Rnai oligonucleotide conjugates

Abstract

RNAi oligonucleotide-ligand conjugates are provided herein that inhibit or reduce expression of target genes. Also provided are compositions including the same and uses thereof, particularly uses relating to treating extrahepatic diseases, disorders and / or conditions.

Description

[0001]Attorney Docket: DCY-13025 RNAi OLIGONUCLEOTIDE CONJUGATES CROSS-REFERENCES TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 537,400 filed September 8, 2023, the contents of which is incorporated by reference herein in its entirety. TECHNICAL FIELD The disclosure relates to oligonucleotides linked to ligands useful in the inhibition of target genes in a variety of tissues (e.g., extrahepatic tissue). Specifically, the present disclosure relates to oligonucleotide-ligand conjugates, methods to prepare them, their chemical configuration, and methods to modulate (e.g., inhibit or reduce) the expression of a target gene using the conjugated nucleic acids and oligonucleotides according to the description provided herein. The disclosure also provides pharmaceutically acceptable compositions comprising the conjugates of the present description and methods of using said compositions in the treatment of various diseases or disorders. BACKGROUND OF THE DISCLOSURE Regulation of gene expression by modified nucleic acids shows great potential as both a research tool in the laboratory and a therapeutic approach in the clinic. Several classes of oligonucleotide or nucleic acid-based therapeutics have been under the clinical investigation, including antisense oligonucleotides (ASO), short interfering RNA (siRNA), double-stranded nucleic acids (dsNA), aptamers, ribozymes, exon-skipping and splice-altering oligonucleotides, immunomodulatory oligonucleotides, mRNAs, and CRISPR. Chemical modifications in the relevant molecules to allow functionality in various tissues, organs and / or cell types play a key role in overcoming challenges of oligonucleotide therapeutics, including improving nuclease stability, RNA-binding affinity, and pharmacokinetics. Various chemical modification strategies for oligonucleotides have been developed in the past three decades including modification of the sugars, nucleobases, and phosphodiester backbone to improve and optimize performance and therapeutic efficacy (Deleavey and Darma, CHEM. BIOL.2012, 19(8):937-54; Wan and Seth, J. MED. CHEM.2016, 59(21):9645-67; and Egli and Manoharan, ACC. CHEM. RES.2019, 54(4):1036-47). Dicer processed RNAi technologies utilize short double-stranded RNA (dsRNA) of approximately 21 base pair length with a two nucleotide (nt) 3’-overhang for the silencing ofFH12501620.1 Attorney Docket: DCY-13025 genes. These dsRNAs are generally called small interfering RNA (siRNA). siRNA 12 to 22 nucleotides in length are the active agent in RNAi. The siRNA duplex serves as a guide for mRNA degradation. Upon siRNA incorporation into the RNA-induced silencing complex (RISC) the complex interacts with a specific mRNA and ultimately suppresses the mRNA signal. The sense strand or passenger strand of siRNA is typically cleaved at the 9th nucleotide downstream from the 5’-end of the sense strand by Argonaute 2 (Ago2) endonuclease. The activated RISC complex containing the antisense strand or guide strand binds to the target mRNA through Watson–Crick base pairing causing degradation or translational blocking of the targeted RNA. However, the in vivo use of RNAi or siRNA molecules as pharmaceuticals has remained difficult due to obstacles encountered such as low biostability and unacceptable toxicity possibly caused by off-target effects. Various types of chemical modifications to improve the pharmacokinetics and to overcome bio-instability problems have been investigated over the years to improve the stability and specificity of the RNAi duplexes. In some cases, the chemical modification in siRNAs has improved the serum stability of siRNAs. However, often RNAi activity was lost, but the careful placement of some specific modified residues enables enhanced siRNA biostability without loss of siRNA potency. Some of these modifications have reduced siRNA side effects, such as the induction of recipient immune responses and inherent off-targeting effects and have even enhanced siRNA potency. Various chemically modified siRNAs have been investigated, among them were bridged nucleic acids (BNA’s) such as 2’,4’- methylene bridged nucleic acid 2’,4’-BNAs, also known as locked nucleic acid or LNA’s. Some of these modified siRNAs showed promising effects. Therapeutic gene silencing mediated by RNAi oligonucleotide-based therapeutics comprising siRNAs or double-stranded nucleic acids (dsNAs) offer the potential for considerable expansion of the druggable target space and the possibility for treating orphan diseases that may be therapeutically unapproachable by other drug modalities (e.g., antibodies and / or small molecules). RNAi oligonucleotide-based therapeutics that inhibit or reduce expression of specific target genes in the liver have been developed and are currently in clinical use (Sehgal et al., (2013) JOURNAL OF HEPATOLOGY 59:1354-59). Technological hurdles remain for the development and clinical use of RNAi oligonucleotides in extrahepatic cells, tissues, and organs. Thus, an ongoing need exists in the art for the successful development of new and effective RNAi oligonucleotides to modulate the expression of a target genes in extrahepatic cells, tissues, and / or organs. This is complicated by the variant nature of the cell types in extrahepatic as well as concerns about circulatory patterns and cell membraneFH12501620.1 Attorney Docket: DCY-13025 constituents such as receptor types. Over the past decade, synthetic RNAi triggers such as double stranded RNAs have become ubiquitous tools in biological research, and extensive basic and clinical development efforts have recently culminated in the FDA approval of ONPATTROtm, the first RNAi drug. Despite a burgeoning drug development pipeline and an extensive compendium of excipients targeting ligands and delivery techniques, the difficulty of delivering RNAi agents to specific populations of disease related cells and or tissues, particularly outside the liver continues to limit the potential of RNAi therapy. Repeated attempts over the past several years to develop useful, active, and persistent RNAi agents and structures for use based on known liver delivery technology have not convincingly demonstrated the intended effects outside the liver. Thus, new dsRNA’s with variant structures have been developed to overcome the limitations in the field. BRIEF SUMMARY OF THE DISCLOSURE The present disclosure is based, in part, on the discovery of RNAi oligonucleotides capable of inhibiting expression of a target gene in extrahepatic tissues while having reduced inhibition in hepatocytes. As demonstrated herein, RNAi oligonucleotides having a ligand comprising a carboxyl conjugated to a nucleotide of the sense strand showed improved efficacy and duration in extrahepatic tissues, including adipose tissue, relative to hepatocytes. Specifically, in some embodiments, target gene expression was reduced in extrahepatic tissue by the RNAi oligonucleotides at a higher amount than reduction of expression of the same target gene in hepatocytes, e.g., reduction by greater than 50% in extrahepatic tissue compared to reduction by 25% in hepatocytes. Accordingly, in some aspects, the disclosure provides a double-stranded oligonucleotide comprising: (i) an antisense strand of 15 to 30 nucleotides in length, a sense strand of 13 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extrahepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more -L-Y-(CO2H)n groups, or a charged form thereof, wherein L is a linker, Y is alkylene, alkenylene, or alkynylene, and n is 1-6, wherein when Y is alkylene, L comprises -O(CH2)a(OCH2CH2)bNH-, wherein a is 1- 6 and b is 0-5, and wherein the ligand is conjugated to a nucleotide of the sense strand.FH12501620.1 Attorney Docket: DCY-13025 In some aspects, the disclosure provides a double-stranded oligonucleotide comprising: (i) a double-stranded oligonucleotide comprising an antisense strand of 15 to 30 nucleotides in length, a sense strand of 15 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extrahepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more C6-24 alkylene-(CO2H)n, or a charged form thereof, conjugated to a nucleotide of the sense strand, wherein n is 1-6, wherein knock down of the target mRNA in the extrahepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, the disclosure provides a double-stranded oligonucleotide comprising: (i) an antisense strand of 15 to 30 nucleotides in length, a sense strand of 13 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extrahepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more -L-Y-Wngroups, or a charged form thereof, wherein L is a linker, Y is alkylene, alkenylene, or alkynylene, and n is 1-6, wherein when Y is alkylene, L comprises -O(CH2)a(OCH2CH2)bNH- or -O(CH2)a(OCH2CH2)b(NH)(CO)-, wherein a is 1-6 and b is 0-5, and wherein W is carboxyl, dicarboxyl, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(aryl), -N(H)SO2(heterocycle), -N(H)SO2(heteroaryl), -O-Benzyl- S(O2NH2), -N(H)C(O)N(H)SO2(alkyl), -N(H)C(O)(phenol), -N(H)(phenol), or heterocycle, and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, the disclosure provides a double-stranded oligonucleotide comprising: (i) a double-stranded oligonucleotide comprising an antisense strand of 15 to 30 nucleotides in length, a sense strand of 15 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extrahepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; andFH12501620.1 Attorney Docket: DCY-13025 (ii) one or more ligands, each ligand comprising one or more C6-24alkylene-Wn, or a charged form thereof, conjugated to a nucleotide of the sense strand, wherein n is 1-6, wherein W is carboxyl, dicarboxyl, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(aryl), -N(H)SO2(heterocycle), -N(H)SO2(heteroaryl), -O-Benzyl- S(O2NH2), -N(H)C(O)N(H)SO2(alkyl), -N(H)C(O)(phenol), -N(H)(phenol), heterocycle, and wherein knock down of the target mRNA in the extrahepatic tissue is greater than knock down of the target mRNA in liver tissue. In certain embodiments, n is 1. In certain such embodiments, W is preferably attached to the terminus of the Y group. For example, in certain such embodiments, W is preferably attached to the terminus of an alkylene group. In alternative embodiments, n is 2. In certain such embodiments, one occurrence of W is preferably attached to the terminus of the Y group. For example, in certain such embodiments, one occurrence of W is preferably attached to the terminus of an alkylene group. The other occurrence of W is attached elsewhere in the Y group, most preferably also at the terminus of the Y group, or one atom removed from the terminus of the Y group. In some or any of the foregoing or related embodiments, each ligand comprises a linker (L), wherein L is conjugated to the one or more C6-24alkylene-CO2H. In some embodiments, L comprises a bivalent or trivalent C1-C50 alkylene, wherein 1-25 methylene groups are optionally and independently replaced by -N(H)-, -N(C1-C4 alkyl)-, - N(cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(C1-C4 alkyl)-, - S(O)2N(cycloalkyl)-, -N(H)C(O)-, -N(C1-C4 alkyl)C(O)-, -N(cycloalkyl)C(O)-, -C(O)N(H)-, -C(O)N(C1-C4 alkyl), -C(O)N(cycloalkyl), aryl, heteroaryl, cycloalkyl, or cycloalkenyl. In some or any of the foregoing or related embodiments, 1-25 methylene groups are optionally and independently replaced by -N(H)-, -N(H)C(O)-, -N(C1-C4alkyl)C(O)-, -O-, or heteroaryl. In some embodiments, the heteroaryl is a triazolyl. In some embodiments, the triazolyl In some or any of the foregoing or related embodiments, Y is an C6-24alkylene, C6-24alkenylene, or C6-24alkynylene. In some embodiments, Y is an C6-24alkylene or C6-24alkenylene. In some embodiments, Y is a C6-24alkenylene. In some embodiments, Y is a C6-20alkylene.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, the alkenylene comprises from 1-6 olefinic bonds. In some or any of the foregoing or related embodiments, the alkynylene comprises from 1-6 acetylenic bonds. In some or any of the foregoing or related embodiments, a is 1. In some or any of the foregoing or related embodiments, b is 0 or 1. In some or any of the foregoing or related embodiments, the -L-Y-(CO2H)n group is: , wherein: M is absent, -NRC(O)-, or heteroaryl, wherein R is H or alkyl. c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. In some embodiments, M is -NRC(O)-. In some embodiments, R is H or methyl. In some embodiments, R is H. In some embodiments, M is heteroaryl. In some embodiments, the heteroaryl is triazolyl. In some embodiments, the triazolyl is . In some embodiments, M is absent. In some embodiments, c is 1. In some or any of the foregoing or related embodiments, d is 0 to 12. In some embodiments, d is 4 to 12. In some embodiments, d is 4 or 12. In some embodiments, d is 0. In some or any of the foregoing or related embodiments, e is 12 to 23. In some embodiments, e is 11, 14, 15, 20, or 21. In some or any of the foregoing or related embodiments, the extrahepatic tissue is adipose tissue, heart tissue, skeletal muscle, or adrenal gland tissue. In some embodiments, the extrahepatic tissue is adipose tissue. In some or any of the foregoing or related embodiments, the antisense strand is 22 nucleotides. In some or any of the foregoing or related embodiments, the antisense strand comprises a 3’ overhang of 2 to 6 nucleotides. In some or any of the foregoing or related embodiments, the sense strand and / or antisense strand comprises at least one modified internucleotide linkage. In some embodiments, the at least one modified internucleotide linkage is a phosphorothioate linkage.FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5’ to 3’. In some embodiments, the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5^ to 3^. In some embodiments, the sense strand comprises a phosphorothioate linkage (i) between positions 1 and 2; (ii) between positions 2 and 3; (iii) between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20; or, (iv) between positions 2 and 3, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^. In some embodiments, the sense strand is 36 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, wherein positions are numbered 1-36 from 5^ to 3^. In some embodiments, the sense strand is 20 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^. In some or any of the foregoing or related embodiments, the oligonucleotide comprises a stem-loop comprising a tetraloop. In some embodiments, the tetraloop comprises a 5’-GAAA-3’ sequence. In some or any of the foregoing or related embodiments, the sense strand and / or antisense strand comprises one or more modified nucleotides. In some or any of the foregoing or related embodiments, the modified nucleotide comprises a modified sugar. In some embodiments, the modified sugar comprises a 2’-OMe group. In some embodiments, the modified sugar comprises a 2’-F substituent. In some or any of the foregoing or related embodiments, the antisense strand comprises up to 4 contiguous nucleotides with a 2’-F modified sugar. In some embodiments, the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, and 14, numbered 5^ to 3^ comprise a 2’-F modification. In some embodiments, the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, 14, 16, and 19, numbered 5^ to 3^, comprise a 2’-F modification. In some or any of the foregoing or related embodiments, the sense strand comprises 20 nucleotides, wherein nucleotides at each of positions 8, 9, 10, and 11 numbered 5^ to 3^, comprise a 2’-F modification. In some embodiments, the sense strand comprises 36FH12501620.1 Attorney Docket: DCY-13025 nucleotides, wherein nucleotides at each of positions 3, 5, 8, 10, 12, 13, 15, and 17, numbered 5^ to 3^, comprise a 2’-F modification. In some or any of the foregoing or related embodiments, the antisense strand comprises a 4’-O-monomethylphosphonate-2’-O-methyl modified nucleotide. In some or any of the foregoing or related embodiments, the antisense strand comprises a phosphorylated nucleotide at the 5’ terminus, and wherein the phosphorylated nucleotide is selected from uridine and adenosine. In some or any of the foregoing or related embodiments, the 4^-carbon of the sugar of the 5^-nucleotide of the antisense strand comprises a phosphate analog. In some embodiments, the phosphate analog is oxymethyl phosphonate, vinyl phosphonate or malonyl phosphonate. In some embodiments, the phosphorylated nucleotide is 4’-O- monomethylphosphonate-2’-O-methyl uridine. In some or any of the foregoing or related embodiments, the one or more ligands is conjugated to a ribose of the sense strand at the 3’- or 5’-position. In some embodiments, the one or more ligands is conjugated to a ribose of the sense strand at the 2’-position. In some or any of the foregoing or related embodiments, one ligand is conjugated to position one of the sense strand, numbered 5^ to 3^. In some or any of the foregoing or related embodiments, the double-stranded oligonucleotide comprises at least two ligands. In some embodiments, the at least two ligands are conjugated to different nucleotides of the sense strand. In some embodiments, the at least two ligands are the same ligand. In some embodiments, the at least two ligands are different ligands. In some embodiments, the at least two ligands are conjugated to position 1, numbered 5^ to 3^, and a nucleotide within a tetraloop. In some or any of the foregoing or related embodiments, (a) at least one ligand is conjugated to position 1 and at least one ligand is conjugated to position 29; (b) at least one ligand is conjugated to position 1 and at least one ligand is conjugated to position 28; (c) at least one ligand is conjugated to position 1 and at least one ligand is conjugated to position 2; or (d) at least one ligand is conjugated to position 1 and at least one ligand is conjugated to position 20, numbered 5^ to 3^, of the sense strand.