4β1 / 7integrin receptor ligand. In some embodiments, each instance of A1, A2, A3, and A4is the same radical of 16 an NMDA receptor ligand. In some embodiments, each instance of A1, A2, A3, and A4is a different radical of a TrkB ligand, CB1 receptor ligand, α4β1 / 7integrin receptor ligand, and / or 18 NMDA receptor ligand. 20 Lipids In an oligonucleotide of the present disclosure, each instance of each of A1, A2, A3, and 22 A4, if present, is independently a radical of a ligand or lipid. In some embodiments, at least one instance of A1, if present, is a radical of a lipid. In some embodiments, at least one instance of A2, 24 if present, is a radical of a lipid. In some embodiments, at least one instance of A3, if present, is a radical of a lipid. In some embodiments, at least one instance of A4, if present, is a radical of a 26 lipid. In certain embodiments, at least one instance of A1, A2, A3, and A4, if present, is independently a radical of a lipid. 28 In some embodiments, each instance of A1is the same radical of a lipid. In some embodiments, each instance of A2is the same radical of a lipid. In some embodiments, each 30 instance of A3is the same radical of a lipid. In some embodiments, each instance of A4is the same radical of a lipid. 32 In some embodiments, at least one instance of A1and at least one instance of A2are the same radical of a lipid. In some embodiments, at least one instance of A1and at least one instance 34 of A3are the same radical of a lipid. In some embodiments, at least one instance of A1and at least one instance of A4are the same radical of a lipid. In some embodiments, at least one 2 instance of A2and at least one instance of A3are the same radical of a lipid. In some embodiments, at least one instance of A2and at least one instance of A4are the same radical of a 4 lipid. In some embodiments, at least one instance of A3and at least one instance of A4are the same radical of a lipid. 6 In some embodiments, each instance of A1, A2, A3, and A4is the same radical of a lipid. In some embodiments, each instance of A1, A2, A3, and A4is a different radical of a lipid 8 compared to any other radical of a lipid in the oligonucleotide. In some embodiments, at least one lipid is a fatty acyl, glycerolipid, glycerophospholipid, 10 sphingolipid, saccharolipid, polyketide, sterol lipid, or prenol lipid. In some embodiments, at least one lipid is a fatty acid or conjugate, octadecanoid, eicosanoid, docosanoid, fatty alcohol, 12 fatty aldehyde, fatty ester, fatty amide, fatty nitrile, fatty ether, hydrocarbon, oxygenated hydrocarbon, or fatty acyl glycoside. 14 In some embodiments, at least one lipid is a hydrocarbon. In some embodiments, the hydrocarbon chain is saturated or unsaturated. In certain embodiments, an unsaturated 16 hydrocarbon chain comprises one, two, three, four, five, or six carbon-carbon double bonds (e.g., cis double bonds and / or trans double bonds). In some embodiments, at least one radical 18 of a lipid is unsubstituted C7-36alkyl, C7-36alkyl substituted with one or more fluoro as valency permits, unsubstituted C7-36alkenyl, or C7-36alkenyl substituted with one or more fluoro as 20 valency permits. In certain embodiments, at least one radical of a lipid is unsubstituted C7-36alkyl or unsubstituted C7-36alkenyl. In certain embodiments, at least one radical of a lipid is22 unsubstituted C7-36alkyl. In some embodiments, at least one radical of a lipid is unsubstituted C7-20 alkyl, C7–20alkyl substituted with one or more fluoro as valency permits, unsubstituted C7–2024 alkenyl, or C7-20alkenyl substituted with one or more fluoro as valency permits. In certain embodiments, at least one radical of a lipid is unsubstituted C7–20alkyl or unsubstituted C7–2026 alkenyl. In certain embodiments, at least one radical of a lipid is unsubstituted C7–20alkyl. In some embodiments, at least one radical of a lipid is unsubstituted C21-28alkyl, C21-28alkyl 28 substituted with one or more fluoro as valency permits, unsubstituted C21-28alkenyl, or C21-28alkenyl substituted with one or more fluoro as valency permits. In certain embodiments, at least 30 one radical of a lipid is unsubstituted C21-28alkyl or unsubstituted C21-28alkenyl. In certain embodiments, at least one radical of a lipid is unsubstituted C21-28alkyl. In some embodiments, 32 at least one radical of a lipid is unsubstituted C29-36alkyl, C29-36alkyl substituted with one or more fluoro as valency permits, unsubstituted C29-36alkenyl, or C29-36alkenyl substituted with 34 one or more fluoro as valency permits. In certain embodiments, at least one radical of a lipid is unsubstituted C29-36alkyl or unsubstituted C29-36alkenyl. In certain embodiments, at least one 2 radical of a lipid is unsubstituted C29-36alkyl. In some embodiments, at least one radical of a lipid is unsubstituted C16-28alkyl or unsubstituted C16-28alkenyl, each of which is independently 4 unbranched, bi-branched, or tri-branched. In certain embodiments, the alkenyl described in this paragraph comprises one C=C bond. In certain embodiments, the alkenyl described in this 6 paragraph comprises two, three, or four C=C bond, as valency permits. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted C18-26alkyl. In certain embodiments, at 8 least one radical of a lipid is –(CH2)17CH3, –(CH2)18CH3, –(CH2)19CH3, –(CH2)20CH3, – (CH2)21CH3, –(CH2)22CH3, –(CH2)23CH3, –(CH2)24CH3, or –(CH2)25CH3. In certain 10 embodiments, at least one radical of a lipid is –(CH2)21CH3. In certain embodiments, at least one radical of a lipid is unbranched unsubstituted C18-26 alkenyl. In certain embodiments, at least one 12 radical of a lipid is unbranched unsubstituted C18-26alkenyl comprising one C=C bond. In certain embodiments, at least one lipid is a monoradylglycerol, diradylglycerol, 14 triradylglycerol, glycosylmonoradylglycerol, glycosyldiradylglycerol, betaine monoradylglycerol, or betaine diradylglycerol. 16 In certain embodiments, at least one lipid is a glycerophosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoglycerol, 18 glycerophosphoglycerophosphate, glycerophosphoinositol, glycerophosphoinositol monophosphate, glycerophosphoinositol bisphosphate, glycerophosphoinositol trisphosphate,20 glycerophosphate, glyceropyrophosphate, glycerophosphoglycerophosphoglycerol, CDP- glycerol, glycosylglycerophospholipid, glycerophosphoinositolglycan, glycerophosphonocholine, 22 glycerophosphonoethanolamine, di-glycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphoethanolamine glycan, 24 dihydroxyacetonephosphate, glycerophosphoethanol, glycerophosphothreonine, or cyclic glycerophosphatidic acid. 26 In certain embodiments, at least one lipid is a sphingoid base, ceramide, phosphosphingolipid, phosphonosphingolipid, neutral glycosphingolipid, acidic 28 glycosphingolipid, basic glycosphingolipid, amphoteric glycosphingolipid, or arsenosphingolipid. 30 In certain embodiments, at least one lipid is a sterol, steroid, secosteroid, bile acid, or a derivative thereof, or steroid conjugate. In certain embodiments, at least one lipid is cholesterol. 32 In certain embodiments, at least one radical of the lipid is of the formula: . 2 In certain embodiments, at least one lipid is lithocholic acid. In certain embodiments, at least one radical of the lipid is of the formula: 4 , In certain embodiments, at least one radical of the lipid is of the formula: 6 , optionally wherein the unsubstituted C7–30 alkyl is unbranched unsubstituted C11-23 alkyl, and the 8 unsubstituted C7-30alkenyl is unbranched unsubstituted C11-23alkenyl (optionally comprising one C=C bond, or optionally comprising two, three, or four C=C bonds). In certain embodiments, at 10 least one radical of the lipid is of the formula: . 12 In certain embodiments, at least one lipid is an isoprenoid, quinone, hydroquinone, polyprenol, or hopanoid. In certain embodiments, at least one lipid is an acylaminosugar, acylaminosugar glycan, 2 acyltrehalose, or acyltrehalose glycan. In certain embodiments, at least one lipid is a linear polyketide, halogenated acetogenin, 4 annonaceae acetogenin, macrolide, lactone polyketide, ansamycin, polyene, linear tetracycline, angucycline, polyether antibiotic, aflatoxin, cytochalasin, flavonoid, aromatic polyketide, non- 6 ribosomal peptide / polyketide hybrid, or phenolic lipid. 8 Additional Oligonucleotide Strand Modifications The modified oligonucleotide strands may further comprise additional modifications. In 10 certain embodiments, the modified oligonucleotide strand further comprises at least one modified sugar, at least one modified nucleobase, at least one modified internucleoside linkage, or a 12 combination thereof. In certain embodiments, a modified oligonucleotide strand further comprises 1, 2, 3, 4, 5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56- 14 60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100, inclusive, modified nucleosides. In certain embodiments, a modified oligonucleotide strand further comprises 1, 2, 3, 4, 5, 6-10,16 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76- 80, 81-85, 86-90, 91-95, or 96-100, inclusive, modified sugars. In certain embodiments, a 18 modified oligonucleotide strand further comprises 1, 2, 3, 4, 5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 20 96-100, inclusive, modified internucleoside linkages. When the oligonucleotides comprise additional oligonucleotide strands, e.g., antisense 22 oligonucleotide strands, the additional oligonucleotide strands may independently comprise one or more of the additional modifications described herein. 24 Sugar Modifications 26 Any modifications known in the art may be used in the oligonucleotides disclosed herein. In some embodiments, a modified sugar is used in the oligonucleotides disclosed herein. In 28 certain embodiments, a modified sugar is a substituted furanosyl sugar or non-bicyclic modified sugar. In certain embodiments, a modified sugar is a bicyclic or tricyclic modified sugar. In 30 certain embodiments, a modified sugar is a sugar surrogate. A sugar surrogate may comprise one or more substitutions described herein. 32 In certain embodiments, a modified sugar is a substituted furanosyl or non-bicyclic modified sugar. In certain embodiments, the furanosyl sugar is a ribosyl sugar. In certain embodiments, the furanosyl sugar comprises one or more substituent groups, including, but not 2 limited to, substituent groups at the 2′, 3′, 4′, and 5′ positions. In certain embodiments, substituents at the 2′ position include, but are not limited to, F 4 and OCH3(“OMe”, “O-methyl” or “methoxy”). In certain embodiments, substituent groups at the 2′ position suitable for non-bicyclic modified sugars include, but are not limited to, halo, 6 allyl, amino, azido, –SH, –CN, –OCN, –CF3, –OCF3, –F, –Cl, –Br, –SCH3, –SOCH3, –SO2CH3, –ΟΝΟ2, –ΝΟ2, –Ν3, and –ΝΗ2. In certain embodiments, substituent groups at the 2′ position 8 include, but are not limited to, –O-(C1-C10) alkoxy, alkoxyalkyl, –O-alkyl, –S-alkyl, –N-alkyl, –O-alkenyl, –S-alkenyl, –N-alkenyl, –O-alkynyl, –S-alkynyl, –N-alkynyl, –O-alkyl-O-alkyl, 10 alkynyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted C1to C10alkyl or C2to C10 alkenyl and alkynyl. In certain embodiments, substituent groups at the 2′ position 12 include, but are not limited to, alkaryl, aralkyl, –O-alkaryl, and –O-aralkyl. In certain embodiments, these 2′ substituent groups can be further substituted with one or more substituent 14 groups independently selected from hydroxyl, alkoxy, carboxy, benzyl, phenyl, nitro (–ΝΟ2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, 16 substituent groups at the 2′ position include, but are not limited to, –O[(CH2)hO]jCH3, –O(CH2)hOCH3, –O(CH2)hCH3, –O(CH2)hONH2, –O(CH2)hNH2, –O(CH2)hSCH3, and 18 –O(CH2)hON[(CH2)hCH3)]2, where h and j are independently from 1 to 10. In certain embodiments, substituent groups at the 2′ position include, but are not limited to, 20 –OCH2CH2OCH3(“MOE”), –O(CH2)2ON(CH3)2(“DMAOE”), –O(CH2)2O(CH2)2N(CH3)2(“DMAEOE”), and –OCH2C(=O)-N(H)CH3(“NMA”). 22 In certain embodiments, substituent groups at the 4′ position suitable for non-bicyclic modified sugars include, but are not limited to, alkoxy .g., methoxy), alkyl, and those described 24 in Manoharan et al., WO 2015 / 106128. In certain embodiments, substituent groups at the 5′ position suitable for non-bicyclic modified sugars include, but are not limited to, methyl (“Me”) 26 (R or S), vinyl, and methoxy. In certain embodiments, the 5' modification is a 5'-monophosphate ((HO)2(O)P-O-5'); 5'-diphosphate ((HO)2(O)P-O-P(HO)(O)-O-5'); 5'-triphosphate ((HO)2(O)P-28 O-(HO)(O)P-O-P(HO)(O)-O-5'); 5'-guanosine cap (7-methylated or non-methylated) (7m-G-O- 5'-(HO)(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5'); 5'adenosine cap (Appp), and any modified or30 unmodified nucleotide cap structure (N-O-5'(HO)(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5'); 5'- monothiophosphate (phosphorothioate; (HO)2(S)P-O-5'); 5'-monodithiophosphate 32 (phosphorodithioate; (HO)(HS)(S)P-O-5'), 5'phosphorothiolate ((HO)2(O)P-S-5'); any additional combination of oxygen / sulfur replaced monophosphate, diphosphate and triphosphates (e.g.5'- 34 alpha-thiotriphosphate, 5'-gammathiotriphosphate, etc.), 5'-phosphoramidates ((HO)2(O)P-NH-5', (HO)(NH2)(O)P-O-5'), 5'alkylphosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., e.g. 2 RP(OH)(O)-O-5'-, 5'alkenylphosphonates (i.e. vinyl, substituted vinyl), (OH)2(O)P-5'-CH2-), 5'alkyletherphosphonates (R=alkylether=methoxymethyl (MeOCH2-), ethoxymethyl, etc., e.g. 4 RP(OH)(O)-O-5'-). In certain embodiments, one or more sugars comprise a 5′-vinylphosphonate modification. In certain embodiments, one or more sugars comprise a 5′-ethylenephosphonate 6 modification. In certain embodiments the 5′ modification is at the terminus of an oligonucleotide. In certain embodiments the 5′ modification is at the terminus of an antisense oligonucleotide. In 8 certain embodiments, substituents described herein for the 2′, 4′, and 5′ position can be added to other specific positions on the sugar. In certain embodiments, such substituents may be added to 10 the 3′ position of the sugar on the 3′ terminal nucleoside or the 5′ position of the 5′ terminal nucleoside. In certain embodiments, a non-bicyclic modified sugar may comprise more than one 12 non-bridging sugar substituent. In certain such embodiments, non-bicyclic modified sugar substituents include, but are not limited to, 5′-Me-2′-F, 5′-Me-2′-OMe (including both R and S 14 isomers). In certain embodiments, modified sugar substituents include those described in Migawa et al., WO 2008 / 101157. 16 In certain embodiments, a modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed via a bridge connecting 18 two of the atoms in the first ring, thereby forming a bicyclic structure. In certain embodiments, a bicyclic sugar comprises a bridging substituent that bridges two atoms of the furanosyl ring to 20 form a second ring. In certain embodiments, a bicyclic sugar does not comprise a furanosyl moiety. A “bicyclic nucleoside” (“BNA”) is a nucleoside having a bicyclic sugar. In certain 22 embodiments, the bicyclic sugar comprises a bridge between the 4′ and 2′ furanose ring atoms. In certain embodiments, the bicyclic sugar comprises a bridge between the 5′ and 3′ furanose ring 24 atoms. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, 4′ to 2′ bridging substituents include, but are not limited to, 4'-CH2-2', 4'-(CH2)2-2', 4'- (CH2)3-2', 4'- 26 CH2-O-2' (“LNA”), 4'-CH2-S-2', 4'-(CH2)2-O-2' (“ENA”), 4'-CH(CH3)-O-2' (“constrained ethyl” or “cEt” when in the S configuration), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 4'- CH(CH2OCH3)-O-28 2' (“constrained MOE” or “cMOE”) and analogs thereof (e.g., U.S. Patent No.7,399,845), 4'- C(CH3)(CH3)-O-2' and analogs thereof (e.g., U.S. Patent No.8,278,283), 4'-CH2-N(OCH3)-2' and 30 analogs thereof (e.g., U.S. Patent No.8,278,425), 4'-CH2-O-N(CH3)-2' (e.g., U.S. Patent Publication No.2004 / 0171570), 4'-CH2-N(R)-O-2', wherein R is Η, C1-C12alkyl, or a protecting 32 group (e.g., U.S. Patent No.7,427,672), 4'-CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118- 134), and 4'-CH2-C(=CH2)-2' and analogs thereof (e.g., U.S. Patent 34 No.8,278,426). Additional representative U.S. Patents and U.S. Patent Publications that teach the preparation of bicyclic nucleic acid nucleotides include, but are not limited to, the following: 2 U.S. Patent Nos.6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133;7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 4 8,278,425; 8,278,426; 8,278,283; US 2008 / 0039618; US 2009 / 0012281; US 2013 / 0190383; and WO 2013 / 036868. Any of the foregoing bicyclic nucleosides can be prepared having one or more 6 stereochemical sugar configurations including, for example, α-L-ribofuranose and β-D- ribofuranose (see, e.g., WO 99 / 14226). Specified bicyclic nucleosides herein are in the β-D 8 configuration, unless otherwise specified. In certain embodiments, a modified sugar is a sugar surrogate. In certain embodiments, a 10 sugar surrogate has the oxygen atom replaced, e.g., with a sulfur, carbon or nitrogen atom. In certain such embodiments, the sugar surrogate may also comprise bridging and / or non-bridging 12 substituents as described herein. In certain embodiments, sugar surrogates comprise rings having other than 5 atoms. In certain such embodiments, the sugar surrogate comprises a cyclobutyl 14 moiety in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a six membered ring in place of the pentofuranosyl sugar. In certain embodiments, the 16 sugar surrogate comprises a tetrahydropyran (“THP”) in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a morpholino in place of the pentofuranosyl 18 sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Patent Nos.4,981,957; 5,118,800; 5,166,315; 5,185,444; 20 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 22 5,670,633; 5,700,920; 7,875,733; 7,939,677, 8,088,904; 8,440,803; and 9,005,906. In some embodiments, sugar surrogates comprise acyclic moieties. In certain 24 embodiments, the sugar surrogate is an unlocked nucleic acid (“UNA”). A UNA is unlocked acyclic nucleic acid, wherein any of the bonds of the sugar has been removed, forming an 26 unlocked “sugar” residue. In one example, UNA also encompasses a monomer where the bonds between C1′-C4′ have been removed (i.e., the covalent carbon-oxygen-carbon bond between the 28 C1′ and C4′ carbons). In another example, the C2′-C3′ bond (i.e., the covalent carbon-carbon bond between the C2′ and C3′ carbons) of the sugar has been removed. Representative U.S. 30 publications that teach the preparation of UNA include, but are not limited to, U.S. Patent No. 8,314,227; and U.S. Patent Publication Nos.2013 / 0096289; 2013 / 0011922; and 2011 / 0313020. 32 In certain embodiments, sugar surrogates comprise peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides 34 and oligonucleotides described in Manoharan et al., US 2013 / 130378. Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified 2 nucleosides. In some embodiments, modified sugars and / or unmodified sugars are arranged along the 4 modified oligonucleotide strand or regions thereof in a defined pattern or “sugar motif”. In certain instances, such sugar motifs include, but are not limited to, any of the patterns of sugar 6 modifications described herein. In certain embodiments, an oligonucleotide strand comprises a gapmer sugar motif. A 8 gapmer oligonucleotide strand comprises or consists of a region having two external “wing” regions and a central or internal “gap” region. The gap and wing regions form a contiguous 10 sequence of nucleosides, wherein the majority of nucleoside sugars of each of the wings differ from the majority of nucleoside sugars of the gap. In certain embodiments, the wing regions 12 comprise a majority of modified sugars, and the gap comprises a majority of unmodified sugars. In certain embodiments, the nucleosides of the gap are deoxynucleosides. Oligonucleotides with 14 a gapmer sugar motif are described in, for example, U.S. Patent No.8,790,919. In certain embodiments, one or both strands of a double-stranded oligonucleotide 16 comprise a triplet sugar motif. An oligonucleotide strand with a triplet sugar motif comprises three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the 18 triplet is at or near the cleavage site of the oligonucleotide (e.g., the site at which a ribonuclease, such as Dicer or Drosha, cleaves the oligonucleotide). In certain embodiments, a strand of a 20 double-stranded oligonucleotide may contain more than one triplet sugar motif. In certain embodiments, the identical sugar modification of the triplet sugar motif is a 2′-F modification. 22 Oligonucleotides with a triplet sugar motif are disclosed, for example, in U.S. Patent No. 10,668,170. 24 In certain embodiments, one or both strands of a double-stranded oligonucleotide comprise a quadruplet sugar motif. An oligonucleotide strand with a quadruplet sugar motif 26 comprises four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplet is at or near the cleavage site. In certain embodiments, a strand of a 28 double-stranded oligonucleotide may contain more than one quadruplet sugar motif. In certain embodiments, the identical sugar modification of the quadruplet sugar motif is a 2′-F 30 modification. For a double-stranded oligonucleotide having a duplex region of 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide strand is typically around the 10, 11, 32 and 12 positions from the 5′-end. In certain embodiments, the quadruplet sugar motif is at the 8, 9, 10, and 11 positions; the 9, 10, 11, and 12 positions; the 10, 11, 12, and 13 positions; the 11, 34 12, 13, and 14 positions; or the 12, 13, 14, and 15 positions of the sense oligonucleotide strand, counting from the first nucleoside of the 5′-end of the sense oligonucleotide strand, or, the count 2 starting from the first paired nucleotide within the duplex region from the 5′-end of the sense oligonucleotide strand. In certain embodiments, the quadruplet sugar motif is at the 8, 9, 10, and 4 11 positions; the 9, 10, 11, and12 positions; the 10, 11, 12, and 13 positions; the 11, 12, 13, and 14 positions; or the 12, 13, 14, and 15 positions of the antisense oligonucleotide strand, counting 6 from the first nucleoside of the 5′-end of the antisense oligonucleotide strand, or, the count starting from the first paired nucleotide within the duplex region from the 5′-end of the antisense 8 oligonucleotide strand. The cleavage site may change according to the length of the duplex region of the double-stranded oligonucleotide and may change the position of the quadruplet 10 accordingly. In certain embodiments, an oligonucleotide strand comprises an alternating sugar motif. 12 In certain embodiments, one or both strands of a double-stranded oligonucleotide comprise an alternating sugar motif. An oligonucleotide with an alternating sugar motif comprises at least two 14 different sugar modifications, wherein one or more consecutive nucleosides comprising a first sugar modification alternates with one or more consecutive nucleosides comprising a second 16 sugar modification, and one or more consecutive nucleosides comprising a third sugar modification, etc. For example, if A, Β, and C each represent one type of modification to the 18 nucleoside, the alternating motif can be “ABABABABABAB ...,” “AABBAABBAABB ...,” “AABAABAABAAB ...,” “AAABAAABAAAB ...,” “AAABBBAAABBB ...,” or 20 “ABCABCABCABC ...,” etc. In certain embodiments, the alternating sugar motif is repeated for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous 22 nucleobases along an oligonucleotide strand. In certain embodiments, the alternating sugar motif is comprised of two different sugar modifications. In certain embodiments, the alternating sugar 24 motif comprises 2′-OMe and 2′-F sugar modifications. In certain embodiments, each nucleoside of an oligonucleotide strand is independently 26 modified with one or more sugar modifications provided herein. In certain embodiments, each strand of a double-stranded oligonucleotide independently has one or more sugar modifications 28 provided herein. In certain embodiments, an oligonucleotide strand containing a sugar motif is fully modified in that each nucleoside comprises a sugar modification. 30 In certain embodiments, a modified sugar is 2′-fluoro-2′-deoxyribose, 2′-O-methylribose, 2′-thioribose, 2′,3′-dideoxyribose, 2′-amino-2′-deoxyribose, 2′ deoxyribose, 2′-azido-2′-32 deoxyribose, 2′-O-methyldeoxyribose, 3′-amino-2′,3′-dideoxyribose, 3′-azido-2′,3′- dideoxyribose, 3′-deoxyribose, 3′-O-(2-nitrobenzyl)-2′-deoxyribose, 3′-O-methylribose, 5′-34 aminoribose, 5′-thioribose, 5-nitro-1-indolyl-2′-deoxyribose, 5′-biotin-ribose, 2′-O,4′-C-amino- linked ribose, 2′-O,4′-C-thio-linked ribose, 2′-O-methoxyethyl ribose, 2′-O,4′-C-methylene- 2 linked ribose, 2′-O,4′-C-ethylene-linked ribose, 2′,4′-constrained ethyl ribose, locked sugar, or a bicyclic sugar. 4 In certain embodiments, a modified sugar is present at the 3′-end of the oligonucleotide strand. In certain embodiments, a modified sugar is present within 3 nucleosides of the 3′-end of 6 the oligonucleotide strand. In certain embodiments, a modified sugar is present at the 5′-end of the oligonucleotide strand. In certain embodiments, a modified sugar is present within 3 8 nucleosides of the 5′-end of the oligonucleotide strand. In certain embodiments, a modified sugar is present at an internal position on an oligonucleotide strand. In certain embodiments, a modified 10 sugar is present more than 3 nucleosides from the 3′-end of the oligonucleotide strand. In certain embodiments, a modified sugar is present more than 3 nucleosides from the 5′-end of the 12 oligonucleotide strand. In certain embodiments, modified sugars are present on a block of modified nucleobases. In certain such embodiments, the block is at the 3′-end of the 14 oligonucleotide strand. In certain embodiments, the block is within 3 nucleosides of the 3′-end of the oligonucleotide strand. In certain embodiments, the block is at the 5′-end of the 16 oligonucleotide strand. In certain embodiments, the block is within 3 nucleosides of the 5′-end of the oligonucleotide strand. In certain embodiments, the block is at an internal position in the18 oligonucleotide strand. In certain embodiments, the block is more than 3 nucleosides from the 3′- end of the oligonucleotide strand. In certain embodiments, the block is more than 3 nucleosides 20 from the 5′-end of the oligonucleotide strand. In certain embodiments, a modified sugar is 2′-O-methyl ribose, 2′-F ribose, or inverted22 abasic deoxyribose. In certain embodiments, a modified nucleoside is 2′-O-methyl adenosine, 2′- O-methyl guanosine, 2′-O-methyl cytosine, 2′-O-methyl uracil, 2′-F adenosine, 2′-F guanosine, 24 2′-F cytosine, or 2′-F uracil. 26 Nucleobase Modifications Any modified nucleobases known in the art may be used in the oligonucleotides provided 28 herein. In certain embodiments, modified oligonucleotides comprise one or more nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise 30 one or more nucleosides that do not comprise a nucleobase, referred to as an abasic nucleoside. In certain embodiments, modified nucleobases are selected from: 5-substituted 32 pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and Ν-2, N-6 and O-6 substituted purines. In certain embodiments, modified 34 nucleobases are selected from: 2-aminopropyladenine, 5- hydroxymethyl cytosine, 5- methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N- 2 methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (C≡C-CH3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil 4 (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8- substituted purines, 5-halo, particularly, 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5- 6 halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-Ν-benzoyladenine, 2-N-isobutyrylguanine, 8 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-Ν-benzoylcytosine, 5-methyl 4-N- benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size expanded bases, and10 fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3- diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one, and 9-(2-aminoethoxy)-1,3- 12 diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example, 7-deaza-adenine, 7- 14 deazaguanosine, and 2-aminopyridine and 2-pyridone. In certain embodiments, a modified nucleobase is xanthine, allyaminouracil, 16 allyaminothymidine, hypoxanthine, digoxigeninated adenine, digoxigeninated cytosine, digoxigeninated guanine, digoxigeninated uracil, 6-chloropurineriboside, N6-methyladenine, 18 methylpseudouracil, 2-thiocytosine, 2-thiouracil, 5-methyluracil, 4-thiothymidine, 4-thiouracil, 5,6-dihydro-5-methyluracil, 5,6-dihydrouracil, 5-[(3-Indolyl)propionamide-N-allyl]uracil, 5-20 aminoallylcytosine, 5-aminoallyluracil, 5-bromouracil, 5-bromocytosine, 5-carboxycytosine, 5- carboxymethylesteruracil, 5-carboxyuracil, 5-fluorouracil, 5-formylcytosine, 5-formyluracil, 5-22 hydroxycytosine, 5-hydroxymethylcytosine, 5-hydroxymethyluracil, 5-hydroxyuracil, 5- iodocytosine, 5-iodouracil, 5-methoxycytosine, 5-methoxyuracil, 5-methylcytosine, 5-24 methyluracil, 5-propargylaminocytosine, 5-propargylaminouracil, 5-propynylcytosine, 5- propynyluracil, 6-azacytosine, 6-azauracil, 6-chloropurine, 6-thioguanine, 7-deazaadenine, 7-26 deazaguanine, 7-deaza-7-propargylaminoadenine, 7-deaza-7-propargylaminoguanine, 8- azaadenine, 8-azidoadenine, 8-chloroadenine, 8-oxoadenine, 8-oxoguanine, araadenine,28 aracytosine, araguanine, arauracil, biotin-16-7-deaza-7-propargylaminoguanine, biotin-16- aminoallylcytosine, biotin-16-aminoallyluracil, cyanine 3-5-propargylaminocytosine, cyanine 3-30 6-propargylaminouracil, cyanine 3-aminoallylcytosine, cyanine 3-aminoallyluracil, cyanine 5-6- propargylaminocytosine, cyanine 5-6-propargylaminouracil, cyanine 5-aminoallylcytosine, 32 cyanine 5-aminoallyluracil, cyanine 7-aminoallyluracil, dabcyl-5-3-aminoallyluracil, desthiobiotin-16-aminoallyl-uracil, desthiobiotin-6-aminoallylcytosine, isoguanine, N1- 34 ethylpseudouracil, N1-methoxymethylpseudouracil, N1-methyladenine, N1-methylpseudouracil, N1-propylpseudouracil, N2-methylguanine, N4-biotin-OBEA-cytosine, N4-methylcytosine, N6- 2 methyladenine, O6-methylguanine, pseudoisocytosine, pseudouracil, thienocytosine, thienoguanine, thienouracil, xanthosine, 3-deaza...