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, the region of complementarity is fully complementary to the mRNA target sequence. In some embodiments, the region of complementarity is partially complementary to the mRNA target sequence. In some or any of the foregoing or related embodiments, the region of complementarity comprises no more than four mismatches to the mRNA target sequence. In some aspects, the disclosure provides an oligonucleotide-ligand conjugate of Formula (AI): (AI), or a pharmaceutically acceptable salt or charged form thereof, wherein: A and A’ are each independently H or one or more nucleotides; B is a nucleobase; Z is O or S; M is absent, NRC(O), or heteroaryl, wherein R is H or alkyl. a is 1, 2, 3, 4, 5, or 6; b is 1, 2, 3, 4, 5, or 6; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23; and f is 0, 1, 2, 3, 4, 5, or 6. In some or any of the foregoing or related embodiments, M is -NRC(O)-. In some or any of the foregoing or related embodiments, R is H or C1-5 alkyl. In some embodiments, R is H or methyl. In some embodiments, R is H. In some or any of the foregoing or related embodiments, c is 1.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, the oligonucleotide-ligand conjugate has a structure of Formula (AII) (AII), or a pharmaceutically acceptable salt or charged form thereof. In some or any of the foregoing or related embodiments, M is heteroaryl. In some embodiments, the heteroaryl is triazolyl. In some embodiments, the triazolyl is . In some or any of the foregoing or related embodiments, the oligonucleotide-ligand conjugate has a structure of Formula (AIII) (AIII), or a pharmaceutically acceptable salt or charged form thereof. In some or any of the foregoing or related embodiments, d is 0 to 12. In some embodiments d is 4 to 12. In some embodiments, d is 4 or 12. In some embodiments, d is 0. In some or any of the foregoing or related embodiments, the oligonucleotide-ligand conjugate has a structure of Formula (AIV)FH12501620.1 Attorney Docket: DCY-13025 (AIV), or a pharmaceutically acceptable salt or a charged form thereof. In some or any of the foregoing or related embodiments, M is absent. In some or any of the foregoing or related embodiments, the oligonucleotide-ligand conjugate has a structure of Formula (AV) (AV), or a pharmaceutically acceptable salt or a charged form thereof, wherein e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. In some or any of the foregoing or related embodiments, a is 1 or 2. In some embodiments, a is 1. In some or any of the foregoing or related embodiments, b is 1 or 2. In some embodiments, b is 1. In some or any of the foregoing or related embodiments, e is 11 to 22. In some embodiments, e is 11, 15, or 21. In some or any of the foregoing or related embodiments, f is 0, 1, or 2. In some embodiments, f is 0. In some or any of the foregoing or related embodiments, B isFH12501620.1 Attorney Docket: DCY-13025 embodiments, In some or any of the foregoing or related embodiments, A is H. In some or any of the foregoing or related embodiments, Z is S. In some aspects, the disclosure provides a double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises the oligonucleotide-ligand conjugate of some or any of the foregoing or related embodiments, and wherein the sense strand and antisense strand form a duplex region. In some or any of the foregoing or related embodiments, the antisense strand is 15 to 30 nucleotides in length. In some or any of the foregoing or related embodiments, the sense strand and / or antisense strand comprises at least one modified internucleotide linkage. In some embodiments, the at least one modified internucleotide linkage is a phosphorothioate linkage. In some or any of the foregoing or related embodiments, A is H and A^ is 12 to 40 nucleotides. In some or any of the foregoing or related embodiments, the nucleotides of A^ comprise at least one modified internucleotide linkage. In some or any of the foregoing or related embodiments, A is 12-29 nucleotides and A^ is 1-10 nucleotides. In some or any of the foregoing or related embodiments, the nucleotides of A comprise at least one modified internucleotide linkage. In some or any of the foregoing or related embodiments, the oligonucleotide-ligand conjugate and at least 14 nucleotides of A’ form the duplex region with the antisense strand. In some or any of the foregoing or related embodiments, the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5’ to 3’. In some embodiments, the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises aFH12501620.1 Attorney Docket: DCY-13025 phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5^ to 3^. In some embodiments, the sense strand comprises a phosphorothioate linkage (i) between positions 1 and 2; (ii) between positions 2 and 3; (iii) between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20; or, (iv) between positions 2 and 3, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^. In some embodiments, the sense strand is 36 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, wherein positions are numbered 1-36 from 5^ to 3^. In some embodiments, the sense strand is 20 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^. In some or any of the foregoing or related embodiments, the duplex region comprises 20 to 30 base pairs. In some or any of the foregoing or related embodiments, the sense strand comprises a stem-loop comprising a tetraloop. In some embodiments, the tetraloop comprises a 5’- GAAA-3’ sequence. In some embodiments, the oligonucleotide-ligand conjugate is a nucleotide of the tetraloop. In some or any of the foregoing or related embodiments, the sense and antisense strand comprise one or more modified nucleotides. In some embodiments, the modified nucleotide comprises a modified sugar. In some embodiments, the modified sugar comprises a 2’-OMe group. In some embodiments, the modified sugar comprises a 2’-F substituent. In some or any of the foregoing or related embodiments, the sense strand comprises 20 nucleotides, wherein nucleotides at each of positions 8, 9, 10, and 11 comprise a 2’-F modification. In some embodiments, the sense strand comprises 36 nucleotides, wherein nucleotides at each of positions 3, 5, 8, 10, 12, 13, 15, and 17 comprise a 2’-F modification. In some embodiments, the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, and 14 comprise a 2’-F modification. In some embodiments, the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, 14, 16, and 19 comprise a 2’-F modification. In some or any of the foregoing or related embodiments, the modified nucleotide comprises a modified nucleobase.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, the double-stranded oligonucleotide comprises a 4’-O-monomethylphosphonate-2’-O-methyl modified nucleotide. In some or any of the foregoing or related embodiments, the antisense strand comprises a phosphorylated nucleotide at the 5’ terminus, and wherein the phosphorylated nucleotide is selected from uridine and adenosine. In some or any of the foregoing or related embodiments, the 4^-carbon of the sugar of the 5^-nucleotide of the antisense strand comprises a phosphate analog. In some embodiments, the phosphate analog is oxymethyl phosphonate, vinyl phosphonate or malonyl phosphonate. In some or any of the foregoing or related embodiments, wherein the phosphorylated nucleotide is 4’-O-monomethylphosphonate-2’-O-methyl uridine. In some aspects, the disclosure provides an oligonucleotide-ligand conjugate of Formula (BI) (BI), or a pharmaceutically acceptable salt or charged form thereof, wherein: B is a nucleobase; A is a one or more nucleotides; Z1and Z2are each independently O or S; M is absent, NRC(O), or heteroaryl, wherein R is H or alkyl; a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23; and f is 0, 1, 2, 3, 4, 5, or 6.FH12501620.1 Attorney Docket: DCY-13025 In some aspects, the disclosure provides an oligonucleotide-ligand conjugate of Formula (BII) (BII), or a salt or charged form thereof, wherein: B is a nucleobase; A is a one or more nucleotides ; Z is O or S; M is absent, NRC(O), or heteroaryl, wherein R is H or alkyl; a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 23; and f is 0, 1, 2, 3, 4, 5, or 6. In some aspects, the disclosure provides an oligonucleotide-ligand conjugate of Formula (CI) (CI), or a pharmaceutically acceptable salt or charged form thereof, wherein: B is a nucleobase; A is one or more nucleotides; Z1and Z2are each independently O or S; M is absent, NRC(O), or heteroaryl, wherein R is H or alkyl;FH12501620.1 Attorney Docket: DCY-13025 a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 23; and f is 0, 1, 2, 3, 4, 5, or 6. In some aspects, the disclosure provides an oligonucleotide-ligand conjugate of Formula (CII) (CII), or a salt or charged form thereof, wherein: B is a nucleobase; A is one or more nucleotides; Z is O or S; M is absent, NRC(O), or heteroaryl, wherein R is H or alkyl; a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 23; and f is 0, 1, 2, 3, 4, 5, or 6. In some aspects, the disclosure provides a double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of some or any of the foregoing or related embodiments, and wherein the sense strand and antisense strand form a duplex region. In some or any of the foregoing or related embodiments, the antisense strand is 15 to 30 nucleotides in length. In some or any of the foregoing or related embodiments, A is 12 to 40 nucleotides. In some or any of the foregoing or related embodiments, the sense strand and / or antisense strand comprises at least one modified internucleotide linkage. In some embodiments, the at least one modified internucleotide linkage is a phosphorothioate linkage.FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, the duplex region includes one or more phosphorothioate linkages. In some embodiments, two phosphorothioate linkages are adjacent to each other. In some embodiments, the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5’ to 3’. In some embodiments, the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5^ to 3^. In some embodiments, the sense strand comprises a phosphorothioate linkage (i) between positions 1 and 2; (ii) between positions 2 and 3; (iii) between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20; or, (iv) between positions 2 and 3, between positions 18 and 19, and between positiosn 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^. In some embodiments, the sense strand is 36 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, wherein positions are numbered 1-36 from 5^ to 3^. In some embodiments, the sense strand is 20 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^. In some or any of the foregoing or related embodiments, the duplex region comprises 20 to 30 base pairs. In some or any of the foregoing or related embodiments, the sense strand comprises a loop region that includes a tetraloop region. In some embodiments, the tetraloop region comprises a 5’-GAAA-3’ sequence. In some or any of the foregoing or related embodiments, the sense and antisense strand comprise one or more modified nucleotides. In some embodiments, the modified nucleotide comprises a modified sugar. In some embodiments, the modified sugar comprises a 2’-OMe group. In some embodiments, the modified sugar comprises a 2’-F substituent. In some or any of the foregoing or related embodiments, the sense strand comprises 20 nucleotides, wherein nucleotides at each of positions 8, 9, 10, and 11 comprise a 2’-F modification. In some embodiments, the sense strand comprises 36 nucleotides, wherein nucleotides at each of positions 3, 5, 8, 10, 12, 13, 15, and 17 comprise a 2’-F modification. In some embodiments, the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, and 14 comprise a 2’-F modification. In someFH12501620.1 Attorney Docket: DCY-13025 embodiments, the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, 14, 16, and 19 comprise a 2’-F modification. In some or any of the foregoing or related embodiments, the modified nucleotide comprises a modified nucleobase. In some or any of the foregoing or related embodiments, the double-stranded oligonucleotide comprises a 4’-O-monomethylphosphonate-2’-O-methyl modified nucleotide. In some or any of the foregoing or related embodiments, the antisense strand comprises a phosphorylated nucleotide at the 5’ terminus, and wherein the phosphorylated nucleotide is selected from uridine and adenosine. In some or any of the foregoing or related embodiments, the 4^-carbon of the sugar of the 5^-nucleotide of the antisense strand comprises a phosphate analog. In some embodiments, the phosphate analog is oxymethyl phosphonate, vinyl phosphonate or malonyl phosphonate. In some embodiments, the phosphorylated nucleotide is 4’-O- monomethylphosphonate-2’-O-methyl uridine. In some or any of the foregoing or related embodiments, the sense strand comprises a second oligonucleotide-ligand conjugate. In some embodiments, the second oligonucleotide- ligand conjugate is selected from the oligonucleotide-ligand conjugate of some or any of the foregoing or related embodiments. In some or any of the foregoing or related embodiments, the antisense strand has a region of complementarity to a target sequence in a target mRNA in extrahepatic tissue, wherein the region of complementarity is at least 15 contiguous nucleotides in length. In some embodiments, the region of complementarity is fully complementary to the mRNA target sequence. In some embodiments, the region of complementarity is partially complementary to the mRNA target sequence. In some embodiments, the region of complementarity comprises no more than four mismatches to the mRNA target sequence. In some or any of the foregoing or related embodiments, the extrahepatic tissue is adipose tissue, heart tissue, skeletal muscle, or adrenal gland tissue. In some embodiments, the extrahepatic tissue is adipose tissue. In some aspects, the disclosure provides a double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises two or more oligonucleotide-ligand conjugates of (i), (ii), or (iii): (i) Formula (AI), (AII), (AIII), (AIV), or (AV); (ii) Formula (BI) or (BII); andFH12501620.1 Attorney Docket: DCY-13025 (iii) Formula (CI) or (CII). In some or any of the foregoing or related embodiments, the two or more oligonucleotide ligand conjugates are conjugated to different nucleotides of the sense strand. In some embodiments, the two or more oligonucleotide ligand conjugates are the same. In some embodiments, the two or more oligonucleotide ligand conjugates are different. In some or any of the foregoing or related embodiments, the sense strand comprises a first oligonucleotide-ligand conjugate and a second oligonucleotide-ligand conjugate. In some or any of the foregoing or related embodiments, the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand and the nucleobase (B) of the second oligonucleotide-ligand conjugate is a nucleobase within a tetraloop of the sense strand. In some or any of the foregoing or related embodiments, (a) the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand, and the nucleobase (B) of the second oligonucleotide-ligand conjugate is the nucleobase at position 29 of the sense strand; (b) the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand, and the nucleobase (B) of the second oligonucleotide-ligand conjugate is the nucleobase at position 28 of the sense strand; (c) the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand, and the nucleobase (B) of the second oligonucleotide-ligand conjugate is the nucleobase at position 20 of the sense strand; or (d) the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand, and the nucleobase (B) of the second oligonucleotide-ligand conjugate is the nucleobase at position 2 of the sense strand. In some or any of the foregoing or related embodiments, the oligonucleotide-ligand conjugate reduces expression of the target mRNA in an extrahepatic tissue, provided the oligonucleotide-ligand conjugate does not reduce expression of the mRNA target in the liver. In some aspects, the disclosure provides a pharmaceutical composition comprising the double-stranded oligonucleotide of some or any of the foregoing or related embodiments, and a pharmaceutically acceptable carrier, delivery agent, or excipient. In some aspects, the disclosure provides a method of inhibiting target mRNA expression in an extrahepatic cell or tissue in a subject, comprising administering to the subject the double-stranded oligonucleotide or the pharmaceutical composition of some orFH12501620.1 Attorney Docket: DCY-13025 any of the foregoing or related embodiments, thereby inhibiting target mRNA expression in the cell of the extrahepatic tissue. In some or any of the foregoing or related embodiments, the extrahepatic cell or tissue is selected from skeletal muscle, adipose tissue, adrenal tissue, heart tissue, and any combination thereof. In some or any of the foregoing or related embodiments, reduction of the target mRNA in the extrahepatic cell or tissue is increased compared to reduction in liver cells or tissue, optionally wherein reduction of the target mRNA is increased by at least 10%. In some or any of the foregoing or related embodiments, reduction of the target mRNA is increased by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50%. In some aspects, the disclosure provides the double-stranded oligonucleotide of some or any of the foregoing or related embodiments in the manufacture of a medicament for inhibiting target mRNA expression in an extrahepatic cell or tissue in a subject. In some aspects, the disclosure provides for use of the double-stranded oligonucleotide of some or any of the foregoing or related embodiments for inhibiting target mRNA expression in a cell of an extrahepatic tissue in a subject. In some aspects, the disclosure provides a kit comprising a container comprising the double-stranded oligonucleotide of some or any of the foregoing or related embodiments, and optionally a pharmaceutically acceptable carrier, and instructions for administering the oligonucleotide-ligand conjugate to a subject in need thereof, wherein the oligonucleotide- ligand conjugate inhibits target mRNA expression in an extrahepatic cell or tissue in the subject. In some or any of the foregoing or related embodiments, the extrahepatic cell or tissue is selected from skeletal muscle, adipose tissue, adrenal tissue, heart tissue, and any combination thereof. In some embodiments, the cell of the extrahepatic cell or tissue is selected from a cardiomyocyte, a cell of skeletal muscle, a cell of adipose tissue, a cell of adrenal tissue, and any combination thereof. In some or any of the foregoing or related embodiments, reduction of the target mRNA in the extrahepatic cell or tissue is increased compared to reduction in a cell of the liver, optionally wherein reduction of the target mRNA is increased by at least 10%. In some or any of the foregoing or related embodiments, reduction of the target mRNA is increased by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50%.FH12501620.1 Attorney Docket: DCY-13025 In some aspects, the disclosure provides a method for treating a subject having a disease, disorder or condition associated with expression of an mRNA in an extrahepatic cell or tissue, the method comprising administering to the subject a therapeutically effective amount of the double-stranded oligonucleotide or pharmaceutical composition of any or some of the foregoing or related aspects. In some aspects, the disclosure provides a method of delivering a double-stranded oligonucleotide to a cell or population of cells in extrahepatic tissue, the method comprising administering the pharmaceutical composition of any or some of the foregoing or related aspects. In some aspects, the disclosure provides a double-stranded oligonucleotide comprising: (i) an antisense strand of 15 to 30 nucleotides in length, a sense strand of 13 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extrahepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more -L-Y-Wngroups, or a charged form thereof, wherein: L is a linker selected from -O(CH2)a(OCH2CH2)bNH- , -O(CH2)a(OCH2CH2)b(NH)(CO)-, -O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-, -OP(=O)(OH)O(CH2)a(OCH2CH2)bNH-, -OP(=O)(OH)O(CH2)a(OCH2CH2)b(NH)(CO)-, -OP(=O)(OH)O(CH2)aM, - OP(=O)(OH)O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-, Y is alkylene, alkenylene, alkynylene, or (CH2)e(OCH2CH2)f; each W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substituted aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N (H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; M is absent, -NHC(O)-, -N(alkyl)C(O)-, or heteroarylene; R^ is H or methyl; n is an integer from 1-6; a is an integer from 1-6;FH12501620.1 Attorney Docket: DCY-13025 b is an integer from 0-8; c is an integer from 0-6; d is an integer from 0-20; e is an integer from 1-6; f is an integer from 1-20; wherein when Y is alkylene, L comprises -O(CH2)a(OCH2CH2)bNH- or -O(CH2)a(OCH2CH2)b(NH)(CO)-; and wherein the ligand is conjugated to a nucleotide of the sense strand. In some aspects, the disclosure provides a double-stranded oligonucleotide comprising: (i) an antisense strand of 15 to 30 nucleotides in length, a sense strand of 13 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extrahepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more -L-Y-Wngroups, or a charged form thereof, wherein: L is a linker selected from -O(CH2)a(OCH2CH2)bNH- , -O(CH2)a(OCH2CH2)b(NH)(CO)-, -O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-, -OP(=O)(OH)O(CH2)a(OCH2CH2)bNH-, -OP(=O)(OH)O(CH2)a(OCH2CH2)b(NH)(CO)-, -OP(=O)(OH)O(CH2)aM, - OP(=O)(OH)O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-, Y is alkylene, alkenylene, alkynylene, or (CH2)e(OCH2CH2)f; each W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substituted aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N (H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; M is absent, -NHC(O)-, -N(alkyl)C(O)-, or heteroarylene; R^ is H or methyl; n is an integer from 1-6; a is an integer from 1-6; b is an integer from 0-8;FH12501620.1 Attorney Docket: DCY-13025 c is an integer from 0-6; d is an integer from 0-20; e is an integer from 1-6; f is an integer from 1-20; and wherein the ligand is conjugated to a nucleotide of the sense strand. In some aspects, the disclosure provides double-stranded oligonucleotide comprising: (i) a double-stranded oligonucleotide comprising an antisense strand of 15 to 30 nucleotides in length, a sense strand of 15 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extrahepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more -L-(C6-24 alkylene)-Wn, or a charged form thereof, conjugated to a nucleotide of the sense strand, wherein: L is a linker selected from -O(CH2)a(OCH2CH2)bNH- , -O(CH2)a(OCH2CH2)b(NH)(CO)-, -O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-, -OP(=O)(OH)O(CH2)a(OCH2CH2)bNH-, -OP(=O)(OH)O(CH2)a(OCH2CH2)b(NH)(CO)-, -OP(=O)(OH)O(CH2)aM, and -OP(=O)(OH)O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-, each W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substituted aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N(H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; M is absent, -NHC(O)-, -N(alkyl)C(O)-, or heteroarylene; R^ is H or methyl; n is an integer from 1-6; a is an integer from 1-6; b is an integer from 0-8; c is an integer from 0-6; d is an integer from 0-20; wherein knock down of the target mRNA in the extrahepatic tissue is greater than knock down of the target mRNA in liver tissue.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, L is a linker selected from -O(CH2)a(OCH2CH2)bNH-, -O(CH2)a(OCH2CH2)b(NH)(CO)-, and -O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-. In some or any of the foregoing or related embodiments, L is -O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-. In some or any of the foregoing or related embodiments, when Y is alkylene, L comprises -O(CH2)a(OCH2CH2)bNH- or -O(CH2)a(OCH2CH2)b(NH)(CO)-. In some or any of the foregoing or related embodiments, M is heteroarylene. In some ebodiments, the heteroarylene is a triazolylene. In some or any of the foregoing or related embodiments, the triazolylene is . In some or any of the foregoing or related embodiments, M is -NHC(O)-. In some or any of the foregoing or related embodiments, Y is an C6-24alkylene, C6-24alkenylene, or C6-24 alkynylene. In some or any of the foregoing or related embodiments, Y is an C6-24 alkylene or C6-24 alkenylene. In some embodiments, Y is a C6-24 alkenylene. In some ebodiments, Y is a C6-20 alkylene. In some embodiments, the alkenylene comprises from 1-6 olefinic bonds. In some embodiments, the alkynylene comprises from 1-6 acetylenic bonds. In some embodiments, the alkenylene comprises from 1-6 olefinic bonds; and the alkynylene comprises from 1-6 acetylenic bonds In some or any of the foregoing or related embodiments, n is 1. In some or any of the foregoing or related embodiments, W is -CO2H, , , , - OH, -N(H)SO2(methyl), -N(H)SO2(ethyl), -N(H)SO2(n-propyl), -N(H)SO2(i-propyl), -N(H)S O2(sec-propyl), -N(H)SO2(n-butyl), -N(H)SO2(i-butyl), -N(H)SO2(sec-butyl), -N(H)SO2(t- butyl), -N(H)SO2(n-pentyl), -N(H)SO2(cyclopropyl), -N(H)SO2(cyclobutyl), -N(H)SO2(cyclopentyl), -N(H)SO2(cyclohexyl), -N(H)SO2(cycloheptyl),FH12501620.1 Attorney Docket: DCY-13025 , In some or any of the foregoing or related embodiments, W is piperazinyl or piperidinyl. In some or any of the foregoing or related embodiments, a is 1. In some or any of the foregoing or related embodiments, b is 0 or 1. In some or any of the foregoing or related embodiments, b is 2. In some or any of the foregoing or related embodiments, c is 2. In some or any of the foregoing or related embodiments, d is 4. In some or any of the foregoing or related embodiments, the -L-Y-(W)ngroup is: wherein g is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. In some or any of the foregoing or related embodiments, M is -NHC(O)-. In some embodiments, M is -N(methyl)C(O). In some embodiments, M is heteroarylene. In some or any of the foregoing or related embodiments, the heteroaryl is triazolylene. In some embodiments, the triazolylene is . In some or any of the foregoing or related embodiments, M is absent.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, W is -CO2H, , , , - OH, -N(H)SO2(methyl), -N(H)SO2(ethyl), -N(H)SO2(n-propyl), -N(H)SO2(i-propyl), -N( H)SO2(sec-propyl), -N(H)SO2(n-butyl), -N(H)SO2(i-butyl), -N(H)SO2(sec- butyl), -N(H)SO2(t-butyl), -N(H)SO2(n- pentyl), -N(H)SO2(cyclopropyl), -N(H)SO2(cyclobutyl), -N(H)SO2(cyclopentyl), -N(H)SO2(cyclohexyl), -N(H)SO2(cycloheptyl), -N(H)SO2(cyclooctyl), -N(H)SO2([1.1.1]propellane), , In some or any of the foregoing or related embodiments, wherein W is piperazinyl or piperidinyl. In some or any of the foregoing or related embodiments, c is 1. In some or any of the foregoing or related embodiments, c is 2. In some or any of the foregoing or related embodiments, d is 0 to 12. In some embodiments, d is 4 to 12. In some embodiments, d is 4. In some or any of the foregoing or related embodiments, g is 12 to 23. In some embodiments, g is 11, 14, 15, 20, or 21.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, the extrahepatic tissue is adipose tissue, heart tissue, skeletal muscle, or adrenal gland tissue. In some embodiments, the extrahepatic tissue is adipose tissue. In some or any of the foregoing or related embodiments, the antisense strand is 22 nucleotides. In some or any of the foregoing or related embodiments, the antisense strand comprises a 3’ overhang of 2 to 6 nucleotides. In some or any of the foregoing or related embodiments, the sense strand and / or antisense strand comprises at least one modified internucleotide linkage. In some embodiments, the at least one modified internucleotide linkage is a phosphorothioate linkage. In some embodiments, the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5’ to 3’. In some embodiments, antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5^ to 3^. In some embodiments, the sense strand comprises a phosphorothioate linkage (i) between positions 1 and 2; (ii) between positions 2 and 3; (iii) between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20; or, (iv) between positions 2 and 3, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^. In some embodiments, the sense strand is 36 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, wherein positions are numbered 1-36 from 5^ to 3^. In some embodiments, the sense strand is 20 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^. In some or any of the foregoing or related embodiments, the oligonucleotide comprises a stem-loop comprising a tetraloop. In some embodiments, the tetraloop comprises a 5’-GAAA-3’ sequence. In some or any of the foregoing or related embodiments, the sense strand and / or antisense strand comprises one or more modified nucleotides. In some embodiments, the modified nucleotide comprises a modified sugar. In some embodiments, the modified sugar comprises a 2’-OMe group. In some embodiments, the modified sugar comprises a 2’-F substituent.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, the antisense strand comprises up to 4 contiguous nucleotides with a 2’-F modified sugar. In some embodiments, the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, and 14, numbered 5^ to 3^ comprise a 2’-F modification. In some embodiments, wherein the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, 14, 16, and 19, numbered 5^ to 3^, comprise a 2’-F modification. In some or any of the foregoing or related embodiments, the sense strand comprises 20 nucleotides, wherein nucleotides at each of positions 8, 9, 10, and 11 numbered 5^ to 3^, comprise a 2’-F modification. In some embodiments, the sense strand comprises 36 nucleotides, wherein nucleotides at each of positions 3, 5, 8, 10, 12, 13, 15, and 17, numbered 5^ to 3^, comprise a 2’-F modification. In some or any of the foregoing or related embodiments, the antisense strand comprises a 4’-O-monomethylphosphonate-2’-O-methyl modified nucleotide. In some or any of the foregoing or related embodiments, the antisense strand comprises a phosphorylated nucleotide at the 5’ terminus, and wherein the phosphorylated nucleotide is selected from uridine and adenosine. In some or any of the foregoing or related embodiments, the 4^-carbon of the sugar of the 5^-nucleotide of the antisense strand comprises a phosphate analog. In some embodiments, phosphate analog is oxymethyl phosphonate, vinyl phosphonate or malonyl phosphonate. In some or any of the foregoing or related embodiments, the phosphorylated nucleotide is 4’-O-monomethylphosphonate-2’-O-methyl uridine. In some or any of the foregoing or related embodiments, the one or more ligands is conjugated to a ribose of the sense strand at the 3’- or 5’-position. In some or any of the foregoing or related embodiments, the one or more ligands is conjugated to a ribose of the sense strand at the 2’-position. In some or any of the foregoing or related embodiments, one ligand is conjugated to position one of the sense strand, numbered 5^ to 3^. In some or any of the foregoing or related embodiments, the double-stranded oligonucleotide comprises at least two ligands. In some embodiments, the at least two ligands are conjugated to different nucleotides of the sense strand. In some embodiments, the at least two ligands are the same ligand. In some embodiments, the at least two ligands are different ligands. In some embodiments, the at least two ligands are conjugated to position 1, numbered 5^ to 3^, and a nucleotide within a tetraloop.