Claims

CLAIMS 2 What is claimed is: 4 1. An oligonucleotide comprising a modified oligonucleotide strand comprising: 6 s1 instances of modified nucleosides independently comprising a moiety of Formula I:8 (I); and v1 instances of the internucleosidic linkers of the modified oligonucleotide strand are 10 independently repla; wherein: 12 s1 is 1, 2, 3, 4, 5, or 6; each instance of N1is independently a radical of a nucleobase or a bond; 14 each instance of t1 is independently 1, 2, or 3; each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least 16 one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; each instance of A1, A2, and A3, if present, is independently a radical of a ligand or a 18 lipid, provided that at least one instance of A1, A2, and A3is a radical of a central nervous system receptor ligand; 20 when y1 of an instanceis 0, L1thereof is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or 22 unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted 24 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –CN, –ORb, –SCN, –SRb, –SSRb, –N3, –NO, –N(Rb)2, –26 NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –S(=O)ORb, –S(=O)SRb, –S(=O)N(Rb)2, –S(=O)2Rb, –S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –OC(=O)Rb, – 2 OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, – OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, – 4 SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, – NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, – 6 NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, –NRbS(=O)2N(Rb)2, – Si(Rb)3, –Si(Rb)2ORb, –Si(Rb)(ORb)2, –Si(ORb)3, –OSi(Rb)3, –OSi(Rb)2ORb, –OSi(Rb)(ORb)2, or – 8 OSi(ORb)3; or when y1 of an instance is 1, 2, 3, 4, 5, or 6, L1thereof is alinker; 10 each instance of Rbis independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or 12 unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, 14 substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen 16 atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to the same intervening atom are joined together with the intervening atom to form an substituted 18 or unsubstituted, monocyclic, heterocyclic or heteroaryl ring;when y2 of an instance ofis 0, L2thereof is –OH, –ORh, halogen, –CN, or20 –N3; or when y2 of an instance ofis 1, 2, 3, 4, 5, or 6, L2thereof is a linker; each instance of Rhis independently substituted or unsubstituted, C1-6alkyl, or an oxygen 22 protecting group; when the moiety of Formula I is part of an instance of the modified nucleoside at the 5’ 24 end or an internal position of the modified oligonucleotide strand: y3 thereof is 0, and L3thereof is an internucleosidic linker; or 26 when the moiety of Formula I is part of an instance of the modified nucleoside at the 3’ end of the modified oligonucleotide strand: 28 when y3 thereof is 0: L3thereof is –OH, –ORd, halogen, –CN, or –N3, and each instance of Rdis independently substituted or unsubstituted, C1-6alkyl, or an oxygen 30 protecting group; orwhen y3 thereof is 1, 2, 3, 4, 5, or 6, L3thereof is a linker; 2 v1 is 0, 1, 2, 3, 4, 5, or 6; each instance of LAand L4, when present, is independently a linker; 4 each instance of y4, when present, is independently 1, 2, 3, 4, 5, or 6; and each instance of A4, when present, is independently a radical of a ligand or lipid. 6 2. A nucleoside comprising a moiety of the formula: 8, wherein: 10 N1is a radical of a nucleobase or a bond; t1 is 1, 2, or 3; 12 each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; 14 each instance of A1, A2, and A3, if present, is independently a radical of a ligand or a lipid, provided that at least one instance of A1, A2, and A3is a radical of a central nervous system 16 receptor ligand;when y1 of an instance of is 0, L1thereof is hydrogen, halogen, 18 substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 20 heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl,22 substituted or unsubstituted heteroaryl, –CN, –ORb, –SCN, –SRb, –SSRb, –N3, –NO, –N(Rb)2, – NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –S(=O)ORb, –S(=O)SRb, –24 S(=O)N(Rb)2, –S(=O)2Rb, –S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –OC(=O)Rb, – OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, –26 OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, – SC(=O)Rb, –SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, –28 NRbC(=O)SRb, –NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, – NRbS(=O)N(Rb)2, –NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, –NRbS(=O)2N(Rb)2, –Si(Rb)3, –Si(Rb)2ORb, –Si(Rb)(ORb)2, –Si(ORb)3, –OSi(Rb)3, –OSi(Rb)2ORb, –OSi(Rb)(ORb)2, or – 2 OSi(ORb)3; or when y1 of an instanthereof is a linker; 4 each instance of Rbis independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or 6 unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, 8 substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen 10 atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to the same intervening atom are joined together with the intervening atom to form an substituted 12 or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; when y2 is 0, L2is –OH, –ORh, halogen, –CN, or –N3; or when y2 is 1, 2, 3, 4, 5, or 6, L214 is a linker; Rhis substituted or unsubstituted, C1-6alkyl, or an oxygen protecting group; 16 when y3 is 0, L3is –OH, –ORd, halogen, –CN, or –N3; or when y3 is 1, 2, 3, 4, 5, or 6, L3is a linker; and 18 Rdis substituted or unsubstituted, C1-6alkyl, or an oxygen protecting group. 20 3. The oligonucleotide of claim 1 or the nucleoside of claim 2, wherein each instance of A1, A2, and A3, if present, is independently a radical of a central nervous system receptor ligand or a 22 lipid, provided that at least one instance of A1, A2, and A3is a radical of a central nervous system receptor ligand. 24 4. The nucleoside of claim 2, wherein the nucleoside is of the formula: 26, or a pharmaceutically acceptable salt or prodrug thereof, wherein E1is –OP(=O)(ORb)2, – 28 SP(=O)(ORb)2, –OP(=O)(ORb)(SRb), –ORb, –SRb, –SSRb, –N(Rb)2, –OC(=O)Rb, –OC(=O)ORb, –OC(=O)SRb, –OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, –OS(=O)N(Rb)2, –OS(=O)2Rb, –OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, –SC(=O)Rb, – 2 SC(=O)ORb, –SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, –NRbC(=O)SRb, – NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, –NRbS(=O)N(Rb)2, – 4 NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, or –NRbS(=O)2N(Rb)2. 6 5. The oligonucleotide of claim 1, wherein the oligonucleotide is a single-stranded oligonucleotide. 8 6. The oligonucleotide of claim 1, wherein the oligonucleotide is a double-stranded 10 oligonucleotide comprising a sense oligonucleotide strand and an antisense oligonucleotide strand. 12 7. The oligonucleotide of any one of claims 1-6, wherein the modified oligonucleotide 14 strand is the sense oligonucleotide strand. 16 8. The oligonucleotide of any one of claims 1-7, wherein the modified oligonucleotide strand is the antisense oligonucleotide strand. 18 9. The oligonucleotide of any one of claims 1-8, wherein the nucleobases of the antisense 20 oligonucleotide strand are complementary to the nucleobases of the sense oligonucleotide strand. 22 10. The oligonucleotide of any one of claims 1-9, wherein the oligonucleotide comprises an RNA. 24 11. The oligonucleotide of any one of claims 1-10, wherein the oligonucleotide is an RNA. 26 12. The oligonucleotide of any one of claims 1-11, wherein the oligonucleotide is an siRNA. 28 13. The oligonucleotide of any one of claims 1-12, wherein the modified oligonucleotide 30 strand comprises between 6 and 100, inclusive, nucleosides. 32 14. The oligonucleotide of any one of claims 1-13, wherein the modified oligonucleotide strand comprises between 10 and 30, inclusive, nucleosides. 3415. The oligonucleotide of any one of claims 1-14, wherein the modified oligonucleotide 2 strand comprises between 14 and 23, inclusive, nucleosides. 4 16. The oligonucleotide of any one of claims 1-15, wherein s1 is 1, and the modified nucleoside is at the 5’ end of the modified oligonucleotide strand. 6 17. The oligonucleotide of any one of claims 1-16, wherein s1 is 1, and the modified 8 nucleoside is at an internal position of the modified oligonucleotide strand. 10 18. The oligonucleotide of any one of claims 1-17, wherein s1 is 1, and the modified nucleoside is at the 3’ end of the modified oligonucleotide strand. 12 19. The oligonucleotide of any one of claims 1-18, wherein: 14 s1 is 2; one instance of the modified nucleoside is at the 5’ end of the modified oligonucleotide 16 strand; and the other instance of the modified nucleoside is at an internal position of the modified 18 oligonucleotide strand. 20 20. The oligonucleotide of any one of claims 1-19, wherein: s1 is 2; 22 one instance of the modified nucleoside is at the 3’ end of the modified oligonucleotide strand; and 24 the other instance of the modified nucleoside is at an internal position of the modified oligonucleotide strand. 26 21. The oligonucleotide of any one of claims 1-20, wherein: 28 s1 is 2; and each instance of the modified nucleoside is at an internal position of the modified 30 oligonucleotide strand. 32 22. The oligonucleotide of any one of claims 1-21, wherein: at least one instance of the internal position is the first n nucleoside of the modified 34 oligonucleotide strand counted from the 5’ end; andn is an integer between 2 and 20, inclusive, as the number of nucleosides of the modified 2 oligonucleotide strand permits. 4 23. The oligonucleotide of any one of claims 1-22, wherein s1 is 3, 4, 5, or 6. 6 24. The oligonucleotide or nucleoside of any one of claims 1-23, wherein at least one instance of N1is a radical of a nucleobase. 8 25. The oligonucleotide or nucleoside of any one of claims 1-24, wherein at least one 10 instance of N1is a radical of adenine, cytosine, guanine, or uracil. 12 26. The oligonucleotide or nucleoside of any one of claims 1-25, wherein at least one instance of N1is a bond. 14 27. The oligonucleotide or nucleoside of any one of claims 1-26, wherein at least one 16 instance of t1 is 1. 18 28. The oligonucleotide or nucleoside of any one of claims 1-27, wherein at least one instance of y1 is 0. 20 29. The oligonucleotide or nucleoside of any one of claims 1-28, wherein y1 of an instance ofis 0, and L1thereof is hydrogen, halogen, substituted or unsubstituted, C1-6alkyl, substituted or unsubstituted, C2-6alkenyl, substituted or unsubstituted, C2-6heteroalkyl, 24 substituted or unsubstituted, monocyclic carbocyclyl, substituted or unsubstituted, monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted, monocyclic 26 heteroaryl, –CN, –ORb, –SCN, –SRb, –SSRb, –N3, –NO, –N(Rb)2, –NO2, –C(=O)Rb, –C(=O)ORb, –C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –S(=O)ORb, –S(=O)SRb, –S(=O)N(Rb)2, –S(=O)2Rb, –28 S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –OC(=O)Rb, –OC(=O)ORb, –OC(=O)SRb, – OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, –OS(=O)N(Rb)2, –OS(=O)2Rb, –30 OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, –SC(=O)Rb, –SC(=O)ORb, – SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, –NRbC(=O)SRb, – 32 NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, –NRbS(=O)N(Rb)2, – NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, or –NRbS(=O)2N(Rb)2.2 30. The oligonucleotide or nucleoside of any one of claims 1-29, wherein y1 of an instance ofis 0, and L1thereof is hydrogen, halogen, substituted or unsubstituted, C1-64 alkyl, substituted or unsubstituted, C2-6alkenyl, substituted or unsubstituted, C2-6heteroalkyl, – CN, –ORb, –SCN, –SRb, –SSRb, –N3, –NO, –N(Rb)2, –NO2, –C(=O)Rb, –C(=O)ORb, – 6 C(=O)SRb, –C(=O)N(Rb)2, –S(=O)Rb, –S(=O)ORb, –S(=O)SRb, –S(=O)N(Rb)2, –S(=O)2Rb, – S(=O)2ORb, –S(=O)2SRb, –S(=O)2N(Rb)2, –OC(=O)Rb, –OC(=O)ORb, –OC(=O)SRb, – 8 OC(=O)N(Rb)2, –OS(=O)Rb, –OS(=O)ORb, –OS(=O)SRb, –OS(=O)N(Rb)2, –OS(=O)2Rb, – OS(=O)2ORb, –OS(=O)2SRb, –OS(=O)2N(Rb)2, –ON(Rb)2, –SC(=O)Rb, –SC(=O)ORb, –10 SC(=O)SRb, –SC(=O)N(Rb)2, –NRbC(=O)Rb, –NRbC(=O)ORb, –NRbC(=O)SRb, – NRbC(=O)N(Rb)2, –NRbS(=O)Rb, –NRbS(=O)ORb, –NRbS(=O)SRb, –NRbS(=O)N(Rb)2, – 12 NRbS(=O)2Rb, –NRbS(=O)2ORb, –NRbS(=O)2SRb, or –NRbS(=O)2N(Rb)2. 14 31. The oligonucleotide or nucleoside of any one of claims 1-30, wherein at least one instance of y1 is 1. 16 32. The oligonucleotide or nucleoside of any one of claims 1-31, wherein at least one 18 instance of y1 is 2. 20 33. The oligonucleotide or nucleoside of any one of claims 1-32, wherein at least one instance of y1 is 3, 4, 5, or 6. 22 34. The oligonucleotide or nucleoside of any one of claims 1-33, wherein each instance of A124 is a radical of a ligand. 26 35. The oligonucleotide or nucleoside of any one of claims 1-34, wherein: at least one instance of A1is a radical of a ligand; and 28 at least one instance of A1is a radical of a lipid. 30 36. The oligonucleotide or nucleoside of any one of claims 1-35, wherein each instance of A1is a radical of a lipid. 3237. The oligonucleotide or nucleoside of any one of claims 1-36, wherein y1 of an instance ofis 1, 2, 3, 4, 5, or 6, and L1thereof is substituted or unsubstituted, C1-100alkylene, substituted or unsubstituted, C2-100alkenylene, substituted or unsubstituted, C2-1004 alkynylene, substituted or unsubstituted, C1-100heteroalkylene, substituted or unsubstituted, C2-100heteroalkenylene, or substituted or unsubstituted, C2-100heteroalkynylene; 6 optionally wherein one or more backbone atoms of the C1-100alkylene, C2-100alkenylene, C2-100alkynylene, C1-100heteroalkylene, C2-100heteroalkenylene, or C2-100heteroalkynylene are 8 independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or 10 unsubstituted heteroarylene, as valency permits. 12 38. The oligonucleotide or nucleoside of any one of claims 1-37, wherein y1 of an instance ofis 1, 2, 3, 4, 5, or 6, and L1thereof is substituted or unsubstituted, C7-7014 alkylene, substituted or unsubstituted, C7-70alkenylene, substituted or unsubstituted, C7-70heteroalkylene, or substituted or unsubstituted, C7-70heteroalkenylene; 16 optionally wherein one, two, three, or four backbone atoms of the C7-70alkylene, C7-70alkenylene, C7-70heteroalkylene, or C7-70heteroalkenylene are independently replaced with 18 substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency 20 permits. 22 39. The oligonucleotide or nucleoside of any one of claims 1-38, wherein y1 of an instance ofis 1, 2, 3, 4, 5, or 6, and L1thereof is substituted or unsubstituted, C7-70alkylene 24 or substituted or unsubstituted, C7-70heteroalkylene; and one, two, three, or four backbone atoms of the C7-70alkylene or C7-70heteroalkylene are 26 independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or 28 unsubstituted heteroarylene, as valency permits. 30 40. The oligonucleotide or nucleoside of any one of claims 1-39, wherein:at least one instance of , if present, is of the formula: 2; each of –L1A1–L1A2–, –L1A3–L1A4–, –L1A5–L1A6–, and –L1A7–L1A8– is independently a 4 single bond, –O–, –S–, –S–S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, – C(=O)NRa–, –C(=NRa)NRa–, –S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–, 6 –OS(=O)2–, –NRaC(=O)–, –NRaC(=NRa)–, –NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, – OC(=NRa)O–, –OS(=O)O–, –OS(=O)2O–, –NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, – 8 NRaS(=O)2O–, –OC(=O)NRa–, –OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, – NRaC(=O)NRa–, –NRaC(=NRa)NRa–, –NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, –10 C(=NRa)–, –S(=O)–, –S(=O)2–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or – OP(=O)(SRa)O–; 12 each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when 14 attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted 16 or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L1B1and L1B2is independently a single bond, substituted or unsubstituted, C1-10018 alkylene, or substituted or unsubstituted, C1-100heteroalkylene; L1C1is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the 20 backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; and 22 bond C1Ais attached to A1. 24 41. The oligonucleotide or nucleoside of any one of claims 1-40, wherein L1thereof is of the formula:

26. 28 42. The oligonucleotide or nucleoside of any one of claims 1-41, wherein L1thereof is of the formula:. 2 43. The oligonucleotide or nucleoside of any one of claims 1-42, wherein y1 of an instance ofis 1, 2, 3, 4, 5, or 6, and L1thereof is substituted or unsubstituted, C7-70heteroalkylene. 6 44. The oligonucleotide or nucleoside of any one of claims 1-43, wherein y1 of an instance of8 is 1, 2, 3, 4, 5, or 6, and L1thereof is –CH2–, –O–, – CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, , or a combination of two or more instances of each one of theforegoing, or a combination of two or more of the foregoing, provided that: 12 the number of backbone atoms of L1thereof is between 7 and 70, inclusive; and L1thereof does not comprise O–O, O–N, N–O, or N–N. 14 45. The oligonucleotide or nucleoside of any one of claims 1-44, wherein y1 of an instance of is 1, 2, 3, 4, 5, or 6, and L1thereof is –CH2– , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O, or a 2 combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: 4 the number of backbone atoms of L1thereof is between 7 and 70, inclusive; L1thereof does not comprise O–O, O–N, N–O, or N–N; and 6 the combined number of –C(=O)NH–, –NHC(=O) of L1thereof is between 0 and 4, inclusive.8 46. The oligonucleotide or nucleoside of any one of claims 1-45, wherein at least one 10 instance of y2 is 0. 12 47. The oligonucleotide or nucleoside of any one of claims 1-46, wherein y2 of an instance ofL2thereof is –OH, –OCH3, or F. 14 48. The oligonucleotide or nucleoside of any one of claims 1-47, wherein at least one 16 instance of y2 is 1. 18 49. The oligonucleotide or nucleoside of any one of claims 1-48, wherein at least one instance of y2 is 2. 20 50. The oligonucleotide or nucleoside of any one of claims 1-49, wherein at least one 22 instance of y2 is 3, 4, 5, or 6. 24 51. The oligonucleotide or nucleoside of any one of claims 1-50, wherein each instance of A2is a radical of a ligand. 26 52. The oligonucleotide or nucleoside of any one of claims 1-51, wherein: 28 at least one instance of A2is a radical of a ligand; and at least one instance of A2is a radical of a lipid2 53. The oligonucleotide or nucleoside of any one of claims 1-52, wherein each instance of A2is a radical of a lipid. 4 54. The oligonucleotide or nucleoside of any one of claims 1-53, wherein y2 of an instance ofis 1, 2, 3, 4, 5, or 6, and L2thereof is substituted or unsubstituted, C1-100alkylene, substituted or unsubstituted, C2-100alkenylene, substituted or unsubstituted, C2-100alkynylene, 8 substituted or unsubstituted, C1-100heteroalkylene, substituted or unsubstituted, C2-100heteroalkenylene, or substituted or unsubstituted, C2-100heteroalkynylene; 10 optionally wherein one or more backbone atoms of the C1-100alkylene, C2-100alkenylene, C2-100alkynylene, C1-100heteroalkylene, C2-100heteroalkenylene, or C2-100heteroalkynylene are 12 independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or 14 unsubstituted heteroarylene, as valency permits. 16 55. The oligonucleotide or nucleoside of any one of claims 1-54, wherein y2 of an instance of is 1, 2, 3, 4, 5, or 6, and L2thereof is substituted or unsubstituted, C7-70alkylene, 18 substituted or unsubstituted, C7-70alkenylene, substituted or unsubstituted, C7-70heteroalkylene, or substituted or unsubstituted, C7-70heteroalkenylene; 20 optionally wherein one, two, or three backbone atoms of the C7-70alkylene, C7-70alkenylene, C7-70heteroalkylene, or C7-70heteroalkenylene are independently replaced with 22 substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency 24 permits. 26 56. The oligonucleotide or nucleoside of any one of claims 1-55, wherein y2 of an instance ofis 1, 2, 3, 4, 5, or 6, and L2thereof is substituted or unsubstituted, C7-70alkylene 28 or substituted or unsubstituted, C7-70heteroalkylene; andone, two, or three backbone atoms of the C7-70alkylene or C7-70heteroalkylene are 2 independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or 4 unsubstituted heteroarylene, as valency permits. 6 57. The oligonucleotide or nucleoside of any one of claims 1-56, wherein at least one instis of the formula: . 8 58. The oligonucleotide or nucleoside of any one of claims 1-57, wherein: 10 at least one instas of the formula:; 12 each of –L2A1–L2A2–, –L2A3–L2A4–, –L2A5–L2A6–, and –L2A7–L2A8– is independently a single bond, –O–, –S–, –S–S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, – 14 C(=O)NRa–, –C(=NRa)NRa–, –S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–, –OS(=O)2–, –NRaC(=O)–, –NRaC(=NRa)–, –NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, –16 OC(=NRa)O–, –OS(=O)O–, –OS(=O)2O–, –NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, – NRaS(=O)2O–, –OC(=O)NRa–, –OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, – 18 NRaC(=O)NRa–, –NRaC(=NRa)NRa–, –NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, – C(=NRa)–, –S(=O)–, –S(=O)2–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or – 20 OP(=O)(SRa)O–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a 22 nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two 24 instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; 26 each of L2B1and L2B2is independently a single bond, substituted or unsubstituted, C1-100alkylene, or substituted or unsubstituted, C1-100heteroalkylene;L2C1is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the 2 backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; and 4 bond C2Ais attached to A2. 6 59. The oligonucleotide or nucleoside of any one of claims 1-58, wherein at least one. 10 60. The oligonucleotide or nucleoside of any one of claims 1-59, wherein at least one instis of the formula:

12. 14 61. The oligonucleotide or nucleoside of any one of claims 1-60, wherein:at least one instas of the formula: 2; each of –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, –L2A15–L2A16–, –L2A17–L2A18–, – 4 L2A19–L2A20–, –L2A21–L2A22–, and –L2A23–L2A24– is independently a single bond, –O–, –S–, –S– S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, –C(=O)NRa–, –C(=NRa)NRa–, – 6 S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–, –OS(=O)2–, –NRaC(=O)–, – NRaC(=NRa)–, –NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, –OC(=NRa)O–, –OS(=O)O–, – 8 OS(=O)2O–, –NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, –NRaS(=O)2O–, –OC(=O)NRa–, –OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, –NRaC(=O)NRa–, –NRaC(=NRa)NRa–, –10 NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, –C(=NRa)–, –S(=O)–, –S(=O)2–, – OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–; 12 each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when 14 attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted 16 or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L2B3, L2B4, L2B5, L2B6, L2B7, and L2B8is independently a single bond, substituted or 18 unsubstituted, C1-100alkylene, or substituted or unsubstituted, C1-100heteroalkylene; each of L2C2and L2C3is independently a single bond, substituted or unsubstituted 20 heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; 22 bond C2Bis attached to a first instance of A2; and bond C2Cis attached to a second instance of A2. 2462. The oligonucleotide or nucleoside of any one of claims 1-61, wherein at least one. 4 63. The oligonucleotide or nucleoside of any one of claims 1-62, wherein at least one.