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, (a) at least one ligand is conjugated to position 1 and at least one ligand is conjugated to position 29; (b) at least one ligand is conjugated to position 1 and at least one ligand is conjugated to position 28; (c) at least one ligand is conjugated to position 1 and at least one ligand is conjugated to position 2; or (d) at least one ligand is conjugated to position 1 and at least one ligand is conjugated to position 20, numbered 5^ to 3^, of the sense strand. In some or any of the foregoing or related embodiments, the region of complementarity is fully complementary to the mRNA target sequence. In some or any of the foregoing or related embodiments, the region of complementarity is partially complementary to the mRNA target sequence. In some or any of the foregoing or related embodiments, the region of complementarity comprises no more than four mismatches to the mRNA target sequence. In some aspects, the disclosure provides an oligonucleotide-ligand conjugate of Formula (AI): or a pharmaceutically acceptable salt or charged form thereof; wherein: A and A’ are each independently H or one or more nucleotides; B is a nucleobase; Z is O or S; M is absent, -NRC(O)-, or heteroarylene, wherein R is H or alkyl; each W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl),FH12501620.1 Attorney Docket: DCY-13025 -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substituted aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N(H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; a is 1, 2, 3, 4, 5, or 6; b is 1, 2, 3, 4, 5, 6, 7, or 8; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23; and f is 0, 1, 2, 3, 4, 5, or 6. In some or any of the foregoing or related embodiments, wherein M is -NRC(O)-. In some or any of the foregoing or related embodiments, wherein R is H or C1-5 alkyl. In some embodiments, R is H or methyl. In some embodiments, R is H. In some or any of the foregoing or related embodiments, W is -CO2H, , , , - OH, -N(H)SO2(methyl), -N(H)SO2(ethyl), -N(H)SO2(n-propyl), -N(H)SO2(i-propyl), -N( H)SO2(sec-propyl), -N(H)SO2(n-butyl), -N(H)SO2(i-butyl), -N(H)SO2(sec- butyl), -N(H)SO2(t-butyl), -N(H)SO2(n- pentyl), -N(H)SO2(cyclopropyl), -N(H)SO2(cyclobutyl), -N(H)SO2(cyclopentyl), -N(H)SO2(cyclohexyl), -N(H)SO2(cycloheptyl), -N(H)SO2(cyclooctyl), -N(H)SO2([1.1.1]propellane), ,FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, W is piperazinyl or piperidinyl. In some or any of the foregoing or related embodiments, c is 1 or 2. In some or any of the foregoing or related embodiments, the oligonucleotide-ligand conjugate has a structure of Formula (AII) or a pharmaceutically acceptable salt or charged form thereof. In some or any of the foregoing or related embodiments, M is heteroarylene. In some or any of the foregoing or related embodiments, the heteroarylene is triazolylene. In some embodiments, the triazolylene is . In some or any of the foregoing or related embodiments, the oligonucleotide-ligand conjugate has a structure of Formula (AIII)FH12501620.1 Attorney Docket: DCY-13025 or a pharmaceutically acceptable salt or charged form thereof. In some or any of the foregoing or related embodiments, d is 0 to 12. In some embodiments, d is 4 to 12. In some embodiments, d is 4. In some or any of the foregoing or related embodiments, the oligonucleotide-ligand has a structure of Formula (AIV) or a pharmaceutically acceptable salt or a charged form thereof. In some or any of the foregoing or related embodiments, M is absent. In some or any of the foregoing or related embodiments, the oligonucleotide-ligand conjugate has a structure of Formula (AV) or a pharmaceutically acceptable salt or a charged form thereof. In some or any of the foregoing or related embodiments, a is 1 or 2. In some or any of the foregoing or related embodiments, a is 1.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, b is 1 or 2. In some embodiments, b is 2. In some or any of the foregoing or related embodiments, e is 11 to 22. In some embodiments, e is 11, 15, or 21. In some or any of the foregoing or related embodiments, f is 0, 1, or 2. In some embodiments, f is 0. . In some or any of the foregoing or related embodiments, A is H. In some or any of the foregoing or related embodiments, Z is S. In some aspects, the disclosure provides a double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises the oligonucleotide-ligand conjugate of some or any of the foregoing or related embodiments, and wherein the sense strand and antisense strand form a duplex region. In some or any of the foregoing or related embodiments, the antisense strand is 15 to 30 nucleotides in length. In some or any of the foregoing or related embodiments, the sense strand and / or antisense strand comprises at least one modified internucleotide linkage. In some embodiments, the at least one modified internucleotide linkage is a phosphorothioate linkage. In some or any of the foregoing or related embodiments, A is H and A^ is 12 to 40 nucleotides. In some or any of the foregoing or related embodiments, the nucleotides of A^ comprise at least one modified internucleotide linkage. In some or any of the foregoing or related embodiments, A is 12-29 nucleotides and A^ is 1-10 nucleotides.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, the nucleotides of A comprise at least one modified internucleotide linkage. In some or any of the foregoing or related embodiments, wherein the oligonucleotide- ligand conjugate and at least 14 nucleotides of A’ form the duplex region with the antisense strand. In some or any of the foregoing or related embodiments, the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5’ to 3’. In some or any of the foregoing or related embodiments, the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5^ to 3^. In some or any of the foregoing or related embodiments, the sense strand comprises a phosphorothioate linkage (i) between positions 1 and 2; (ii) between positions 2 and 3; (iii) between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20; or, (iv) between positions 2 and 3, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^. In some or any of the foregoing or related embodiments, the sense strand is 36 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, wherein positions are numbered 1-36 from 5^ to 3^. In some or any of the foregoing or related embodiments, the sense strand is 20 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^. In some or any of the foregoing or related embodiments, the duplex region comprises 20 to 30 base pairs. In some or any of the foregoing or related embodiments, the sense strand comprises a stem-loop comprising a tetraloop. In some embodiments, the tetraloop comprises a 5’- GAAA-3’ sequence. In some or any of the foregoing or related embodiments, the oligonucleotide-ligand conjugate is a nucleotide of the tetraloop. In some or any of the foregoing or related embodiments, the sense and antisense strand comprise one or more modified nucleotides. In some embodiments, the modifiedFH12501620.1 Attorney Docket: DCY-13025 nucleotide comprises a modified sugar. In some embodiments, the modified sugar comprises a 2’-OMe group. In some embodiments, the modified sugar comprises a 2’-F substituent. In some or any of the foregoing or related embodiments, the sense strand comprises 20 nucleotides, wherein nucleotides at each of positions 8, 9, 10, and 11 comprise a 2’-F modification. In some or any of the foregoing or related embodiments, the sense strand comprises 36 nucleotides, wherein nucleotides at each of positions 3, 5, 8, 10, 12, 13, 15, and 17 comprise a 2’-F modification. In some or any of the foregoing or related embodiments, the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, and 14 comprise a 2’-F modification. In some or any of the foregoing or related embodiments, antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, 14, 16, and 19 comprise a 2’-F modification. In some or any of the foregoing or related embodiments, the modified nucleotide comprises a modified nucleobase. In some or any of the foregoing or related embodiments, the double-stranded oligonucleotide comprises a 4’-O-monomethylphosphonate-2’-O-methyl modified nucleotide. In some or any of the foregoing or related embodiments, the antisense strand comprises a phosphorylated nucleotide at the 5’ terminus, and wherein the phosphorylated nucleotide is selected from uridine and adenosine. In some or any of the foregoing or related embodiments, the 4^-carbon of the sugar of the 5^-nucleotide of the antisense strand comprises a phosphate analog. In some embodiments, the phosphate analog is oxymethyl phosphonate, vinyl phosphonate or malonyl phosphonate. In some or any of the foregoing or related embodiments, the phosphorylated nucleotide is 4’-O-monomethylphosphonate-2’-O-methyl uridine. In some aspects, the disclosure provides an oligonucleotide-ligand conjugate of Formula (BI):FH12501620.1 Attorney Docket: DCY-13025 or a pharmaceutically acceptable salt or charged form thereof, wherein: B is a nucleobase; A is a one or more nucleotides; Z1and Z2are each independently O or S; M is absent, -NRC(O)-, or heteroarylene, wherein R is H or alkyl; W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substituted aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N(H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23; and f is 0, 1, 2, 3, 4, 5, or 6. In some aspects, the disclosure provides an oligonucleotide-ligand conjugate of Formula (BII):FH12501620.1 Attorney Docket: DCY-13025 or a salt or charged form thereof, wherein: B is a nucleobase; A is a one or more nucleotides ; Z is O or S; M is absent, NRC(O), or heteroarylene, wherein R is H or alkyl; W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substituted aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N(H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 23; and f is 0, 1, 2, 3, 4, 5, or 6. In some aspects, the disclosure provides an oligonucleotide-ligand conjugate of Formula (CI) or a pharmaceutically acceptable salt or charged form thereof, wherein:FH12501620.1 Attorney Docket: DCY-13025 B is a nucleobase; A is one or more nucleotides; Z1and Z2are each independently O or S; M is absent, NRC(O), or heteroarylene, wherein R is H or alkyl; W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substituted aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N(H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 23; and f is 0, 1, 2, 3, 4, 5, or 6. In some aspects, the disclosure provides an oligonucleotide-ligand conjugate of Formula (CII) or a salt or charged form thereof, wherein: B is a nucleobase; A is one or more nucleotides; Z is O or S; M is absent, NRC(O), or heteroarylene, wherein R is H or alkyl; W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substitutedFH12501620.1 Attorney Docket: DCY-13025 aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N(H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 23; and f is 0, 1, 2, 3, 4, 5, or 6. In some aspects, the disclosure provides a double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of some or any of the foregoing or related embodiments, and wherein the sense strand and antisense strand form a duplex region. In some or any of the foregoing or related embodiments, the antisense strand is 15 to 30 nucleotides in length. In some or any of the foregoing or related embodiments, A is 12 to 40 nucleotides. In some or any of the foregoing or related embodiments, the sense strand and / or antisense strand comprises at least one modified internucleotide linkage. In some embodiments, the at least one modified internucleotide linkage is a phosphorothioate linkage. In some embodiments, the duplex region includes one or more phosphorothioate linkages. In some embodiments, two phosphorothioate linkages are adjacent to each other. In some or any of the foregoing or related embodiments, the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5’ to 3’. In some or any of the foregoing or related embodiments, the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5^ to 3^. In some or any of the foregoing or related embodiments, the sense strand comprises a phosphorothioate linkage (i) between positions 1 and 2; (ii) between positions 2 and 3; (iii) between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20; or, (iv) between positions 2 and 3, between positions 18 and 19, and between positiosn 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, wherein the sense strand is 36 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, wherein positions are numbered 1-36 from 5^ to 3^. In some or any of the foregoing or related embodiments, the sense strand is 20 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^. In some or any of the foregoing or related embodiments, the duplex region comprises 20 to 30 base pairs. In some or any of the foregoing or related embodiments, the sense strand comprises a loop region that includes a tetraloop region. In some embodiments, the tetraloop region comprises a 5’-GAAA-3’ sequence. In some or any of the foregoing or related embodiments, the sense and antisense strand comprise one or more modified nucleotides. In some embodiments, the modified nucleotide comprises a modified sugar. In some embodiments, the modified sugar comprises a 2’-OMe group. In some embodiments, the modified sugar comprises a 2’-F substituent. In some or any of the foregoing or related embodiments, the sense strand comprises 20 nucleotides, wherein nucleotides at each of positions 8, 9, 10, and 11 comprise a 2’-F modification. In some or any of the foregoing or related embodiments, the sense strand comprises 36 nucleotides, wherein nucleotides at each of positions 3, 5, 8, 10, 12, 13, 15, and 17 comprise a 2’-F modification. In some or any of the foregoing or related embodiments, the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, and 14 comprise a 2’-F modification. In some or any of the foregoing or related embodiments, the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, 14, 16, and 19 comprise a 2’-F modification. In some or any of the foregoing or related embodiments, the modified nucleotide comprises a modified nucleobase. In some or any of the foregoing or related embodiments, the double-stranded oligonucleotide of comprises a 4’-O-monomethylphosphonate-2’-O-methyl modified nucleotide.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, the antisense strand comprises a phosphorylated nucleotide at the 5’ terminus, and wherein the phosphorylated nucleotide is selected from uridine and adenosine. In some or any of the foregoing or related embodiments, the 4^-carbon of the sugar of the 5^-nucleotide of the antisense strand comprises a phosphate analog. In some embodiments, the phosphate analog is oxymethyl phosphonate, vinyl phosphonate or malonyl phosphonate. In some or any of the foregoing or related embodiments, the phosphorylated nucleotide is 4’-O-monomethylphosphonate-2’-O-methyl uridine. In some or any of the foregoing or related embodiments, the sense strand comprises a second oligonucleotide-ligand conjugate. In some embodiments, the second oligonucleotide- ligand conjugate is selected from the oligonucleotide-ligand conjugate of any some or any of the foregoing or related aspects. In some or any of the foregoing or related embodiments, the antisense strand has a region of complementarity to a target sequence in a target mRNA in extrahepatic tissue, wherein the region of complementarity is at least 15 contiguous nucleotides in length. In some or any of the foregoing or related embodiments, the region of complementarity is fully complementary to the mRNA target sequence. In some or any of the foregoing or related embodiments, the region of complementarity is partially complementary to the mRNA target sequence. In some or any of the foregoing or related embodiments, the region of complementarity comprises no more than four mismatches to the mRNA target sequence. In some or any of the foregoing or related embodiments, the extrahepatic tissue is adipose tissue, heart tissue, skeletal muscle, or adrenal gland tissue. In some embodiments, the extrahepatic tissue is adipose tissue. In some aspects, the disclosure provides a double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises two or more oligonucleotide-ligand conjugates of (i), (ii), or (iii): (i) Formula (AI), (AII), (AIII), (AIV), or (AV); (ii) Formula (BI) or (BII); and (iii) Formula (CI) or (CII). In some or any of the foregoing or related embodiments, the two or more oligonucleotide ligand conjugates are conjugated to different nucleotides of the sense strand.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, the two or more oligonucleotide ligand conjugates are the same. In some or any of the foregoing or related embodiments, the two or more oligonucleotide ligand conjugates are different. In some or any of the foregoing or related embodiments, the sense strand comprises a first oligonucleotide-ligand conjugate and a second oligonucleotide-ligand conjugate. In some or any of the foregoing or related embodiments, nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand and the nucleobase (B) of the second oligonucleotide-ligand conjugate is a nucleobase within a tetraloop of the sense strand. In some or any of the foregoing or related embodiments, (a) the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand, and the nucleobase (B) of the second oligonucleotide-ligand conjugate is the nucleobase at position 29 of the sense strand; (b) the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand, and the nucleobase (B) of the second oligonucleotide-ligand conjugate is the nucleobase at position 28 of the sense strand; (c) the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand, and the nucleobase (B) of the second oligonucleotide-ligand conjugate is the nucleobase at position 20 of the sense strand; or (d) the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand, and the nucleobase (B) of the second oligonucleotide-ligand conjugate is the nucleobase at position 2 of the sense strand. In some or any of the foregoing or related embodiments, the oligonucleotide-ligand conjugate reduces expression of the target mRNA in an extrahepatic tissue, provided the oligonucleotide-ligand conjugate does not reduce expression of the mRNA target in the liver. In some aspect, the disclosure provides a pharmaceutical composition comprising the double-stranded oligonucleotide of some or any of the foregoing or related embodiments, and a pharmaceutically acceptable carrier, delivery agent, or excipient. In some aspects, the disclosure provides a method of inhibiting target mRNA expression in an extrahepatic cell or tissue in a subject, comprising administering to the subject the double-stranded oligonucleotide of some or any of the foregoing or related embodiments, or the pharmaceutical composition of any of the foregoing or relatedFH12501620.1 Attorney Docket: DCY-13025 embodiments, thereby inhibiting target mRNA expression in the cell of the extrahepatic tissue. In some or any of the foregoing or related embodiments, the extrahepatic cell or tissue is selected from skeletal muscle, adipose tissue, adrenal tissue, heart tissue, and any combination thereof. In some or any of the foregoing or related embodiments, reduction of the target mRNA in the extrahepatic cell or tissue is increased compared to reduction in liver cells or tissue, optionally wherein reduction of the target mRNA is increased by at least 10%. In some or any of the foregoing or related embodiments, reduction of the target mRNA is increased by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50%. In some aspects, the disclosure provides the double-stranded oligonucleotide of any one of the foregoing or related embodiments in the manufacture of a medicament for inhibiting target mRNA expression in an extrahepatic cell or tissue in a subject. In some aspects, the disclosure provides for use of the double-stranded oligonucleotide of any one of the foregoing or related embodiments for inhibiting target mRNA expression in a cell of an extrahepatic tissue in a subject. In some aspects, the disclosure provides a kit comprising a container comprising the double-stranded oligonucleotide of some or any of the foregoing or related embodiments, and optionally a pharmaceutically acceptable carrier, and instructions for administering the oligonucleotide-ligand conjugate to a subject in need thereof, wherein the oligonucleotide- ligand conjugate inhibits target mRNA expression in an extrahepatic cell or tissue in the subject. In some or any of the foregoing or related embodiments, the extrahepatic cell or tissue is selected from skeletal muscle, adipose tissue, adrenal tissue, heart tissue, and any combination thereof. In some or any of the foregoing or related embodiments, the cell of the extrahepatic cell or tissue is selected from a cardiomyocyte, a cell of skeletal muscle, a cell of adipose tissue, a cell of adrenal tissue, and any combination thereof. In some or any of the foregoing or related embodiments, reduction of the target mRNA in the extrahepatic cell or tissue is increased compared to reduction in a cell of the liver, optionally wherein reduction of the target mRNA is increased by at least 10%.FH12501620.1 Attorney Docket: DCY-13025 In some or any of the foregoing or related embodiments, reduction of the target mRNA is increased by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50%. In some aspects, the disclosure provides a method for treating a subject having a disease, disorder or condition associated with expression of an mRNA in an extrahepatic cell or tissue, the method comprising administering to the subject a therapeutically effective amount of the double-stranded oligonucleotide of some or any of the foregoing or related embodiments, or the pharmaceutical composition of any of the foregoing or related embodiments. In some aspects, the disclosure provides a method of delivering a double-stranded oligonucleotide to a cell or population of cells in extrahepatic tissue, the method comprising administering the pharmaceutical composition of some or any of the foregoing or related embodiments. BRIEF DESCRIPTION OF FIGURES FIG.1A provides structures of alkyl and alkylene-COOH groups suitable for conjugation to RNAi oligonucleotides. FIG.1B provides the structure of RNAi oligonucleotides having chemical modifications with a C22 conjugate linked to a nucleotide in a stem loop (Duplex A); a C16- COOH conjugate linked to a nucleotide in a stem loop (Duplex B); a C16-COOH conjugate linked to position 1 (P1) of the sense strand (Duplex C); or, a C16 conjugate linked to P1 of the sense strand and a C22 conjugate linked to a nucleotide in a the stem loop (Duplex D). FIGs.2A-2B are graphs demonstrating remaining mouse Aldh2 mRNA levels in the liver (FIG.2A) or adipose tissue (FIG.2B) of mice following intravenous treatment with a single dose (15mg / kg) of the corresponding oligonucleotide in FIG.1B. Tissue was collected 7 days post administration. Control mice were administered PBS. FIG.3 provides the structure of RNAi oligonucleotide molecules comprising a C22 conjugate (Duplex A) or a C16-COOH conjugate (Duplex B) linked to the stem loop of the sense strand. FIGs.4A-4D are graphs demonstrating remaining mouse Aldh2 mRNA levels in the liver (FIG.4A), gonadal white adipose tissue (gWAT) (FIG.4B), quadricep (FIG.4C), and subcutaneous white adipose tissue (scWAT) (FIG.4D) of mice following intravenous treatment with a single dose (15 mg / kg) of a corresponding oligonucleotide in FIG.3. Tissue was collected 7 days post administration. Control mice were administered PBS.FH12501620.1 Attorney Docket: DCY-13025 FIG.5 provides structures of RNAi oligonucleotide conjugates. The key for the depicted molecules is the same as that provided in FIG.1B. FIGs.6A-6F are graphs demonstrating remaining mouse Aldh2 mRNA levels in the liver (FIG.6A), scWAT (FIG.6B), gWAT (FIG.6C), heart (FIG.6D), quadricep (FIG. 6E), and adrenal tissue (FIG.6F) of mice following intravenous treatment with a single dose (15 mg / kg) of oligonucleotides comprising a modified sense strand of SEQ ID NO: 2 or 4 and a modified antisense strand of SEQ ID NO: 9 linked to conjugates as depicted in FIG.5 and the parent C22 conjugate shown in FIG.1B. Tissue was collected 7 days post administration. Control mice were administered PBS. FIG.7 provides structures of RNAi oligonucleotide conjugates. The key for the depicted molecules is the same as that provided in FIG.1B. FIGs.8A-8D are graphs demonstrating remaining mouse Aldh2 mRNA levels in the liver (FIG.8A), adipose tissue (FIG.8B), quadricep (FIG.8C), and heart (FIG.8D) of mice following subcutaneous treatment with a single dose (10 mg / kg) of oligonucleotides comprising a modified sense strand of SEQ ID NO: 10 and a modified antisense strand of SEQ ID NO: 5 or 6 linked to conjugates as depicted in FIG.7 and the parent C22 conjugate shown in FIG.1B. Tissue was collected 7 days post administration. Control mice were administered PBS. FIG.9 provides structures of RNAi oligonucleotide conjugates. The key for the depicted molecules is the same as that provided in FIG.1B. FIGs.10A-10D are graphs demonstrating remaining mouse Aldh2 mRNA levels in the liver (FIG.10A), skeletal muscle (FIG.10B), heart (FIG.10C), and gWAT (FIG.10D) of mice following subcutaneous treatment with a single dose (10 mg / kg) of oligonucleotides comprising a modified sense strand of SEQ ID NO: 5 and a modified antisense strand of SEQ ID NO: 10 linked to conjugates as depicted in FIG.9. Tissue was collected 7 days post administration. Control mice were administered PBS. FIGs.11A-11D are graphs demonstrating remaining mouse Aldh2 mRNA levels in the liver (FIG.11A), skeletal muscle (FIG.11B), heart (FIG.11C), and gWAT (FIG.11D) of mice following subcutaneous treatment with a single dose (10 mg / kg) of oligonucleotides comprising a modified sense strand of SEQ ID NO: 5 and a modified antisense strand of SEQ ID NO: 10 linked to conjugates as depicted in FIG.9. Tissue was collected 21 days post administration. Control mice were administered PBS.FH12501620.1 Attorney Docket: DCY-13025 FIG.12 provides structures of RNAi oligonucleotide molecules comprising a C16 conjugate and / or a C16-COOH conjugate at different positions of the sense strand. The key for the depicted molecules is the same as that provided in FIG.1B. FIGs.13A-13D are graphs demonstrating remaining mouse Aldh2 mRNA levels in the liver (FIG.13A), quadricep (FIG.13B), heart (FIG.13C), and adipose tissue (FIG. 13D) of mice following subcutaneous treatment with a single dose (10 mg / kg) of oligonucleotides comprising a modified sense strand of SEQ ID NO: 5, 7, or 8 and a modified antisense strand of SEQ ID NO: 10 linked to conjugates as depicted in FIG.12. Tissue was collected 7 days post administration. Control mice were administered PBS. FIG.14 provides structures of RNAi oligonucleotide conjugates. The key for the depicted molecules is the same as that provided in FIG.1B. FIGs.15A-15B are graphs demonstrating remaining monkey Aldh2 mRNA levels in liver (FIG.15A) and muscle (FIG.15B) of cynomolgus monkeys following subcutaneous treatment with a single dose 10 mg / kg of oligonucleotides comprising a modified sense strand of SEQ ID NO: 5 and a modified antisense strand of SEQ ID NO: 10 linked to conjugates as depicted in FIG.14. Tissue was collected 28 days post administration. Control animals were administered PBS. FIG.16 provides structures of RNAi oligonucleotide conjugates. The key for the depicted molecules is the same as that provided in FIG.1B. FIGs.17A-17D are graphs demonstrating remaining monkey Aldh2 mRNA levels in liver (FIG.17A), skeletal muscle (FIG.17B), heart (FIG.17C), and gWAT (FIG.17D) of cynomolgus monkeys following subcutaneous treatment with a single dose 10 mg / kg of oligonucleotides comprising a modified sense strand of SEQ ID NO: 5 and a modified antisense strand of SEQ ID NO: 10 linked to conjugates as depicted in FIG.16. Tissue was collected 28 days post administration. Control animals were administered PBS. FIG.18 provides structures of RNAi oligonucleotide conjugates. The key for the depicted molecules is the same as that provided in FIG.1B. FIGs.19A-19D are graphs demonstrating remaining monkey Aldh2 mRNA levels in liver (FIG.19A), skeletal muscle (FIG.19B), heart (FIG.19C), and gWAT (FIG.19D) of cynomolgus monkeys following subcutaneous treatment with a single dose 10 mg / kg of oligonucleotides comprising a modified sense strand of SEQ ID NO: 5 and a modified antisense strand of SEQ ID NO: 10 linked to conjugates as depicted in FIG.18. Tissue was collected 28 days post administration. Control animals were administered PBS.FH12501620.1 Attorney Docket: DCY-13025 FIG.20 provides structures of RNAi oligonucleotide conjugates. The key for the depicted molecules is the same as that provided in FIG.1B. FIGs.21A-21D are graphs demonstrating remaining monkey Aldh2 mRNA levels in liver (FIG.21A), skeletal muscle (FIG.21B), heart (FIG.21C), and gWAT (FIG.21D) of cynomolgus monkeys following subcutaneous treatment with a single dose 10 mg / kg of oligonucleotides comprising a modified sense strand of SEQ ID NO: 5 and a modified antisense strand of SEQ ID NO: 10 linked to conjugates as depicted in FIG.20. Tissue was collected 28 days post administration. Control animals were administered PBS. FIG.22 provides structures of RNAi oligonucleotide conjugates. The key for the depicted molecules is the same as that provided in FIG.1B. FIGs.23A-23D are graphs demonstrating remaining monkey Aldh2 mRNA levels in liver (FIG.23A), skeletal muscle (FIG.23B), heart (FIG.23C), and gWAT (FIG.23D) of cynomolgus monkeys following subcutaneous treatment with a single dose 10 mg / kg of oligonucleotides comprising a modified sense strand of SEQ ID NO: 5 and a modified antisense strand of SEQ ID NO: 10 linked to conjugates as depicted in FIG.22. Tissue was collected 28 days post administration. Control animals were administered PBS. FIG.24 provides structures of RNAi oligonucleotide conjugates. The key for the depicted molecules is the same as that provided in FIG.1B. FIGs.25A-25D are graphs demonstrating remaining monkey Aldh2 mRNA levels in liver (FIG.25A), skeletal muscle (FIG.25B), heart (FIG.25C), and gWAT (FIG.25D) of cynomolgus monkeys following subcutaneous treatment with a single dose 10 mg / kg of oligonucleotides comprising a modified sense strand of SEQ ID NO: 5 or 7 and a modified antisense strand of SEQ ID NO: 10 linked to conjugates as depicted in FIG.24. Tissue was collected 28 days post administration. Control animals were administered PBS. DETAILED DESCRIPTION In some aspects, the disclosure provides oligonucleotide-conjugates (e.g., RNAi oligonucleotides comprising an oligonucleotide-ligand conjugate) that reduce expression of a target gene in extrahepatic tissue. In other aspects, the disclosure provides methods of treating a disease or disorder associated with expression of a target gene. In other aspects, the disclosure provides methods of treating a disease or disorder associated with expression of a target gene using the oligonucleotide-conjugates, or pharmaceutically acceptable compositions thereof, described herein. In other aspects, the disclosure provides methods of using theFH12501620.1 Attorney Docket: DCY-13025 oligonucleotide-conjugates described herein in the manufacture of a medicament for treating a disease or disorder associated with expression of a target gene. The oligonucleotide-conjugates described herein comprise one or more ligands bearing carboxyl groups. The ligands comprise alkylene, alkenylene, or alkynylene groups, and one or more carboxyl groups are located on the alkylene, alkenylene, or alkynylene (referred to interchangeably herein as a “hydrocarbon chain bearing one or more carboxyl groups’). It was surprisingly discovered that such ligands containing hydrocarbon chains bearing one or more carboxyl groups target extrahepatic tissue, and thus are capable of modulating the expression of a target genes in extrahepatic cells, tissues, and / or organs. Without being bound by theory, the size of the alkylene, alkenylene or alkynylene chain bearing the carboxyl group was discovered to be important in targeting extrahepatic tissue. More specifically, when carboxylic acids were located on hydrocarbon chains having from 6 to 24 carbons (not including the number of carbons in the linker as described here), the conjugates effectively modified expression of a target gene in extrahepatic tissue at a higher amount than reduction of expression of the same target gene in hepatocytes. This unexpected discovery allows for oligonucleotide-conjugates to be used in treating disease with specificity for extrahepatic tissue. In nucleic acid chemistry, many different artificial nucleic acids have been developed to alter the behavior of siRNAs under physiological conditions. In particular, phosphorothioate (PS), 2^-methoxy (2^-OMe), and 2^-fluoro nucleic acid have often been used to modify the siRNA its behavior, toxicity and thermostability. Oligonucleotide-Ligand Conjugates The disclosure provides, inter alia, RNAi oligonucleotides comprising at least one oligonucleotide-ligand conjugate that reduce expression of a target gene in extrahepatic tissue. In some embodiments, an