864. The oligonucleotide or nucleoside of any one of claims 1-63, wherein y2 of an instance ofis 1, 2, 3, 4, 5, or 6, and L2thereof is substituted or unsubstituted, C7-70heteroalkylene. 4 65. The oligonucleotide or nucleoside of any one of claims 1-64, wherein y2 of an instance of6 is 1, 2, 3, 4, 5, or 6, and L2thereof is –CH2, , , –O–, – CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–,, or a combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: 10 the number of backbone atoms of L2thereof is between 7 and 70, inclusive; and L2thereof does not comprise O–O, O–N, N–O, or N–N. 12 66. The oligonucleotide or nucleoside of any one of claims 1-65, wherein y2 of an instance ofis 1, 2, 3, 4, 5, or 6, and L2thereof is –CH2, –O–, – CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O , or a16 combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: 18 the number of backbone atoms of L2thereof is between 7 and 70, inclusive; L2thereof does not comprise O–O, O–N, N–O, or N–N; and 20 the combined number of –C(=O)NH–, –NHC(=O)– of L2thereof is between 0 and 4, inclusive.2267. The oligonucleotide or nucleoside of any one of claims 1-66, wherein at least one 2 instance of y3 is 1. 4 68. The oligonucleotide or nucleoside of any one of claims 1-67, wherein at least one instance of y3 is 2. 6 69. The oligonucleotide or nucleoside of any one of claims 1-68, wherein at least one 8 instance of y3 is 3, 4, 5, or 6. 10 70. The oligonucleotide or nucleoside of any one of claims 1-69, wherein each instance of A3is a radical of a ligand. 12 71. The oligonucleotide or nucleoside of any one of claims 1-70, wherein: 14 at least one instance of A3is a radical of a ligand; and at least one instance of A3is a radical of a lipid. 16 72. The oligonucleotide or nucleoside of any one of claims 1-71, wherein each instance of A318 is a radical of a lipid. 20 73. The oligonucleotide of any one of claims 1-72, wherein: the moiety of Formula I is part of an instance of the modified nucleoside at the 5’ end or 22 an internal position of the modified oligonucleotide strand; y3 thereof is 0; and 24 L3thereof is an internucleosidic linker, e.g., phosphate internucleosidic linker, phosphorothioate internucleosidic linker, or methylphosphonate internucleosidic linker. 26 74. The oligonucleotide of any one of claims 1-73, wherein: 28 the moiety of Formula I is part of an instance of the modified nucleoside at the 3’ end of the modified oligonucleotide strand; 30 y3 thereof is 0; L3thereof is –OH, –ORd, halogen, –CN, or –N3; and 32 each instance of Rdis independently substituted or unsubstituted, C1-6alkyl, or an oxygen protecting group. 3475. The oligonucleotide or nucleoside of any one of claims 1-74, wherein L3is –OH, –OCH3, 2 or F. 4 76. The oligonucleotide of any one of claims 1-75, wherein: the moiety of Formula I is part of an instance of the modified nucleoside at the 3’ end of 6 the modified oligonucleotide strand; y3 thereof is 1, 2, 3, 4, 5, or 6; and 8 L3thereof is a linker. 10 77. The oligonucleotide or nucleoside of any one of claims 1-76, wherein L3thereof is substituted or unsubstituted, C1-100alkylene, substituted or unsubstituted, C2-100alkenylene, 12 substituted or unsubstituted, C2-100alkynylene, substituted or unsubstituted, C1-100heteroalkylene, substituted or unsubstituted, C2-100heteroalkenylene, or substituted or unsubstituted, C2-10014 heteroalkynylene; optionally wherein one or more backbone atoms of the C1-100alkylene, C2-100alkenylene, 16 C2-100alkynylene, C1-100heteroalkylene, C2-100heteroalkenylene, or C2-100heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or 18 unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. 20 78. The oligonucleotide or nucleoside of any one of claims 1-77, wherein L3thereof is 22 substituted or unsubstituted, C7-70alkylene, substituted or unsubstituted, C7-70alkenylene, substituted or unsubstituted, C7-70heteroalkylene, or substituted or unsubstituted, C7-7024 heteroalkenylene; optionally wherein one, two, or three backbone atoms of the C7-70alkylene, C7-7026 alkenylene, C7-70heteroalkylene, or C7-70heteroalkenylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, 28 substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. 30 79. The oligonucleotide or nucleoside of any one of claims 1-78, wherein L3thereof is 32 substituted or unsubstituted, C7-70alkylene or substituted or unsubstituted, C7-70heteroalkylene; andone, two, or three backbone atoms of the C7-70alkylene or C7-70heteroalkylene are 2 independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or 4 unsubstituted heteroarylene, as valency permits. 6 80. The oligonucleotide or nucleoside of any one of claims 1-79, wherein at least one instis of the formula: . 8 81. The oligonucleotide or nucleoside of any one of claims 1-80, wherein: 10 at least one instanceo is of the formula:; 12 each of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, and –L3A7–L3A8– is independently a single bond, –O–, –S–, –S–S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, – 14 C(=O)NRa–, –C(=NRa)NRa–, –S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–, –OS(=O)2–, –NRaC(=O)–, –NRaC(=NRa)–, –NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, –16 OC(=NRa)O–, –OS(=O)O–, –OS(=O)2O–, –NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, – NRaS(=O)2O–, –OC(=O)NRa–, –OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, – 18 NRaC(=O)NRa–, –NRaC(=NRa)NRa–, –NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, – C(=NRa)–, –S(=O)–, –S(=O)2–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or – 20 OP(=O)(SRa)O–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a 22 nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two 24 instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; 26 each of L3B1and L3B2is independently a single bond, substituted or unsubstituted, C1-100alkylene, or substituted or unsubstituted, C1-100heteroalkylene; 28 L3C1is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone 30 atoms; andbond C3Ais attached to A3. 2 82. The oligonucleotide or nucleoside of any one of claims 1-81, wherein at least one. 6 83. The oligonucleotide or nucleoside of any one of claims 1-82, wherein at least one 8 instis of the formula:. 10 84. The oligonucleotide or nucleoside of any one of claims 1-83, wherein L3thereof is 12 substituted or unsubstituted, C7-70heteroalkylene. 14 85. The oligonucleotide or nucleoside of any one of claims 1-84, wherein L3thereof is – , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –a combination of two or more 2 instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: 4 the number of backbone atoms of L3thereof is between 7 and 70, inclusive; and L3thereof does not comprise O–O, O–N, N–O, or N–N. 6 86. The oligonucleotide or nucleoside of any one of claims 1-85, wherein L3thereof is – 8, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O)–,r a combination of two or more instances of each one of the 10 foregoing, or a combination of two or more of the foregoing, provided that: the number of backbone atoms of L3thereof is between 7 and 70, inclusive; 12 L3thereof does not comprise O–O, O–N, N–O, or N–N; and the combined number of –C(=O)NH–, –NHC(=O)– of L314 thereof is between 0 and 4, inclusive. 16 87. The oligonucleotide or nucleoside of any one of claims 1-86, wherein: y3 thereof is 1; 18 thereof is ; each of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, and –L3A7–L3A8– is independently a20 single bond, –O–, –S–, –S–S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, – C(=O)NRa–, –C(=NRa)NRa–, –S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–,22 –OS(=O)2–, –NRaC(=O)–, –NRaC(=NRa)–, –NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, – OC(=NRa)O–, –OS(=O)O–, –OS(=O)2O–, –NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, –24 NRaS(=O)2O–, –OC(=O)NRa–, –OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, – NRaC(=O)NRa–, –NRaC(=NRa)NRa–, –NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, –C(=NRa)–, –S(=O)–, –S(=O)2–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or – 2 OP(=O)(SRa)O–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a 4 nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two 6 instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; 8 each of L3B1and L3B2is independently a single bond, substituted or unsubstituted, C1-100alkylene, or substituted or unsubstituted, C1-100heteroalkylene; 10 L3C1is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone 12 atoms. 14 88. The oligonucleotide or nucleoside of any one of claims 1-87, wherein: y3 thereof is 1; and 16. 18 89. The oligonucleotide or nucleoside of any one of claims 1-88, wherein: y3 thereof is 2;; 22 each of –L3A9–L3A10–, –L3A11–L3A12–, –L3A13–L3A14–, –L3A15–L3A16–, –L3A17–L3A18–, – L3A19–L3A20–, and –L3A21–L3A22– is independently a single bond, –O–, –S–, –S–S–, –NRa–, –24 C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, –C(=O)NRa–, –C(=NRa)NRa–, –S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–, –OS(=O)2–, –NRaC(=O)–, –NRaC(=NRa)–, – 2 NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, –OC(=NRa)O–, –OS(=O)O–, –OS(=O)2O–, – NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, –NRaS(=O)2O–, –OC(=O)NRa–, – 4 OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, –NRaC(=O)NRa–, –NRaC(=NRa)NRa–, – NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, –C(=NRa)–, –S(=O)–, –S(=O)2–, – 6 OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a 8 nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two 10 instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; 12 each of L3B3, L3B4, L3B5, L3B6, and L3B7is independently a single bond, substituted or unsubstituted, C1-100alkylene, or substituted or unsubstituted, C1-100heteroalkylene; and 14 each of L3C2and L3C3is independently a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted 16 heteroarylene that replaces one of the backbone atoms. 18 90. The oligonucleotide or nucleoside of any one of claims 1-89, wherein: y3 thereof is 2; and ,. 2 91. The oligonucleotide of any one of claims 1-90, wherein v1 is 0. 4 92. The oligonucleotide of any one of claims 1-91, wherein v1 is 1. 6 93. The oligonucleotide of any one of claims 1-92, wherein v1 is 2, 3, 4, 5, or 6. 8 94. The oligonucleotide of any one of claims 1-93, wherein at least one instance of 1, when present, is between the first and second nucleosides of the modified oligonucleotide strand counted from the 5’ end. 12 95. The oligonucleotide of any one of claims 1-94, wherein: 14 at least one insta, when present, is between the first n and n+1 nucleosides of the modified oligonucleotide strand counted from the 5’ end; and 16 n is an integer between 2 and 20, inclusive, as the number of nucleosides of the modified oligonucleotide strand permits. 18 96. The oligonucleotide of any one of claims 1-95, wherein: 20 at least one instance of LA, when present, is of the formula:;each instance of ZA1and ZA2is independently a single bond, substituted or unsubstituted, 2 C1-6alkylene, or substituted or unsubstituted, C2–6alkenylene; each instance of WAis independently a radical, as valency permits, of substituted or 4 unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, 6 substituted or unsubstituted heteroarylene, -O-, -OP(=O)(ORc)O-, -N(Rc)-, -S-, -C(=O)-, - C(=O)O-, -C(=O)NRc-, -NRcC(=O)-, -C(=O)Rc-, -NRcC(=O)O-, -NRcC(=O)NRc-, -OC(=O)-, - 8 OC(=O)O-, -OC(=O)N(Rc)-, -S(=O)2NRc-, -NRcS(=O)2-, or a combination thereof; each instance of Rcis independently hydrogen, substituted or unsubstituted acyl, 10 substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 12 heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, 14 substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two instances of Rcare 16 joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; and 18 bond C4Ais attached to L4. 20 97. The oligonucleotide of any one of claims 1-96, wherein at least one instance of LA, when present, is of the formu. 22 98. The oligonucleotide of any one of claims 1-97, wherein at least one instance of LA, when 24 present, is of the formu. 26 99. The oligonucleotide of any one of claims 1-98, wherein ZA1is unsubstituted C1-3alkylene. 28 100. The oligonucleotide of any one of claims 1-99, wherein ZA2is unsubstituted C1–330 alkylene.2 101. The oligonucleotide of any one of claims 1-100, wherein at least one instance of LA, when present, is of the formula: ,6 102. The oligonucleotide of any one of claims 1-101, wherein at least one instance of y4, when 8 present, is 1. 10 103. The oligonucleotide of any one of claims 1-102, wherein at least one instance of y4, when present, is 2, 3, 4, 5, or 6. 12 104. The oligonucleotide of any one of claims 1-103, wherein at least one instance of L4, when 14 present, is substituted or unsubstituted, C1-100alkylene, substituted or unsubstituted, C2-100alkenylene, substituted or unsubstituted, C2-100alkynylene, substituted or unsubstituted, C1-10016 heteroalkylene, substituted or unsubstituted, C2-100heteroalkenylene, or substituted or unsubstituted, C2-100heteroalkynylene; 18 optionally wherein one or more backbone atoms of the C1-100alkylene, C2-100alkenylene, C2-100alkynylene, C1-100heteroalkylene, C2-100heteroalkenylene, or C2-100heteroalkynylene are 20 independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or 22 unsubstituted heteroarylene, as valency permits. 24 105. The oligonucleotide of any one of claims 1-104, wherein at least one instance of L4, when present, is substituted or unsubstituted, C7-70alkylene, substituted or unsubstituted, C7-7026 alkenylene, substituted or unsubstituted, C7-70alkynylene, substituted or unsubstituted, C7-70heteroalkylene, substituted or unsubstituted, C7-70heteroalkenylene, or substituted or 28 unsubstituted, C7-70heteroalkynylene; optionally wherein one, two, three, or four backbone atoms of the C7-70alkylene, C7-70alkenylene, 30 C7-70alkynylene, C7-70heteroalkylene, C7-70heteroalkenylene, or C7-70heteroalkynylene areindependently replaced with substituted or unsubstituted carbocyclylene, substituted or 2 unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. 4 106. The oligonucleotide of any one of claims 1-105, wherein at least one instance of L4, when 6 present, is substituted or unsubstituted, C7-70alkylene or substituted or unsubstituted, C7-70heteroalkylene; and 8 one, two, three, or four backbone atoms of the C7-70alkylene or C7-70heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or 10 unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits. 12 107. The oligonucleotide of any one of claims 1-106, wherein: 14 at least one instance of y4 is 1; 1each of –L4A1–L4A2–, –L4A3–L4A4–, –L4A5–L4A6–, –L4A7–L4A8–, –L4A17–L4A18–, and – 18 L4A19–L4A20– is independently a single bond, –O–, –S–, –S–S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, –C(=O)NRa–, –C(=NRa)NRa–, –S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–,20 –OC(=NRa)–, –OS(=O)–, –OS(=O)2–, –NRaC(=O)–, –NRaC(=NRa)–, –NRaS(=O)–, – NRaS(=O)2–, –OC(=O)O–, –OC(=NRa)O–, –OS(=O)O–, –OS(=O)2O–, –NRaC(=O)O–, –22 NRaC(=NRa)O–, –NRaS(=O)O–, –NRaS(=O)2O–, –OC(=O)NRa–, –OC(=NRa)NRa–, – OS(=O)NRa–, –OS(=O)2NRa–, –NRaC(=O)NRa–, –NRaC(=NRa)NRa–, –NRaS(=O)NRa–, –24 NRaS(=O)2NRa–, –C(=O)–, –C(=NRa)–, –S(=O)–, –S(=O)2–, –OP(=O)(ORa)O–, – SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–; 26 each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when 28 attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted 30 or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;each of L4B1, L4B2, and L4B3is independently a single bond, substituted or unsubstituted, 2 C1-100alkylene, or substituted or unsubstituted, C1-100heteroalkylene; each of L4C1and L4C2is a single bond, substituted or unsubstituted heterocyclylene that 4 replaces one of the backbone atoms, or substituted or unsubstituted heteroarylene that replaces one of the backbone atoms; and 6 bond C4Ais attached to A4. 8 108. The oligonucleotide of any one of claims 1-107, wherein: at least one instance of y4 is 2; 112 each of –L4A21–L4A22–, –L4A23–L4A24–, –L4A25–L4A26–, –L4A27–L4A28–, –L4A29–L4A30–, – L4A31–L4A32–, –L4A33–L4A34–, –L4A35–L4A36–, –L4A37–L4A38–, –L4A39–L4A40–, –L4A41–L4A42–, –14 L4A43–L4A44–, –L4A45–L4A46–, –L4A47–L4A48–, and –L4A49–L4A50– is independently a single bond, – O–, –S–, –S–S–, –NRa–, –C(=O)O–, –C(=NRa)O–, –S(=O)O–, –S(=O)2O–, –C(=O)NRa–, –16 C(=NRa)NRa–, –S(=O)NRa–, –S(=O)2NRa–, –OC(=O)–, –OC(=NRa)–, –OS(=O)–, –OS(=O)2–, – NRaC(=O)–, –NRaC(=NRa)–, –NRaS(=O)–, –NRaS(=O)2–, –OC(=O)O–, –OC(=NRa)O–, – 18 OS(=O)O–, –OS(=O)2O–, –NRaC(=O)O–, –NRaC(=NRa)O–, –NRaS(=O)O–, –NRaS(=O)2O–, – OC(=O)NRa–, –OC(=NRa)NRa–, –OS(=O)NRa–, –OS(=O)2NRa–, –NRaC(=O)NRa–, – 20 NRaC(=NRa)NRa–, –NRaS(=O)NRa–, –NRaS(=O)2NRa–, –C(=O)–, –C(=NRa)–, –S(=O)–, – S(=O)2–, –OP(=O)(ORa)O–, –SP(=O)(ORa)O–, –OP(=O)(ORa)S–, or –OP(=O)(SRa)O–; 22 each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when 24 attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to a nitrogen atom are joined with the nitrogen atom to form substituted 26 or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;each of L4B4, L4B5, L4B6, L4B7, L4B8, L4B9, L4B10, L4B11, and L4B12is independently a single 2 bond, substituted or unsubstituted, C1-100alkylene, or substituted or unsubstituted, C1-100heteroalkylene; 4 each of L4C3, L4C4, L4C5, L4C6, L4C7, and L4C8is a single bond, substituted or unsubstituted heterocyclylene that replaces one of the backbone atoms, or substituted or unsubstituted 6 heteroarylene that replaces one of the backbone atoms; bond C4Bis attached to a first instance of A4; and 8 bond C4Cis attached to a second instance of A4. 10 109. The oligonucleotide of any one of claims 1-108, wherein at least one instance of L4, when present, is substituted or unsubstituted, C7-70heteroalkylene. 12 110. The oligonucleotide of any one of claims 1-109, wherein at least one instance of L4, when 14 present, is –C , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O), , , or a combination of 16 two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: 18 the number of backbone atoms of the at least one instance of L4is between 10 and 100, inclusive; and 20 the at least one instance of L4does not comprise O–O, O–N, N–O, or N–N. 22 111. The oligonucleotide of any one of claims 1-110, wherein at least one instance of L4, when present, is –C, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, – 24 NHC(=, or a combination of two or more instances of each one of the foregoing, or a combination of two or more of the foregoing, provided that: 26 the number of backbone atoms of the at least one instance of L4is between 10 and 100, inclusive; the at least one instance of L4does not comprise O–O, O–N, N–O, or N–N; andthe combined number of –C(=O)NH–, –NHC(=O)–, , of the at least 2 one instance of L4is between 0 and 4, inclusive. 4 112. The oligonucleotide of any one of claims 1-111, wherein each instance of A4is a radical of a ligand. 6 113. The oligonucleotide of any one of claims 1-112, wherein: 8 at least one instance of A4is a radical of a ligand; and at least one instance of A4is a radical of a lipid. 10 114. The oligonucleotide of any one of claims 1-113, wherein each instance of A4is a radical 12 of a lipid. 14 115. The oligonucleotide or nucleoside of any one of claims 1-114, wherein: the substituted or unsubstituted heteroarylene or substituted or unsubstituted 16 heterocyclylene that replaces one of the backbone atoms is of the formula: 182; k21 is 0, 1, 2, 3, or 4; 4 each instance of Rd, if present, is independently halogen, substituted or unsubstituted, C1-6alkyl, or –O–(substituted or unsubstituted, C1-6alkyl); 6 k22 is 0, 1, 2, 3, or 4; each instance of Re, if present, is independently halogen, substituted or unsubstituted, C1-68 alkyl, or –O–(substituted or unsubstituted, C1-6alkyl); k23 is an integer between 0 and 11, inclusive; 10 each instance of Rf, if present, is independently halogen, substituted or unsubstituted, C1-6alkyl, or –O–(substituted or unsubstituted, C1-6alkyl); and 12 Rgis hydrogen, halogen, substituted or unsubstituted, C1-6alkyl, or –O–(substituted or unsubstituted, C1-6alkyl). 14 116. The oligonucleotide of any one of claims 1-115, wherein in at least one instance of the 16 moiety of Formula I: each instance of y1 is 0; 18 y2 is 0; and y3 is 1. 20 117. The oligonucleotide of any one of claims 1-116, wherein in at least one instance of the 22 moiety of Formula I: each instance of y1 is 0; 24 y2 is 0; and y3 is 2. 26118. The oligonucleotide of any one of claims 1-117, wherein in at least one instance of the 2 moiety of Formula I: t1 is 1; 4 y1 is 1; y2 is 0; and 6 y3 is 1. 8 119. The oligonucleotide of any one of claims 1-118, wherein in at least one instance of the moiety of Formula I: 10 each instance of y1 is 0; y2 is 1; and 12 y3 is 1. 14 120. The oligonucleotide of any one of claims 1-119, wherein in at least one instance of the moiety of Formula I, each of t1, y1, y2, and y3 is 1. 16 121. The oligonucleotide of any one of claims 1-120, wherein in at least one instance of the 18 moiety of Formula I: y1 is 0; 20 y2 is 2; and y3 is 1. 22 122. The oligonucleotide of any one of claims 1-121 further comprising one or more 24 modifications independently selected from modified sugars, modified nucleobases, and modified internucleosidic linkers. 26 123. The oligonucleotide of any one of claims 1-122, wherein at least one instance of the28 modified sugars is a 2′-fluoro-2′-deoxyribose, 2′-O-methylribose, 2′-thioribose, 2′,3′- dideoxyribose, 2′-amino-2′-deoxyribose, 2′ deoxyribose, 2′-azido-2′-deoxyribose, 2′-O- 30 methyldeoxyribose, 3′-amino-2′,3′-dideoxyribose, 3′-azido-2′,3′-dideoxyribose, 3′-deoxyribose, 3′-O-(2-nitrobenzyl)-2′-deoxyribose, 3′-O-methylribose, 5′-aminoribose, 5′-thioribose, 5-nitro-1- 32 indolyl-2′-deoxyribose, 5′-biotin-ribose, 2′-O,4′-C-amino-linked ribose, 2′-O,4′-C-thio-linked ribose, 2’-O-methoxyethyl ribose, 2’-O,4’-C-methylene-linked ribose, 2’-O,4’-C-ethylene-linked 34 ribose, 2’,4’-constrained ethyl ribose, locked sugar, or a bicyclic sugar.2 124. The oligonucleotide of any one of claims 1-123, wherein at least one instance of the modified nucleobases is xanthine, allyaminouracil, allyaminothymidine, hypoxanthine, 4 digoxigeninated adenine, digoxigeninated cytosine, digoxigeninated guanine, digoxigeninated uracil, 6-chloropurineriboside, N6-methyladenine, methylpseudouracil, 2-thiocytosine, 2- 6 thiouracil, 5-methyluracil, 4-thiothymidine, 4-thiouracil, 5,6-dihydro-5-methyluracil, 5,6- dihydrouracil, 5-[(3-Indolyl)propionamide-N-allyl]uracil, 5-aminoallylcytosine, 5- 8 aminoallyluracil, 5-bromouracil, 5-bromocytosine, 5-carboxycytosine, 5- carboxymethylesteruracil, 5-carboxyuracil, 5-fluorouracil, 5-formylcytosine, 5-formyluracil, 5-10 hydroxycytosine, 5-hydroxymethylcytosine, 5-hydroxymethyluracil, 5-hydroxyuracil, 5- iodocytosine, 5-iodouracil, 5-methoxycytosine, 5-methoxyuracil, 5-methylcytosine, 5-12 methyluracil, 5-propargylaminocytosine, 5-propargylaminouracil, 5-propynylcytosine, 5- propynyluracil, 6-azacytosine, 6-azauracil, 6-chloropurine, 6-thioguanine, 7-deazaadenine, 7-14 deazaguanine, 7-deaza-7-propargylaminoadenine, 7-deaza-7-propargylaminoguanine, 8- azaadenine, 8-azidoadenine, 8-chloroadenine, 8-oxoadenine, 8-oxoguanine, araadenine,16 aracytosine, araguanine, arauracil, biotin-16-7-deaza-7-propargylaminoguanine, biotin-16- aminoallylcytosine, biotin-16-aminoallyluracil, cyanine 3-5-propargylaminocytosine, cyanine 3-18 6-propargylaminouracil, cyanine 3-aminoallylcytosine, cyanine 3-aminoallyluracil, cyanine 5-6- propargylaminocytosine, cyanine 5-6-propargylaminouracil, cyanine 5-aminoallylcytosine, 20 cyanine 5-aminoallyluracil, cyanine 7-aminoallyluracil, dabcyl-5-3-aminoallyluracil, desthiobiotin-16-aminoallyl-uracil, desthiobiotin-6-aminoallylcytosine, isoguanine, N1- 22 ethylpseudouracil, N1-methoxymethylpseudouracil, N1-methyladenine, N1-methylpseudouracil, N1-propylpseudouracil, N2-methylguanine, N4-biotin-OBEA-cytosine, N4-methylcytosine, N6- 24 methyladenine, O6-methylguanine, pseudoisocytosine, pseudouracil, thienocytosine, thienoguanine, thienouracil, xanthosine, 3-deazaadenine, 2,6-diaminoadenine, 2,6-26 daminoguanine, 5-carboxamide-uracil, 5-ethynyluracil, N6-isopentenyladenine (i6A), 2-methyl- thio-N6-isopentenyladenine (ms2i6A), 2-methylthio-N6-methyladenine (ms2m6A), N6-(cis- 28 hydroxyisopentenyl)adenine (io6A), 2-methylthio-N6-(cis-hydroxyisopentenyl)adenine (ms2io6A), N6-glycinylcarbamoyladenine (g6A), N6-threonylcarbamoyladenine (t6A), 2- 30 methylthio-N6-threonyl carbamoyladenine (ms2t6A), N6-methyl-N6-threonylcarbamoyladenine (m6t6A), N6-hydroxynorvalylcarbamoyladenine (hn6A), 2-methylthio-N6-hydroxynorvalyl 32 carbamoyladenine (ms2hn6A), N6,N6-dimethyladenine (m62A), and N6-acetyladenine (ac6A).

125. The oligonucleotide of any one of claims 1-124, wherein at least one instance of the 2 modified internucleosidic linkers is a phosphorothioate internucleosidic linker, phosphorothiolate internucleosidic linker, or a methylphosphonate internucleosidic linker. 4 126. The oligonucleotide or nucleoside of any one of claims 1-125 comprising at least two 6 ligands that are of the same ligand type. 8 127. The oligonucleotide or nucleoside of any one of claims 1-126 comprising at least two ligands that are the same. 10 128. The oligonucleotide or nucleoside of any one of claims 1-127 comprising at least two 12 ligands that are different ligands of the same ligand type. 14 129. The oligonucleotide or nucleoside of any one of claims 1-128 comprising at least two ligands that are of different ligand types. 16 130. The oligonucleotide or nucleoside of any one of claims 1-129, wherein at least one ligand 18 is a small molecule, peptide, or protein. 20 131. The oligonucleotide or nucleoside of any one of claims 1-130, wherein at least one ligand is a central nervous system receptor ligand. 22 132. The oligonucleotide or nucleoside of any one of claims 1-131, wherein at least one ligand 24 is a tropomyosin receptor B (TrkB) ligand. 26 133. The oligonucleotide or nucleoside of any one of claims 1-132, wherein: at least one TrkB ligand is a compound of the formula: 2824 R2is hydrogen, -OR7, -SR8, or -NR9R10; R3is hydrogen, -OR31, -SR32, or -NR33R34; 6 R4is hydrogen, -OR35, -SR36, or -NR37R38; R5is hydrogen, -OR39, -SR40, or -NR41R42; 8 R6is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH2, optionally substituted -NHAc, -SH, or =O; 10 R7, R8, R9, R10, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, and R42are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, 12 optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; 14 Y is CH2, NH, S, or O; Z is optionally substituted aryl or optionally substituted heteroaryl; 16 R11and R13are each independently absent, hydrogen, or optionally substituted alkyl; R12, R14, and R15are each independently hydrogen, optionally substituted alkyl, 18 optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R16is hydrogen, halogen, –CN, –N3, –SOn16R1A, –SOv16NR16BR16C, -NHNR16BR16C, 2 -ONR16BR16C, -NHC(O)NHNR16BR16C, -NHC(O)NR16BR16C, –N(O)m16, –NR16BR16C, –C(O)R16D, –C(O)OR16D, –C(O)NR16BR16C, –OR16A, -NR16BSO2R16A, -NR16BC(O)R16D, - 4 NR16BC(O)OR16D, –NR16BOR16D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted 6 aryl, or optionally substituted heteroaryl;and are each independently a single bond or a double bond, wherein ifis a 8 single bond,then is a double bond and R13is absent; and further wherein ifis a single bond, then is a double bond and R11is absent; 10 R16A, R16B, R16C, R16Dare each independently hydrogen, halogen, –CF3, –CCl3, –CBr3, – CI3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted 12 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R16Band R16C14 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 16 R17, R18, and R19are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted 18 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R20is hydrogen, halogen, –CN, –N3, –SOn20R1A, –SOv20NR20BR20C, -NHNR20BR20C, 20 -ONR20BR20C, -NHC(O)NHNR20BR20C, -NHC(O)NR20BR20C, –N(O)m20, –NR20BR20C, –C(O)R20D, –C(O)OR20D, –C(O)NR20BR20C, –OR20A, -NR20BSO2R20A, -NR20BC(O)R20D, - 22 NR20BC(O)OR20D, –NR20BOR20D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted 24 aryl, or optionally substituted heteroaryl; R21is hydrogen, halogen, –CN, –N3, –SOn21R1A, –SOv21NR21BR21C, -NHNR21BR21C, 26 -ONR21BR21C, -NHC(O)NHNR21BR21C, -NHC(O)NR21BR21C, –N(O)m21, –NR21BR21C, –C(O)R21D, –C(O)OR21D, –C(O)NR21BR21C, –OR21A, -NR21BSO2R21A, -NR21BC(O)R21D, - 28 NR21BC(O)OR21D, –NR21BOR21D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted 30 aryl, or optionally substituted heteroaryl; R22and R23are each independently hydrogen, optionally substituted alkyl, optionally 32 substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;R24is hydrogen, halogen, –CN, –N3, –SOn24R1A, –SOv24NR24BR24C, -NHNR24BR24C, 2 -ONR24BR24C, -NHC(O)NHNR24BR24C, -NHC(O)NR24BR24C, –N(O)m24, –NR24BR24C, –C(O)R24D, –C(O)OR24D, –C(O)NR24BR24C, –OR24A, -NR24BSO2R24A, -NR24BC(O)R24D, – 4 NR24BC(O)OR24D, –NR24BOR24D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted 6 aryl, or optionally substituted heteroaryl; R20A, R20B, R20C, R20D, R21A, R21B, R21C, R21D, R24A, R24B, R24C, and R24Dare each 8 independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3,–COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 10 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R20B, R20C, R21B, R21C, R24B, R24C, R24B, and R24C12 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 14 n16, n20, n21, n23, n24, z6, and z8 are each independently 0, 1, 2, 3, or 4; v16, v20, v21, m16, m20, m21, and m24 are each independently 1 or 2; 16 z3 is 0, 1, 2, 3, 4, or 5; z4 and z7 are each independently 0, 1, or 2; 18 z5 is 0, 1, 2, or 3; and z6 and z8 are each independently 0, 1, 2, 3, or 4. 20 134. The oligonucleotide or nucleoside of any one of claims 1-133, wherein at least one radical 22 of a TrkB ligand is of the formula:. 24 135. The oligonucleotide or nucleoside of any one of claims 1-134, wherein at least one radical 26 of a TrkB ligand is of the formula:10137. The oligonucleotide or nucleoside of any one of claims 1-136, wherein at least one TrkB 2 ligand is 3,7-dihydroxyflavone, 3,7,8,2燵-tetrahydroxyflavone, 7,3 -dihydroxyflavone, 7,8,2燵- trihydroxyflavone, 7,8,3 -trihydroxyflavone, 7,8,4-trihydroxyflavone, diosmetin (5,7,3 - 4 trihydroxy-4-methoxyflavone), 7-hydroxy-4-methoxyflavone, 8-hydroxy-7-methoxyflavone, eutropoflavin (4-dimethylamino-7,8-dihydroxyflavone), norwogonin (5,7,8-trihydroxyflavone), 6 R7, R13, tropoflavin (7,8-dihydroxyflavone), 7,8-dimethoxyflavone, quercetin (3,3燵,4燵,5,7- pentahydroxyflavone), apigenin (4燵,5,7-trihydroxyflavone), isocoumarin, gossypetin (3,5,7,8,3燵,4燵 8 -hexahydroxyflavone), 2-methyl-8-phenylchromeno[7,8-d]imidazol-6(3H)-one, 8- phenylchromeno[7,8-d]imidazol-6(3H)-one, 4-oxo-2-phenyl-4H-chromene-7,8-diyl diacetate, 10 ANA-12, or an anti-TrkB antibody. 12 138. The oligonucleotide or nucleoside of any one of claims 1-137, wherein at least one ligand is an α4β1 / 7integrin ligand. 14 139. The oligonucleotide or nucleoside of any one of claims 1-138, wherein at least one α4β1 / 716 integrin ligand is a compound of the formula:,,,or is a radical of an anti-α4β1 / 7integrin antibody. 4 140. The oligonucleotide or nucleoside of any one of claims 1-139, wherein: 6 at least one radical of an α4β1 / 7integrin ligand is of the formula:8 R2Zis hydrogen, polyethylene glycol, substituted or unsubstituted heteroalkyl, or substituted or unsubstituted heteroaryl; and 10 each of R3Zand R4Zis independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted –O–alkyl. 12 141. The oligonucleotide or nucleoside of any one of claims 1-140, wherein: 14 at least one radical of an α4β1 / 7integrin ligand is of the formula:2 R4Zis hydrogen, halogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted –O–alkyl, or 4 optionally substituted cycloalkyl; R5Zis optionally substituted heteroalkyl or optionally substituted heterocyclyl; and 6 n1Z is 1, 2, or 3. 8 142. The oligonucleotide or nucleoside of any one of claims 1-141, wherein: at least one radical of an α4β1 / 7integrin ligand is of the formula: 10 12R6Zis hydrogen, –OH, –NH2, –NHR7Z, –OR7Z, or absent; and 14 R7Zis hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. 16 143. The oligonucleotide or nucleoside of any one of claims 1-142, wherein: 18 at least one radical of an α4β1 / 7integrin ligand is of the formula:; 2 n2Z is 0, 1, 2, or 3. 4 144. The oligonucleotide or nucleoside of any one of claims 1-143, wherein: at least one radical of an α4β1 / 7integrin ligand is of the formula: 6 8r24 145. The oligonucleotide or nucleoside of any one of claims 1-144, wherein: at least one radical of an α4β1 / 7integrin ligand is of the formula:8 each of R8Z, R9Z, R10Z, and R11Zis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted –O–alkyl, or substituted or unsubstituted cycloalkyl;each of R12Zand R13Zis independently H, halogen, optionally substituted alkyl, optionally ,4 R14Zis optionally substituted C1-C5alkyl, optionally substituted C1-C5alkylene-(C3-C6)- cycloalkyl, or optionally substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. 6 146. The oligonucleotide or nucleoside of any one of claims 1-145, wherein: 8 at least one radical of an α4β1 / 7integrin ligand is of the formula:. 10 147. The oligonucleotide or nucleoside of any one of claims 1-146, wherein: 12 at least one radical of an α4β1 / 7integrin ligand is of the formula:,r 2; R15Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted 4 heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; each of R16Zand R17Zis independently H, halogen, optionally substituted alkyl, or 6 optionally substituted –O–alkyl; and YZis –CH2– or –(CH2)2–. 8 148. The oligonucleotide or nucleoside of any one of claims 1-147, wherein: 10 at least one radical of an α4β1 / 7integrin ligand is of the formula: r 12; R18Zis H, –OH, –NH2, –NHR19Z, –OR19Z, or –CONHR19Z; 14 each instance of R19Zis independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally 16 substituted heteroaryl; and n4Z is 1 or 2. 18 149. The oligonucleotide or nucleoside of any one of claims 1-148, wherein: 20 at least one radical of an α4β1 / 7integrin ligand is of the formula:; 2 R19Zis H, –CH2OR20Z, –(CH2)2OR20Z, –CH2NHCOR20Z, or –OR20Z; and R20Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted 4 heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. 6 150. The oligonucleotide or nucleoside of any one of claims 1-149, wherein: at least one radical of an α4β1 / 7integrin ligand is of the formula: 8R21Zis H, –CONHR22Z, –CH2OR22Z, –(CH2)2OR22Z, –CH2NHCOR22Z, or –OR22Z; 10 R22Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and 12 X1Zis H or halogen. 14 151. The oligonucleotide or nucleoside of any one of claims 1-150, wherein: at least one radical of an α4β1 / 7integrin ligand is of the formula: 16 r; 18 R23Zis H, -CONHR24Z, -CH2OR24Z, -(CH2)2OR24Z, -CH2NHCOR24Z, or -OR24Z; R24Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted 20 heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n5Z is 0 1 2 or 32 152. The oligonucleotide or nucleoside of any one of claims 1-151, wherein: at least one radical of an α4β1 / 7integrin ligand is of the formula: ,4 R25Zis H, –CONHR27Z, –CH2OR27Z, –(CH2)2OR27Z, –CH2NHCOR27Z, or –OR27Z; R26Zis H, optionally substituted alkyl, or optionally substituted cycloalkyl; 6 R27Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and 8 X2Zis optionally substituted CH2or optionally substituted NH. 10 153. The oligonucleotide or nucleoside of any one of claims 1-152, wherein: at least one radical of an α4β1 / 7integrin ligand is of the formula: 12; R28Zis H, –CH2OR30Z, –(CH2)2OR30Z, –CH2NHCOR30Z, or –OR30Z; 14 R29Zis H, –OH, –NH2, –NHR31Z, or –OR31Z; R30Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted 16 heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;R31Zis H, polyethylene glycol, optionally substituted alkyl, optionally substituted 2 heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n3Z is 1, 2, or 3. 4 154. The oligonucleotide or nucleoside of any one of claims 1-153, wherein at least one ligand 6 is a cannabinoid receptor type 1 (CB1) ligand. 8 155. The oligonucleotide or nucleoside of any one of claims 1-154, wherein: at least one CB1 ligand is a compound of the formula: 10; X1Yis NR10Yor CR11YR12Y; 12 each of R10Y, R11Y, and R12Yis independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted 14 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R19Yis hydrogen, –SOn19YR19YA, –SOv19YNR19YBR19YC, -NHNR19YBR19YC,16 -ONR19YBR19YC, -NHC(O)NHNR19YBR19YC, -NHC(O)NR19YBR19YC, –NR19YBR19YC, – C(O)R19YD, –C(O)OR19YD, –C(O)NR19YBR19YC, –OR19YA, -NR19YBSO2R19YA, -NR19YBC(O)R19YD, 18 –NR19YBC(O)OR19YD, –NR19YBOR19YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally 20 substituted aryl, or optionally substituted heteroaryl; each of R19YA, R19YB, R19YC, and R19YDis independently hydrogen, halogen, –CF3, –CCl3, 22 –CBr3, –Cl3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, 24 substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R19YBand R19YCbonded to the same nitrogen atom are joined to form a substituted or unsubstituted 26 heterocycloalkyl or substituted or unsubstituted heteroaryl; n19Y is 0, 1, 2, 3, or 4; and 28 v19Y is 1 or 2.2 156. The oligonucleotide or nucleoside of any one of claims 1-155, wherein: at least one radical of a CB1ligand is of the formula:

4. 6 157. The oligonucleotide or nucleoside of any one of claims 1-156, wherein: at least one radical of a CB1ligand is of the formula:

8. 10 158. The oligonucleotide or nucleoside of any one of claims 1-157, wherein: at least one CB1 ligand is a compound of the formula: 12, wherein: 14 R17Yis hydrogen, –SOn17YR17YA, –SOv17YNR17YBR17YC, -NHNR17YBR17YC, -ONR17YBR17YC, -NHC(O)NHNR17YBR17YC, -NHC(O)NR17YBR17YC, –NR17YBR17YC, –16 C(O)R17YD, –C(O)OR17YD, –C(O)NR17YBR17YC, –OR17YA, –NR17YBSO2R17YA, – NR17YBC(O)R17YD, –NR17YBC(O)OR17YD, –NR17YBOR17YD, optionally substituted alkyl, 18 optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;each of R17YA, R17YB, R17YC, and R17YDis independently hydrogen, halogen, –CF3, –CCl3, 2 –CBr3, –Cl3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, 4 substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R17YBand R17YCsubstituents bonded to the same nitrogen atom may optionally be joined to form a 6 substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; n17Y is 0, 1, 2, 3, or 4; and 8 v17Y is 1 or 2. 10 159. The oligonucleotide or nucleoside of any one of claims 1-158, wherein: at least one radical of a CB1 ligand is of the formula:

12. 14 160. The oligonucleotide or nucleoside of any one of claims 1-159, wherein: at least one CB1 ligand is a compound of the formula:

16. 18 161. The oligonucleotide or nucleoside of any one of claims 1-160, wherein: at least one radical of a CB1ligand is of the formula:. 2 162. The oligonucleotide or nucleoside of any one of claims 1-161, wherein: 4 at least one CB1 ligand is a compound of the formula:, 6 R3Y, R4Y, R5Y, R6Y, and R8Yare each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally 8 substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R9Yis hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl; or R6Y10 and R9Ysubstituents may be joined together form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl; 12 R7Yis hydrogen, –SOn7YR7YA, –SOv7YNR7YBR7YC, -NHNR7YBR7YC, -ONR7YBR7YC, -NHC(O)NHNR7YBR7YC, -NHC(O)NR7YBR7YC, –NR7YBR7YC, –C(O)R7YD, –C(O)OR7YD, –14 C(O)NR7YBR7YC, –OR7YA, –NR7YBSO2R7YA, –NR7YBC(O)R7YD, –NR7YBC(O)OR7YD, – NR7YBOR7YD, optionally substituted alkyl, optionally substituted heteroalkyl, optionally 16 substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 18 R7YA, R7YB, R7YC, R7YDare each independently hydrogen, halogen, –CF3, –CCl3, –CBr3, – CI3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted 20 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 22 wherein R7YBand R7YCsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; 24 n7Y is 0, 1, 2, 3, or 4; and v7Y is 1 or 2.2 163. The oligonucleotide or nucleoside of any one of claims 1-162, wherein: 4 ,, . 6 164. The oligonucleotide or nucleoside of any one of claims 1-163, wherein: 8 at least one CB1ligand is a compound of the formula:, 10 R16Yis hydrogen, halogen, –CN, –N3, –NO2, –NR16YBR16YC, –C(O)R16YD, –C(O)OR16YD, –C(O)NR16YBR16YC, –OR16YA, –NR16YBC(O)R16YD, optionally substituted alkyl, optionally 12 substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and 14 R16YA, R16YB, R16YC, and R16YDare each independently hydrogen, halogen, –CF3, –CCl3, – CBr3, –Cl3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted 16 heteroalkyl substituted or unsubstituted cycloalkyl substituted or unsubstituted heterocycloalkylsubstituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R16YBand R16YC2 bonded to the same nitrogen atom are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. 4 165. The oligonucleotide or nucleoside of any one of claims 1-164, wherein: 6 at least one radical of a CB1 ligand is of the formula:. 8 166. The oligonucleotide or nucleoside of any one of claims 1-165, wherein: 10 at least one CB1 ligand is a compound of the formula: , 1. 14 167. The oligonucleotide or nucleoside of any one of claims 1-166, wherein at least one ligand is a N-methyl-D-aspartate (NMDA) receptor ligand. 16 168. The oligonucleotide or nucleoside of any one of claims 1-167, wherein at least one 18 NMDA receptor ligand is a compound of the formula:4 or is a radical of an anti-NMDA receptor antibody. 6 169. The oligonucleotide or nucleoside of any one of claims 1-168, wherein at least one radical of an NMDA receptor ligand is of the formula:

8. 10 170. The oligonucleotide or nucleoside of any one of claims 1-169, wherein at least one radical of an NMDA receptor ligand is of the formula:

12. 14 171. The oligonucleotide or nucleoside of any one of claims 1-170, wherein at least one radical of an NMDA receptor ligand is of the formula:. 2 172. The oligonucleotide or nucleoside of any one of claims 1-171, wherein at least one radical 4 of an NMDA receptor ligand is of the formula:. 6 173. The oligonucleotide or nucleoside of any one of claims 1-172, wherein at least one radical 8 of an NMDA receptor ligand is of the formula:. 10 174. The oligonucleotide or nucleoside of any one of claims 1-173, wherein at least one radical 12 of an NMDA receptor ligand is of the formula:. 14 175. The oligonucleotide or nucleoside of any one of claims 1-174, wherein at least one radical 16 of an NMDA receptor ligand is of the formula:.2 176. The oligonucleotide or nucleoside of any one of claims 1-175, wherein at least one radical of an NMDA receptor ligand is of the formula:

4. 6 177. The oligonucleotide or nucleoside of any one of claims 1-176, wherein at least one radical of an NMDA receptor ligand is of the formula:

8. 10 178. The oligonucleotide or nucleoside of any one of claims 1-177, wherein at least one radical of an NMDA receptor ligand is of the formula:

12. 14 179. The oligonucleotide or nucleoside of any one of claims 1-178, wherein at least one radical of an NMDA receptor ligand is of the formula:

1. 18 180. The oligonucleotide or nucleoside of any one of claims 1-179, wherein at least one lipid is a radical of: a fatty acyl, glycerolipid, glycerophospholipid, sphingolipid, saccharolipid, 20 polyketide sterol lipid or prenol lipid2 181. The oligonucleotide or nucleoside of any one of claims 1-180, wherein at least one lipid is a radical of: a fatty acid or conjugate, octadecanoid, eicosanoid, docosanoid, fatty alcohol, fatty 4 aldehyde, fatty ester, fatty amide, fatty nitrile, fatty ether, hydrocarbon, oxygenated hydrocarbon, or fatty acyl glycoside. 6 182. The oligonucleotide or nucleoside of any one of claims 1-181, wherein at least one lipid is 8 a radical of a hydrocarbon. 10 183. The oligonucleotide or nucleoside of any one of claims 1-182, wherein at least one lipid is unsubstituted C6-30 alkyl, C6-30 alkyl substituted with one or more fluoro as valency permits, 12 unsubstituted C6-30alkenyl, or C6-30alkenyl substituted with one or more fluoro as valency permits. 14 184. The oligonucleotide or nucleoside of any one of claims 1-183, wherein at least one lipid is 16 unsubstituted C16-28alkyl or unsubstituted C16-28alkenyl, each of which is independently unbranched, bi-branched, or tri-branched. 18 185. The oligonucleotide or nucleoside of any one of claims 1-184, wherein at least one lipid is 20 unbranched unsubstituted C18-26alkyl. 22 186. The oligonucleotide or nucleoside of any one of claims 1-185, wherein at least one lipid is –(CH2)21CH3. 24 187. The oligonucleotide or nucleoside of any one of claims 1-186, wherein at least one lipid is 26 a radical of: a monoradylglycerol, diradylglycerol, triradylglycerol, glycosylmonoradylglycerol, glycosyldiradylglycerol, betaine monoradylglycerol, or betaine diradylglycerol. 28 188. The oligonucleotide or nucleoside of any one of claims 1-187, wherein at least one lipid is 30 a radical of: a glycerophosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoglycerol, glycerophosphoglycerophosphate, glycerophosphoinositol, 32 glycerophosphoinositol monophosphate, glycerophosphoinositol bisphosphate, glycerophosphoinositol trisphosphate, glycerophosphate, glyceropyrophosphate, 34 glycerophosphoglycerophosphoglycerol, CDP-glycerol, glycosylglycerophospholipid,glycerophosphoinositolglycan, glycerophosphonocholine, glycerophosphonoethanolamine, di- 2 glycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphoethanolamine glycan, dihydroxyacetonephosphate, 4 glycerophosphoethanol, glycerophosphothreonine, or cyclic glycerophosphatidic acid. 6 189. The oligonucleotide or nucleoside of any one of claims 1-188, wherein at least one lipid is a radical of: a sphingoid base, ceramide, phosphosphingolipid, phosphonosphingolipid, neutral 8 glycosphingolipid, acidic glycosphingolipid, basic glycosphingolipid, amphoteric glycosphingolipid, or arsenosphingolipid. 10 190. The oligonucleotide or nucleoside of any one of claims 1-189, wherein at least one lipid is 12 a radical of: a sterol, steroid, secosteroid, bile acid or a derivative thereof, or steroid conjugate. 14 191. The oligonucleotide or nucleoside of any one of claims 1-190, wherein at least one lipid is a radical of cholesterol. 16 192. The oligonucleotide or nucleoside of any one of claims 1-191, wherein at least one lipid is 18 a radical of: an isoprenoid, quinone, hydroquinone, polyprenol, or hopanoid. 20 193. The oligonucleotide or nucleoside of any one of claims 1-192, wherein at least one lipid is an acylaminosugar, acylaminosugar glycan, acyltrehalose, or acyltrehalose glycan. 22 194. The oligonucleotide or nucleoside of any one of claims 1-193, wherein at least one lipid is 24 a linear polyketide, halogenated acetogenin, annonaceae acetogenin, macrolide, lactone polyketide, ansamycin, polyene, linear tetracycline, angucycline, polyether antibiotic, aflatoxin, 26 cytochalasin, flavonoid, aromatic polyketide, non-ribosomal peptide / polyketide hybrid, or phenolic lipid. 28 195. The oligonucleotide of any one of claims 1-194, wherein Formula I is:2 , 4,,, 2,2 196. The oligonucleotide of any one of claims 1-195, wherein the sense oligonucleotide strand has at least 80%, at least 85%, at least 90%, or at least 95% identity to SEQ ID NO.: 1 or 2. 4 197. The oligonucleotide of any one of claims 1-196, wherein the sense oligonucleotide strand 6 has at least 80%, at least 85%, at least 90%, or at least 95% identity to SEQ ID NO.: 3 or 4. 8 198. The oligonucleotide of any one of claims 1-197, wherein the sense oligonucleotide strand has at least 80%, at least 85%, at least 90%, or at least 95% identity to SEQ ID NO.: 5 or 6. 10 199. A pharmaceutical composition comprising the oligonucleotide of any one of claims 1- 12 198, or pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient. 14 200. The pharmaceutical composition of claim 199 further comprising an additional 16 pharmaceutical agent. 18 201. A kit comprising: the oligonucleotide of any one of claims 1-198, or pharmaceutically acceptable salt or 20 prodrug thereof, or the pharmaceutical composition of claim 199 or 200; and instructions for using the oligonucleotide, pharmaceutically acceptable salt or prodrug, or 22 pharmaceutical composition. 24 202. A method for delivering an oligonucleotide to a subject comprising administering to the subject the oligonucleotide of any one of claims 1-198, or a pharmaceutically acceptable salt or 26 prodrug thereof, or the pharmaceutical composition of claim 199 or 200. 28 203. Use of the oligonucleotide of any one of claims 1-198, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 199 or 200, for the 30 manufacture of a medicament for delivering the oligonucleotide to a subject. 32 204. The oligonucleotide of any one of claims 1-198, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of any one of claims 199 or 200, for use in 34 delivering the oligonucleotide to a subject.2 205. The method of claim 202, the use of claim 203, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of 4 claim 204, wherein the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition is delivered to the brain of the subject. 6 206. The method of claim 202, the use of claim 203, and the oligonucleotide, or a 8 pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 204, wherein the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, 10 or the pharmaceutical composition is delivered to the striatum, cerebellum, brain stem, hippocampus, frontal cortex, or spinal cord of the subject. 12 207. A method for treating a disease in a subject in need thereof comprising administering to 14 the subject an effective amount of the oligonucleotide of any one of claims 1-198, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 16 199 or 200. 18 208. Use of the oligonucleotide of any one of claims 1-198, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 199 or 200, for the 20 manufacture of a medicament for treating a disease in a subject in need thereof. 22 209. The oligonucleotide of any one of claims 1-198, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 199 or 200, for use in treating a 24 disease in a subject in need thereof. 26 210. A method for preventing a disease in a subject in need thereof comprising administering to the subject an effective amount of the oligonucleotide of any one of claims 1-198, or a 28 pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 199 or 200. 30 211. Use of the oligonucleotide of any one of claims 1-198, or a pharmaceutically acceptable 32 salt or prodrug thereof, or the pharmaceutical composition of claim 199 or 200, for the manufacture of a medicament for preventing a disease in a subject in need thereof. 34212. The oligonucleotide of any one of claims 1-198, or a pharmaceutically acceptable salt or 2 prodrug thereof, or the pharmaceutical composition of claim 199 or 200, for use in preventing a disease in a subject in need thereof. 4 213. The method of claim 207 or 210, the use of claim 208 or 211, and the oligonucleotide, or 6 a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 209 or 212, wherein the disease is a central nervous system disease. 8 214. The method of claim 207 or 210, the use of claim 208 or 211, and the oligonucleotide, or 10 a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 209 or 212, wherein the disease is a brain disease, Edwards syndrome, gliosis, 12 hyperekplexia, Meckel syndrome, myoclonic epilepsy myopathy sensory ataxia, narcolepsy, prion diseases, serotonin syndrome, or spinal cord disease. 14 215. The method of claim 207 or 210, the use of claim 208 or 211, and the oligonucleotide, or 16 a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 209 or 212, wherein the disease is a neurodegenerative disease. 18 216. The method of claim 207 or 210, the use of claim 208 or 211, and the oligonucleotide, or 20 a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 209 or 212, wherein the disease is ABri amyloidosis, aceruloplasminemia, acute 22 neurodegenerative disease, amyotrophic lateral sclerosis, ataxia with vitamin E deficiency, atypical Rett syndrome, beta-propeller protein-associated neurodegeneration, COASY protein- 24 associated neurodegeneration, central nervous system degenerative disease, demyelination, fatty acid hydroxylase-associated neurodegeneration, fragile X tremor ataxia syndrome, Gemignani 26 syndrome, Gerstmann-Straussler syndrome, Huntington disease, Huntington-like syndrome, hypomyelination with atrophy of basal ganglia and cerebellum, infantile cerebellar-retinal 28 degeneration, infantile neuroaxonal dystrophy, Kosaki overgrowth syndrome, mitochondrial membrane protein-associated neurodegeneration, multiple sclerosis, multiple system atrophy, 30 muscular dystrophy, Nasu-Hakola disease, neuroacanthocytosis, neurogenic ataxia and retinitis pigmentosa syndrome, neuronal ceroid lipofuscinosis, neuronal intranuclear inclusion disease, 32 neuropil thread, pantothenate kinase-associated neurodegeneration, Parkinson disease, posterior column ataxia, pure autonomic failure, retrograde degeneration, Rett syndrome, SPOANsyndrome, Salla disease, spinocerebellar ataxia, subacute combined degeneration, Tabes dorsalis, 2 tauopathy, or Wolfram syndrome. 4 217. The method of claim 207 or 210, the use of claim 208 or 211, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use 6 of claim 209 or 212, wherein the disease is a neurocognitive disorder. 8 218. The method of claim 207 or 210, the use of claim 208 or 211, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use 10 of claim 209 or 212, wherein the disease is a dementia, HIV-associated neurocognitive disorder, or memory disorder. 12 219. The method of claim 207 or 210, the use of claim 208 or 211, and the oligonucleotide, or 14 a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 209 or 212, wherein the disease is Parkinson’s disease. 16 220. The method of claim 207 or 210, the use of claim 208 or 211, and the oligonucleotide, or 18 a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 209 or 212, wherein the disease is amyotrophic lateral sclerosis. 20 221. The method of claim 207 or 210, the use of claim 208 or 211, and the oligonucleotide, or 22 a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 209 or 212, wherein the disease is Alzheimer’s disease. 24 222. The method of claim 207 or 210, the use of claim 208 or 211, and the oligonucleotide, or 26 a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 209 or 212, wherein the disease is a tauopathy, frontotemporal dementia (FTD), FTDP- 28 17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglionic degeneration (CBD), epilepsy, or Dravet’s Syndrome. 30 223. The method of claim 207 or 210, the use of claim 208 or 211, and the oligonucleotide, or 32 a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use of claim 209 or 212, wherein the oligonucleotide, or a pharmaceutically acceptable salt or 34 prodrug thereof, or the pharmaceutical composition, is administered to the subject parenterally.2 224. The method of claim 207 or 210, the use of claim 208 or 211, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use 4 of claim 209 or 212, wherein the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition, is administered to the subject intrathecally, 6 intracerebroventricularly, or intravenously. 8 225. The method of claim 207 or 210, the use of claim 208 or 211, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use 10 of claim 209 or 212, wherein the subject is a human.

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