RNAi oligonucleotide provided by the disclosure targets an mRNA encoding the target gene. Messenger RNA (mRNA) that encodes a target gene and is targeted by an RNAi oligonucleotide of the disclosure is referred to herein as “target mRNA”. In some embodiments, the ligand comprises one or more Y-(CO2H)ngroups, or a charged form thereof, wherein Y is alkylene, alkenylene, or alkynylene, and n is 1-6. In some embodiments, the alkylene, alkenylene, or alkynylene comprises at least 5, at least 6, at least 7 at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, or at least 26 carbon atoms. In some embodiments, the alkylene, alkenylene, orFH12501620.1 Attorney Docket: DCY-13025 alkynylene comprises from 6-26 carbon atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, including all values and ranges therein), or from 10-22 carbon atoms (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, including all values and ranges therein). In some embodiments, the alkylene, alkenylene, or alkynylene comprises at least 6 (e.g., at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, or at least 26) carbon atoms. In some embodiments, the alkylene, alkenylene, or alkynylene comprises less than or equal to 30, less than or equal to 29, less than or equal to 28, less than or equal to 27, less than or equal to 26, or less than equal to 25 carbon atoms. In some embodiments, n is 1, 2, 3, 4, 5 or 6. In some embodiments, n is 1 or 2. In some embodiments, the ligand comprises 1, 2, 3, 4, 5, 6 or more Y-(CO2H)n groups, or a charged form thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, or more ligands. In some embodiments, the ligand further comprises a linker moiety, L. In some embodiments, L comprises a bivalent or trivalent C1-C50alkylene, wherein 1-25 methylene groups are optionally and independently replaced by -N(H)-, -N(C1-C4alkyl)-, -N(cycloalkyl)- , -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(C1-C4 alkyl)-, -S(O)2N(cycloalkyl)-, - N(H)C(O)-, -N(C1-C4alkyl)C(O)-, -N(cycloalkyl)C(O)-, -C(O)N(H)-, -C(O)N(C1-C4alkyl), - C(O)N(cycloalkyl), aryl, heteroaryl, cycloalkyl, or cycloalkenyl. In some embodiments, b is 0, 1, 2, 3, 4 or 5. When, Y is alkylene and L comprises -O(CH2)a(OCH2CH2)bNH-, L may further comprises a total of 50 carbon atoms in which up to 25 methylene groups are optionally and independently replaced as described above. In some embodiments when Y is alkylene, L comprises -O(CH2)a(OCH2CH2)bNH-, wherein a is 1-6 and b is 0-5, and optionally the methylene groups and substitutions mentioned above, such that L comprises up to C1-C50 alkylene, wherein 1-25 methylene groups are optionally and independently replaced as described above. In some embodiments, a is 1, 2, 3, 4, 5 or 6. In some embodiments, a is 2. In some embodiments, b is 1, 2, 3, 4, 5 or 6. In some embodiments, provided herein is an RNAi oligonucleotide comprising: (i) an antisense strand of 15 to 30 nucleotides in length and a sense strand of 13 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extrahepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more -L-Y-(CO2H)n groups, or a charged form thereof, wherein L is a linker, Y is alkylene, alkenylene, or alkynylene, and nFH12501620.1 Attorney Docket: DCY-13025 is 1-6, wherein when Y is alkylene, L comprises -O(CH2)a(OCH2CH2)bNH-, wherein a is 1-6, and b is 0-5, and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, the RNAi oligonucleotide comprises: (i) an antisense strand of 15 to 30 nucleotides in length and a sense strand of 15 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extrahepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more C6-24 alkylene-(CO2H)n, or a charged form thereof, conjugated to a nucleotide of the sense strand, wherein n is 1-6, wherein knock down of the target mRNA in the extrahepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, the extra-hepatic tissue is adipose, heart, skeletal muscle, the central nervous system, or adrenal gland tissue. In some embodiments, the extrahepatic tissue is adipose tissue. In some embodiments, the extrahepatic tissue is heart tissue. In some embodiments, the extrahepatic tissue is skeletal muscle. In some embodiments, the extrahepatic tissue is adrenal gland tissue. In some embodiments, the extrahepatic tissue is central nervous system tissue. In some embodiments, the RNAi oligonucleotide comprises an antisense strand of about 15 to 30 nucleotides in length, for example, about 15 to 30 nucleotides in length, about 15 to 29 nucleotides in length, about 15 to 28 nucleotides in length, about 15 to 27 nucleotides in length, about 15 to 26 nucleotides in length, about 15 to 25 nucleotides in length, about 15 to 24 nucleotides in length, about 15 to 23 nucleotides in length, about 15 to 22 nucleotides in length, about 15 to 21 nucleotides in length, about 15 to 20 nucleotides in length, including any values or ranges therebetween. In some embodiments, the antisense strand comprises 22 nucleotides. In some embodiments, the RNAi oligonucleotide comprises a sense strand of about 13 to 40 nucleotides in length, for example, about 13 to 40 nucleotides in length, about 13 to 38 nucleotides in length, about 13 to 36 nucleotides in length, about 13 to 34 nucleotides in length, about 13 to 32 nucleotides in length, about 13 to 30 nucleotides in length, about 13 to 28 nucleotides in length, about 15 to 40 nucleotides in length, about 15 to 38 nucleotides in length, about 15 to 36 nucleotides in length, about 15 to 34 nucleotides in length, about 15 to 32 nucleotides in length, about 15 to 30 nucleotides in length, about 15 to 28 nucleotides in length, about 20 to 40 nucleotides in length, about 20 to 38 nucleotides in length, about 20 to 36 nucleotides in length, about 20 to 34 nucleotides in length, about 20 to 32 nucleotides in length,FH12501620.1 Attorney Docket: DCY-13025 about 20 to 30 nucleotides in length, about 20 to 28 nucleotides in length, including any values or ranges therebetween. In some embodiments, the sense strand comprises 28 nucleotides. In some embodiments, each of the one or more ligands comprises one or more -L-Y- CO2H group of a charged form thereof. In some embodiments, each of the one or more ligands comprises two or more -L-Y-CO2H group of a charged form thereof. In some embodiments, each of the three or more ligands comprises one or more -L-Y-CO2H group of a charged form thereof. In some embodiments, Y is alkylene. In some embodiments, Y is C6-C30 alkylene, for example, C6-C28 alkylene, C6-C26 alkylene, C6-C24 alkylene, C6-C22 alkylene, C6-C20 alkylene, C8-C30 alkylene, C10-C30 alkylene, C10-C28 alkylene, C12-C28 alkylene, C14-C28 alkylene, C16- C28 alkylene, or C16-C22 alkylene. In some embodiments, Y is C16-C22 alkylene. In some embodiments, when Y is alkylene, then L comprises -O(CH2)a(OCH2CH2)bNH-, wherein a is 1-6, and b is 0-5. In some embodiments, a is 1 and b is 2. In some embodiments, a is 1 and b is 0. In some embodiments, a is 1 and b is 1. In some embodiments, Y is alkenylene. In some embodiments, Y is C6-C30alkenylene, for example, C6-C28alkenylene, C6-C26alkenylene, C6-C24alkenylene, C6-C22alkenylene, C6- C20 alkenylene, C8-C30 alkenylene, C10-C30 alkenylene, C10-C28 alkenylene, C12-C28 alkenylene, C14-C28alkenylene, C16-C28alkenylene, or C16-C22alkenylene. In some embodiments, the alkenylene comprises from 1-6 olefinic bonds, including 1-5 olefinic bonds, 1-4 olefinic bonds, 1-3 olefinic bonds, or 1-2 olefinic bonds. In some embodiments, Y is alkynylene. In some embodiments, Y is C6-C30 alkynylene, for example, C6-C28 alkynylene, C6-C26 alkynylene, C6-C24 alkynylene, C6-C22 alkynylene, C6- C20 alkynylene, C8-C30 alkynylene, C10-C30 alkynylene, C10-C28 alkynylene, C12-C28 alkynylene, C14-C28 alkynylene, C16-C28 alkynylene, or C16-C22 alkynylene. In some embodiments, the alkynylene comprises from 1-6 olefinic bonds, including 1-5 olefinic bonds, 1-4 olefinic bonds, 1-3 olefinic bonds, or 1-2 olefinic bonds. In some embodiments, each ligand comprises a linker (L), wherein L is conjugated the one or more alkylene-CO2H, alkenylene-CO2H, or alkynylene-CO2H, or a charged form thereof. In some embodiments, the alkylene-CO2H, alkenylene-CO2H, or alkynylene-CO2H is C5-24alkylene-CO2H, C5-24alkenylene-CO2H, or C5-24alkynylene-CO2,or a charged form thereof. In some embodiments, the alkylene-CO2H, alkenylene-CO2H, or alkynylene-CO2H is C9-24 alkylene-CO2H, C9-24 alkenylene-CO2H, or C9-24 alkynylene-CO2, or a charged form thereof. In some embodiments, the alkylene-CO2H, alkenylene-CO2H, or alkynylene-CO2H isFH12501620.1 Attorney Docket: DCY-13025 C15-22alkylene-CO2H, C15-22alkenylene-CO2H, or C15-22or alkynylene-CO2H, or a charged form thereof. In some embodiments, L comprises a bivalent or trivalent C1-C50alkylene, wherein 1- 25 methylene groups are optionally and independently replaced by -N(H)-, -N(C1-C4alkyl)-, -N(cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(C1-C4 alkyl)-, - S(O)2N(cycloalkyl)-, -N(H)C(O)-, -N(C1-C4 alkyl)C(O)-, -N(cycloalkyl)C(O)-, -C(O)N(H)-, -C(O)N(C1-C4 alkyl), -C(O)N(cycloalkyl), aryl, heteroaryl, cycloalkyl, or cycloalkenyl. In some embodiments, the 1-25 methylene groups are optionally and independently replaced by -C(O)-, -N(H)-, -N(H)C(O)-, -N(C1-C4 alkyl)C(O)-, -O-, or heteroaryl, or combinations thereof. In some embodiments, at least one methylene group is replaced by a 5-12 membered heteroaryl. In some embodiments, the 5-12 membered heteroaryl comprises 1-5 heteroatoms (e.g., 1, 2, 3, 4, or 5, including any values or ranges therebetween) selected from N, O, or S. In some embodiments, the 1-25 methylene groups are optionally and independently replaced by a 5-8 membered heteroaryl with up to 1-3 heteroatoms (e.g., 1, 2, or 3, including any values or ranges therebetween) selected from N, O, or S. In some embodiments, the heteroaryl is a 5 membered heteroaryl with up to 1-3 heteroatoms selected from N, O, or S. In some embodiments, heteroaryl is triazolyl, pyrrolyl, pyrazolyl, imidazolyl, isozazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments, the heteroaryl is a triazolyl. In some embodiments, the triazolyl is . In some embodiments, the ligand is L-Y-CO2H. In some embodiments, the ligand M is absent, or a bonding group (as described herein) such as NRC(O), or heteroaryl, wherein R is H or alkyl. a is 1, 2, 3, 4, 5, or 6; b is 1, 2, 3, 4, 5, 6, 7, or 8; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, -L-Y-CO2H is , wherein: M is absent, or a bonding group (as described herein) such as -NRC(O)-, or heteroaryl, wherein R is H or alkyl. c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. In some embodiments, M is -NRC(O)-. In some embodiments, R is H or methyl. In some embodiments, R is H. In some embodiments, M is heteroaryl. In some embodiments, the heteroaryl is triazolyl. In some embodiments, the triazolyl is . In some embodiments, M is absent. In some embodiments, c is 1. In some embodiments, d is 0 to 12. In some embodiments, d is 4 to 12. In some embodiments, d is 0. In some embodiments, e is 12 to 23. In some embodiments, e is 11, 15, or 21. In some embodiments, the antisense strand includes an overhang at the 3’ end of 2 to 6 nucleotides (e.g., 2, 3, 4, 5, or 6 nucleotides). In some embodiments, the antisense strand comprises at least one phosphorothioate linkage. In some embodiments, the antisense strand comprises one or more modified nucleotides. In some embodiments, modified nucleotide comprises a modified sugar. In some embodiments, the modified sugar comprises a 2’-OMe group. In some embodiments, the modified sugar comprises a 2’-F substituent. In some embodiments, the antisense strand comprises up to 4 contiguous nucleotides with a 2’-F modified sugar. In some embodiments, the antisense strand comprises a 4’-O-monomethylphosphonate-2’-O-methyl modified nucleotide. In some embodiments, the ligand is conjugated to a ribose of the sense strand at the 3’- or 5’-position. In some embodiments, at least one ligand is conjugated to a ribose of the sense strand at the 2’-position.FH12501620.1 Attorney Docket: DCY-13025 Formulas In some embodiments, the present disclosure provides an oligonucleotide-ligand conjugate of Formula (AI): (AI) or a pharmaceutically acceptable salt or charged form thereof, wherein: A and A’ are each independently H or one or more nucleotide; B is a nucleobase; Z is O or S; M is absent, or a moiety formed by conjugating the carboxyl containing component to the remainder of the ligand, such as NRC(O), or heteroaryl, wherein R is H or alkyl. a is 1, 2, 3, 4, 5, or 6; b is 1, 2, 3, 4, 5, 6, 7, or 8; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23; and f is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, the oligonucleotide-ligand conjugate of Formula (AI) has a structure of Formula (AII): FH12501620.1 Attorney Docket: DCY-13025 (AII), or a pharmaceutically acceptable salt or charged form thereof, wherein A, A’, B, Z, a, b, d, e, and f are defined above in Formula (AI). In some embodiments, the oligonucleotide-ligand conjugate of Formula (AI) has a structure of Formula (AIII): (AIII), or a pharmaceutically acceptable salt or charged form thereof, wherein A, A’, B, Z, a, b, d, e, and f are defined above in Formula (AI). In some embodiments, the oligonucleotide-ligand conjugate of Formula (AI) or (AIII) has a structure of Formula (AIV): (AIV), or a pharmaceutically acceptable salt or charged form thereof, wherein A, A’, B, Z, a, b, e, and f are defined above in Formula (AI). In some embodiments, the oligonucleotide-ligand conjugate of Formula (AI) has a structure of Formula (AV): FH12501620.1 Attorney Docket: DCY-13025 (AV), or a pharmaceutically acceptable salt or charged form thereof, wherein A, A’, B, Z, a, b, d, and f are defined above in Formula (AI), and wherein e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. In some embodiments, the present disclosure provides an oligonucleotide-ligand conjugate of Formula (BI) (BI), or a pharmaceutically acceptable salt or charged form thereof, wherein: A is one or more nucleotide; B is a nucleobase; Z1and Z2are each independently O or S; M is absent, NRC(O), or heteroaryl, wherein R is H or alkyl. a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d1 and d2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 23; and f is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, the present disclosure provides an oligonucleotide-ligand conjugate of Formula (BII):FH12501620.1 Attorney Docket: DCY-13025 (BII), or a salt or charged form thereof, wherein B, A, M, a, c, d1, d2, e, and f are defined above in Formula (BI), and wherein Z is O or S. In some embodiments, the present disclosure provides an oligonucleotide-ligand conjugate of Formula (CI): (CI), or a pharmaceutically acceptable salt or charged form thereof, wherein: A is one or more nucleotide; B is a nucleobase; Z1and Z2are each independently O or S; M is absent, NRC(O), or heteroaryl, wherein R is H or alkyl. a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d1 and d2 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23; and f is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, the present disclosure provides an oligonucleotide-ligand conjugate of Formula (CII):FH12501620.1 Attorney Docket: DCY-13025 (CII), or a salt or charged form thereof, wherein B, A, M, a, c, d1, d2, e, and f are defined above in Formula (CI), and wherein Z is O or S. M In some embodiments of the oligonucleotide-ligand conjugate of Formula (AI), (AII), (BI), (BII), (CI), or (CII), M is any suitable group (e.g., a reaction product) that couples the hydrocarbon bearing one or more carboxyl groups to the linker (L). In some embodiments of the oligonucleotide-ligand conjugate of Formula (AI), (AII), (BI), (BII), (CI), or (CII), M is -NRC(O)-. In some embodiments of the oligonucleotide-ligand conjugate of Formula (AI), (AII), (BI), (BII), (CI), or (CII), R is H. In some embodiments of the oligonucleotide-ligand conjugate of Formula (AI), (BI), (BII), (CI), or (CII), R is alkyl. In some embodiments, R is C1-6 alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments of the oligonucleotide-ligand conjugate of Formula (AI), (AIII) (BI), (BII), (CI), or (CII), M is heteroaryl. In some embodiments M is a 5-12 membered heteroaryl. In some embodiments, M is a 5-12 membered heteroaryl containing 1-5 heteroatoms (e.g., 1, 2, 3, 4, or 5, including any ranges therebetween) selected from N, O, or S. In some embodiments, M is a 5-8 membered heteroaryl containing 1-3 heteroatoms (e.g., 1, 2, or 3, including any values or ranges therebetween) selected from N, O, or S. In some embodiments, M is a 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S. In some embodiments, M is triazolyl, pyrrolyl, pyrazolyl, imidazolyl, isozazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments, M is triazolyl. In some embodiments of the oligonucleotide-ligand conjugate of Formula In some embodiments of the oligonucleotide-ligand conjugate of Formula (AI), (AV), (BI), (BII), (CI), or (CII), M is absent.FH12501620.1 Attorney Docket: DCY-13025 Additional examples of M groups include: , , , B In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), B is a natural or non-natural base. In some embodiments, the base is FH12501620.1 Attorney Docket: DCY-13025 some embodiments, B is . In some embodiments, B is . In some embodiments, Z In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), Z is O. In some embodiments, Z is S. a, b, c, d, e, f In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), a is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, a is 4. In some embodiments, a is 5. In some embodiments, a is 6. In some embodiments, a is 1 or 2. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), or (AV), b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In some embodiments, b is 4. In some embodiments, b is 5. In some embodiments, b is 6. In some embodiments, b is 1 or 2. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, c is 2. In some embodiments, c is 3. In some embodiments, c is 4. In some embodiments, c is 5. In some embodiments, c is 6. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), or (AV), d is 0. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 5. In some embodiments, d is 6. In some embodiments, d is 7. In some embodiments, d is 8. In some embodiments, d is 9. In some embodiments, d is 10. In some embodiments, d is 11. InFH12501620.1 Attorney Docket: DCY-13025 some embodiments, d is 12. In some embodiments, d is 13. In some embodiments, d is 14. In some embodiments, d is 15. In some embodiments, d is 16. In some embodiments, d is 17. In some embodiments, d is 18. In some embodiments, d is 19. In some embodiments, d is 20. In some embodiments, d is 0, 4, or 12. In some embodiments, d is 0 or 12. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (BI), (BII), (CI), or (CII), d1 is 0. In some embodiments, d1 is 1. In some embodiments, d1 is 2. In some embodiments, d1 is 3. In some embodiments, d1 is 4. In some embodiments, d1 is 5. In some embodiments, d1 is 6. In some embodiments, d1 is 7. In some embodiments, d1 is 8. In some embodiments, d1 is 9. In some embodiments, d1 is 10. In some embodiments, d1 is 11. In some embodiments, d1 is 12. In some embodiments, d1 is 13. In some embodiments, d1 is 14. In some embodiments, d1 is 15. In some embodiments, d1 is 16. In some embodiments, d1 is 17. In some embodiments, d1 is 18. In some embodiments, d1 is 19. In some embodiments, d1 is 20. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (BI), (BII), (CI), or (CII), d2is 0. In some embodiments, d2is 1. In some embodiments, d2is 2. In some embodiments, d2is 3. In some embodiments, d2is 4. In some embodiments, d2is 5. In some embodiments, d2 is 6. In some embodiments, d2 is 7. In some embodiments, d2 is 8. In some embodiments, d2is 9. In some embodiments, d2is 10. In some embodiments, d2is 11. In some embodiments, d2 is 12. In some embodiments, d2 is 13. In some embodiments, d2 is 14. In some embodiments, d2 is 15. In some embodiments, d2 is 16. In some embodiments, d2 is 17. In some embodiments, d2 is 18. In some embodiments, d2 is 19. In some embodiments, d2 is 20. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), e is 5. In some embodiments, e is 6. In some embodiments, e is 7. In some embodiments, e is 8. In some embodiments, e is 9. In some embodiments, e is 10. In some embodiments, e is 11. In some embodiments, e is 12. In some embodiments, e is 13. In some embodiments, e is 14. In some embodiments, e is 15. In some embodiments, e is 16. In some embodiments, e is 17. In some embodiments, e is 18. In some embodiments, e is 19. In some embodiments, e is 20. In some embodiments, e is 21. In some embodiments, e is 22. In some embodiments, e is 23. In some embodiments, e is 11 or 22. In some embodiments of the oligonucleotide-ligand, e is 7, 15, or 21. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), e is 11, 15, or 21.FH12501620.1 Attorney Docket: DCY-13025 In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), f is 0. In some embodiments, f is 1. In some embodiments, f is 2. In some embodiments, f is 3. In some embodiments, f is 4. In some embodiments, f is 5. In some embodiments, f is 6. In some embodiments f is 0, 1, or 2. A and A^ In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), A is H. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), or (AV) A^ is H. In some embodiments, A is 13 to 40 nucleotides in length. In some embodiments, A is 13 to 36 nucleotides in length. In some embodiments, A is 12 to 29 nucleotides in length. In some embodiments, A is 15 to 20 nucleotides in length. In some embodiments, A is 13 nucleotides in length. In some embodiments, A is 14 nucleotides in length. In some embodiments, A is 15 nucleotides in length. In some embodiments, A is 16 nucleotides in length. In some embodiments, A is 17 nucleotides in length. In some embodiments, A is 18 nucleotides in length. In some embodiments, A is 19 nucleotides in length. In some embodiments, A is 20 nucleotides in length. In some embodiments, A is 21 nucleotides in length. In some embodiments, A is 22 nucleotides in length. In some embodiments, A is 14 nucleotides in length. In some embodiments, A is 23 nucleotides in length. In some embodiments, A is 24 nucleotides in length. In some embodiments, A is 25 nucleotides in length. In some embodiments, A is 26 nucleotides in length. In some embodiments, A is 27 nucleotides in length. In some embodiments, A is 28 nucleotides in length. In some embodiments, A is 29 nucleotides in length. In some embodiments, A is 30 nucleotides in length. In some embodiments, A is 31 nucleotides in length. In some embodiments, A is 32 nucleotides in length. In some embodiments, A is 33 nucleotides in length. In some embodiments, A is 34 nucleotides in length. In some embodiments, A is 35 nucleotides in length. In some embodiments, A is 36 nucleotides in length. In some embodiments, A is 37 nucleotides in length. In some embodiments, A is 38 nucleotides in length. In some embodiments, A is 39 nucleotides in length. In some embodiments, A is 40 nucleotides in length. In some embodiments, A^ is 13 to 40 nucleotides in length. In some embodiments, A^ is 13 to 36 nucleotides in length. In some embodiments, A^ is 15 to 20 nucleotides in length. In some embodiments, A^ is 13 nucleotides in length. In some embodiments, A^ is 14 nucleotides in length. In some embodiments, A^ is 15 nucleotides in length. In some embodiments, A^ isFH12501620.1 Attorney Docket: DCY-13025 16 nucleotides in length. In some embodiments, A^ is 17 nucleotides in length. In some embodiments, A^ is 18 nucleotides in length. In some embodiments, A^ is 19 nucleotides in length. In some embodiments, A is 20 nucleotides in length. In some embodiments, A^ is 21 nucleotides in length. In some embodiments, A^ is 22 nucleotides in length. In some embodiments, A^ is 14 nucleotides in length. In some embodiments, A^ is 23 nucleotides in length. In some embodiments, A^ is 24 nucleotides in length. In some embodiments, A^ is 25 nucleotides in length. In some embodiments, A^ is 26 nucleotides in length. In some embodiments, A^ is 27 nucleotides in length. In some embodiments, A^ is 28 nucleotides in length. In some embodiments, A^ is 29 nucleotides in length. In some embodiments, A^ is 30 nucleotides in length. In some embodiments, A^ is 31 nucleotides in length. In some embodiments, A^ is 32 nucleotides in length. In some embodiments, A^ is 33 nucleotides in length. In some embodiments, A^ is 34 nucleotides in length. In some embodiments, A^ is 35 nucleotides in length. In some embodiments, A^ is 36 nucleotides in length. In some embodiments, A^ is 37 nucleotides in length. In some embodiments, A^ is 38 nucleotides in length. In some embodiments, A^ is 39 nucleotides in length. In some embodiments, A^ is 40 nucleotides in length. In some embodiments, A is 12-36 nucleotides in length and A^ is 1-10 nucleotides in length. In some embodiments, A is 12-29 nucleotides in length and A^ is 1-10 nucleotides in length. In some embodiments, A is 1-10 nucleotides in length and A^ is 12-29 nucleotides in length. In some embodiments, A is 13 to 40 nucleotides in length and A^ is H. In some embodiments, A is 13 to 20 nucleotides in length and A^ is H. In some embodiments, A is 18 to 30 nucleotides in length and A^ is H. In some embodiments, A is 27 nucleotides in length and A^ is 8 nucleotides in length. In some embodiments, A is 28 nucleotides in length and A^ is 8 nucleotides in length. In some embodiments, A is H and A^ is 12 to 40 nucleotides in length. In some embodiments, A is H and A^ is 36 nucleotides in length. In some embodiments, A is H and A^ is 19 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprising a sense strand and an antisense strand comprises an oligonucleotide-ligand conjugate of any one Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII). In some embodiments, an RNAi oligonucleotide comprising a sense strand and an antisense strand comprises at least one oligonucleotide-ligand conjugate of any one of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII). In some embodiments, an RNAi oligonucleotide comprising a sense strand and an antisense strand comprises at least two oligonucleotide-ligand conjugates of any one of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII).FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AI), wherein A is H and A^ is 19 nucleotides, and wherein the antisense strand is 15 to 30 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AI), wherein A is H and A^ is 19 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AI), wherein A is 27 nucleotides and A^ is 8 nucleotides, and wherein the antisense strand is 15 to 30 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AI), wherein A is 27 nucleotides and A^ is 8 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AI), wherein A is 28 nucleotides and A^ is 8 nucleotides, and wherein the antisense strand is 15 to 30 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AI), wherein A is 28 nucleotides and A^ is 8 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AII), wherein A is H and A^ is 19 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AII), wherein A is 27 nucleotides and A^ is 8 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AII), wherein A is 28 nucleotides and A^ is 8 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AIII), wherein A is H and A^ is 19 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense andFH12501620.1 Attorney Docket: DCY-13025 antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AIII), wherein A is 27 nucleotides and A^ is 8 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AIII), wherein A is 28 nucleotides and A^ is 8 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AIV), wherein A is H and A^ is 19 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AIV), wherein A is 27 nucleotides and A^ is 8 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AIV), wherein A is 28 nucleotides and A^ is 8 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AV), wherein A is H and A^ is 19 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AV), wherein A is 27 nucleotides and A^ is 8 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of Formula (AV), wherein A is 28 nucleotides and A^ is 8 nucleotides, and wherein the antisense strand is 22 nucleotides in length. In some embodiments, the RNAi oligonucleotide comprises a duplex region. In some embodiments, the duplex region includes one or more phosphorothioate linkages (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more phosphorothioate linkages). In some embodiments, the duplex region includes two phosphorothioate linkages. In some embodiments, the duplex region includes three phosphorothioate linkages. In some embodiments, the duplex region includes four phosphorothioate linkages. In some embodiments, the duplex region includes two or more phosphorothioate linkages, and two phosphorothioate linkages are adjacent to each other. In some embodiments, the duplex region includes two phosphorothioate linkages, andFH12501620.1 Attorney Docket: DCY-13025 the two phosphorothioate linkages are adjacent to each other. In some embodiments, the duplex region comprises 20 to 30 base pairs, including 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 base pairs, including any values or ranges therebetween. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A and A^ comprise at least 14 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 14 nucleotides of A and A^ form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A comprises at least 14 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 14 nucleotides of A form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A^ comprises at least 14 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 14 nucleotides of A^ form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A and A^ comprise at least 15 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 15 nucleotides of A and A^ form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A comprises at least 15 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 15 nucleotides of A form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A^ comprises at least 15 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 15 nucleotides of A^ form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A and A^ comprise at least 16 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 16 nucleotidesFH12501620.1 Attorney Docket: DCY-13025 of A and A^ form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A comprises at least 16 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 16 nucleotides of A form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A^ comprises at least 16 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 16 nucleotides of A^ form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A and A^ comprise at least 17 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 17 nucleotides of A and A^ form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A comprises at least 17 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 17 nucleotides of A form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A^ comprises at least 17 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 17 nucleotides of A^ form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A and A^ comprise at least 18 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 18 nucleotides of A and A^ form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A comprises at least 18 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 18 nucleotides of A form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any ofFH12501620.1 Attorney Docket: DCY-13025 Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A^ comprises at least 18 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 18 nucleotides of A^ form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A and A^ comprise at least 19 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 19 nucleotides of A and A^ form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A comprises at least 19 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 19 nucleotides of A form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (AI), (AII), (AIII), (AIV), and (AV), wherein A^ comprises at least 19 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 19 nucleotides of A^ form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (BI), (BII), (CI), and (CII), wherein A comprises at least 14 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 14 nucleotides of A form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide- ligand conjugate of any of Formula (BI), (BII), (CI), and (CII), wherein A comprises at least 15 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 15 nucleotides of A form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (BI), (BII), (CI), and (CII), wherein A comprises at least 16 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 16 nucleotides of A form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (BI), (BII), (CI), and (CII), wherein A comprises at least 17 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 17 nucleotides of A form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a senseFH12501620.1 Attorney Docket: DCY-13025 strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (BI), (BII), (CI), and (CII), wherein A comprises at least 18 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 18 nucleotides of A form a duplex region with the antisense strand. In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any of Formula (BI), (BII), (CI), and (CII), wherein A comprises at least 19 nucleotides, and wherein the oligonucleotide-ligand conjugate and the at least 19 nucleotides of A form a duplex region with the antisense strand. In some embodiments the RNAi oligonucleotide comprises a loop region. In some embodiments, the RNAi oligonucleotide comprises a loop region, wherein the loop comprises an oligonucleotide-ligand conjugate of any of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII). In some embodiments, the RNAi oligonucleotide comprises a loop region, wherein the loop is a tetraloop comprising an oligonucleotide-ligand conjugate of any of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII).In some embodiments, an oligonucleotide-ligand conjugate of any of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII) is position 1 of the tetraloop. In some embodiments, an oligonucleotide-ligand conjugate of any of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII) is position 2 of the tetraloop. In some embodiments, an oligonucleotide- ligand conjugate of any of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII) is position 3 of the tetraloop. In some embodiments, an oligonucleotide-ligand conjugate of any of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII) is position 4 of the tetraloop. In some embodiments, the tetraloop region comprises a 5’- GAAA-3’ sequence. In some embodiments, an RNAi oligonucleotide comprising an oligonucleotide- ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII) comprises one or more modified nucleotides, e.g., as described herein. In some embodiments, the modified nucleotide comprises a modified sugar. In some embodiments, the modified sugar comprises a 2’-OMe substituent. In some embodiments, the modified sugar comprises a 2’-F substituent. In some embodiments, the modified nucleotide comprises a modified nucleobase. In some embodiments, the modified nucleotide is a 4’-O- monomethylphosphonate-2’-O-methyl modified nucleotide. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein A is at least one nucleotide, one or more nucleotides of A is a modified nucleotide. In some embodiments of theFH12501620.1 Attorney Docket: DCY-13025 oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein A is 13 to 40 nucleotides, one or more nucleotides of A is a modified nucleotide. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein A is 13 to 40 nucleotides, one or more nucleotides of A comprises a modified sugar. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein A is 13 to 40 nucleotides, one or more nucleotides of A comprises a 2’-OMe substituent. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein A is 13 to 40 nucleotides, one or more nucleotides of A comprises a 2’-F substituent. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein A is 13 to 40 nucleotides, every nucleotide of A is a modified nucleotide. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), or (AIII), wherein A^ is at least one nucleotide, one or more nucleotides of A^ is a modified nucleotide. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), or (AIII), wherein A is 13 to 40 nucleotides, one or more nucleotides of A^ is a modified nucleotide. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), or (AIII), wherein A is 13 to 40 nucleotides, one or more nucleotides of A^ comprises a modified sugar. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), or (AIII), wherein A is 13 to 40 nucleotides, one or more nucleotides of A^ comprises a 2’-OMe substituent. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), or (AIII), wherein A is 13 to 40 nucleotides, one or more nucleotides of A^ comprises a 2’-F substituent. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), or (AIII), wherein A^ is 13 to 40 nucleotides, every nucleotide of A^ is a modified nucleotide. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), the conjugate further comprises one or more ligands having the structure -L-Y-(CO2H)nas described herein. In some embodiments of the oligonucleotide-ligand conjugate of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), the ligand is conjugated to a ribose of the sense strand at the 2’-position. In some embodiments, ligand is conjugated to a ribose of the sense strand at the 3’- or 5’-position.FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, the present disclosure provides an oligonucleotide-ligand conjugate comprises two or more of (i), (ii), or (iii): (i) Formula (AI), (AII), (AIII), (AIV), or (AV); (ii) Formula (BI) or (BII); and (iii) Formula (CI) or (CII). RNAi Oligonucleotide Targeting Sequences In some embodiments, the RNAi oligonucleotides provided by the disclosure comprise a targeting sequence. As used herein, the term “targeting sequence” refers to a nucleotide sequence having a region of complementarity to a specific nucleotide sequence comprising an mRNA. In some embodiments, the RNAi oligonucleotides provided by the disclosure comprise a gene targeting sequence having a region of complementarity to a nucleotide sequence comprising a target sequence of a target mRNA. The targeting sequence imparts the RNAi oligonucleotides with the ability to specifically target an mRNA by binding or annealing to a target sequence comprising a target mRNA by complementary (Watson-Crick) base pairing. In some embodiments, the RNAi oligonucleotides herein (or a strand thereof, e.g., an antisense strand or a guide strand of a double-stranded oligonucleotide) comprise a targeting sequence having a region of complementarity that binds or anneals to a target sequence comprising a target mRNA by complementary (Watson-Crick) base pairing. In some embodiments, the RNAi oligonucleotides herein (or a strand thereof, e.g., an antisense strand or a guide strand of a double-stranded oligonucleotide) comprise a targeting sequence having a region of complementarity that binds or anneals to a target sequence within a target mRNA by complementary (Watson-Crick) base pairing. The targeting sequence is generally of suitable length and base content to enable binding or annealing of the RNAi oligonucleotide (or a strand thereof) to a specific target mRNA for purposes of inhibiting target gene expression. In some embodiments, the targeting sequence is at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29 or at least about 30 nucleotides in length. In some embodiments, the targeting sequence is at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19 or at least 20 nucleotides. In some embodiments, the targeting sequence is about 12 to about 30 (e.g., 12 to 30, 12 to 22, 15 to 25, 17 to 21, 18 to 27, 19 to 27, or 15 to 30) nucleotides in length. In some embodiments, the targeting sequence is about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides in length. In some embodiments, the targeting sequence is 18 nucleotidesFH12501620.1 Attorney Docket: DCY-13025 in length. In some embodiments, the targeting sequence is 19 nucleotides in length. In some embodiments, the targeting sequence is 20 nucleotides in length. In some embodiments, the targeting sequence is 21 nucleotides in length. In some embodiments, the targeting sequence is 22 nucleotides in length. In some embodiments, the targeting sequence is 23 nucleotides in length. In some embodiments, the targeting sequence is 24 nucleotides in length. In some embodiments, the RNAi oligonucleotides herein comprise a targeting sequence that is fully complementary to a target sequence comprising a target mRNA. In some embodiments, the RNAi oligonucleotides herein comprise a targeting sequence that is fully complementary to a target sequence within a target mRNA. In some embodiments, the targeting sequence is partially complementary to a target sequence comprising a target mRNA. In some embodiments, the targeting sequence is partially complementary to a target sequence within a target mRNA. In some embodiments, the targeting sequence comprises a region of contiguous nucleotides comprising the antisense strand. In some embodiments, the RNAi oligonucleotides herein comprise a targeting sequence that is complementary to a contiguous sequence of nucleotides comprising a target mRNA, wherein the contiguous sequence of nucleotides is about 12 to about 30 nucleotides in length (e.g., 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 20, 12 to 18, 12 to 16, 14 to 22, 16 to 20, 18 to 20 or 18 to 19 nucleotides in length). In some embodiments, the RNAi oligonucleotides comprise a targeting sequence that is complementary to a contiguous sequence of nucleotides comprising a target mRNA, wherein the contiguous sequence of nucleotides is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 nucleotides in length. In some embodiments, the RNAi oligonucleotides comprise a targeting sequence that is complementary to a contiguous sequence of nucleotides comprising a target mRNA, wherein the contiguous sequence of nucleotides is 15 nucleotides in length. In some embodiments, the RNAi oligonucleotides comprise a targeting sequence that is complementary to a contiguous sequence of nucleotides comprising a target mRNA, wherein the contiguous sequence of nucleotides is 19 nucleotides in length. In some embodiments, the RNAi oligonucleotide comprises a targeting sequence that is complementary to a contiguous sequence of nucleotides comprising a target mRNA, wherein the contiguous sequence of nucleotides is 15 nucleotides in length. In some embodiments, the RNAi oligonucleotide comprises a targeting sequence that is complementary to a contiguous sequence of nucleotides comprising a target mRNA, wherein the contiguous sequence of nucleotides is 19 nucleotides in length.FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, a targeting sequence of an RNAi oligonucleotide herein is fully complementary (e.g., having no mismatches) to a target sequence comprising a target mRNA and comprises the entire length of an antisense strand. In some embodiments, a targeting sequence of an RNAi oligonucleotide herein is fully complementary (e.g., having no mismatches) to a target sequence comprising a target mRNA and comprises a portion of the entire length of an antisense strand. In some embodiments, a targeting sequence of an RNAi oligonucleotide herein is fully complementary (e.g., having no mismatches) to a target sequence comprising a target mRNA and comprises 10 to 20 nucleotides of the antisense strand. In some embodiments, a targeting sequence of an RNAi oligonucleotide herein is fully complementary (e.g., having no mismatches) to a target sequence comprising a target mRNA and comprises 15 to 19 nucleotides of the antisense strand. In some embodiments, a targeting sequence of an RNAi oligonucleotide herein is fully complementary (e.g., having no mismatches) to a target sequence comprising a target mRNA and comprises 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, or 22 nucleotides of the antisense strand. In some embodiments, a targeting sequence of an RNAi oligonucleotide herein is fully complementary (e.g., having no mismatches) to a target sequence comprising a target mRNA and comprises 19 nucleotides of the antisense strand. In some embodiments, an RNAi oligonucleotide herein comprises a targeting sequence having one or more base pair (bp) mismatches with the corresponding target sequence comprising a target mRNA. In some embodiments, the targeting sequence has a 1 bp mismatch, a 2 bp mismatch, a 3 bp mismatch, a 4 bp mismatch, or a 5 bp mismatch with the corresponding target sequence comprising a target mRNA provided that the ability of the targeting sequence to bind or anneal to the target sequence under appropriate hybridization conditions and / or the ability of the RNAi oligonucleotide to inhibit or reduce target gene expression is maintained (e.g., under physiological conditions). Alternatively, in some embodiments, the targeting sequence comprises no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 bp mismatches with the corresponding target sequence comprising a target mRNA provided that the ability of the targeting sequence to bind or anneal to the target sequence under appropriate hybridization conditions and / or the ability of the RNAi oligonucleotide to inhibit or reduce target gene expression is maintained. In some embodiments, the RNAi oligonucleotide comprises a targeting sequence having 1 mismatch with the corresponding target sequence. In some embodiments, the RNAi oligonucleotide comprises a targeting sequence having 2 mismatches with the corresponding target sequence.FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, the RNAi oligonucleotide comprises a targeting sequence having 3 mismatches with the corresponding target sequence. In some embodiments, the RNAi oligonucleotide comprises a targeting sequence having 4 mismatches with the corresponding target sequence. In some embodiments, the RNAi oligonucleotide comprises a targeting sequence having 5 mismatches with the corresponding target sequence. In some embodiments, the RNAi oligonucleotide comprises a targeting sequence having more than one mismatch (e.g., 2, 3, 4, 5 or more mismatches) with the corresponding target sequence, wherein at least 2 (e.g., all) of the mismatches are positioned consecutively (e.g., 2, 3, 4, 5 or more mismatches in a row), or wherein the mismatches are interspersed in any position throughout the targeting sequence. In some embodiments, the RNAi oligonucleotide comprises a targeting sequence having more than one mismatch (e.g., 2, 3, 4, 5 or more mismatches) with the corresponding target sequence, wherein at least 2 (e.g., all) of the mismatches are positioned consecutively (e.g., 2, 3, 4, 5 or more mismatches in a row), or wherein at least one or more non-mismatched base pair is located between the mismatches, or a combination thereof. Types of Oligonucleotides A variety of RNAi oligonucleotide types and / or structures are useful for reducing target gene expression in the methods herein. Any of the RNAi oligonucleotide types described herein or elsewhere are contemplated for use as a framework to incorporate a targeting sequence herein for the purposes of inhibiting or reducing corresponding target gene expression. In some embodiments, the RNAi oligonucleotides herein inhibit target gene expression by engaging with RNA interference (RNAi) pathways upstream or downstream of Dicer involvement. For example, RNAi oligonucleotides have been developed with each strand having sizes of about 19-25 nucleotides with at least one 3^ overhang of 1 to 5 nucleotides (see, e.g., US Patent No. 8,372,968). Longer oligonucleotides also have been developed that are processed by Dicer to generate active RNAi products (see, e.g., US Patent No. 8,883,996). Further work produced extended double-stranded oligonucleotides where at least one end of at least one strand is extended beyond a duplex targeting region, including structures where one of the strands includes a thermodynamically stabilizing tetraloop structure (see, e.g., US Patent Nos. 8,513,207 and 8,927,705, as well as Intl. Patent Application Publication No. WO 2010 / 033225). Such structures may include single-stranded extensions (on one or both sides of the molecule) as well as double-stranded extensions. In some embodiments, the RNAi oligonucleotides conjugates herein engage with the RNAi pathway downstream of the involvement of Dicer (e.g., Dicer cleavage). In someFH12501620.1 Attorney Docket: DCY-13025 embodiments, the oligonucleotides described herein are Dicer substrates. In some embodiments, upon endogenous Dicer processing, double-stranded nucleic acids of 19-23 nucleotides in length capable of reducing expression of a target mRNA are produced. In some embodiments, the RNAi oligonucleotide has an overhang (e.g., of 1, 2, or 3 nucleotides in length) in the 3^ end of the sense strand. In some embodiments, the RNAi oligonucleotide (e.g., siRNA conjugate) comprises a 21-nucleotide guide strand that is antisense to a target mRNA and a complementary passenger strand, in which both strands anneal to form a 19-bp duplex and 2 nucleotide overhangs at either or both 3^ ends. Longer oligonucleotide designs also are contemplated including oligonucleotides having a guide strand of 23 nucleotides and a passenger strand of 21 nucleotides, where there is a blunt end on the right side of the molecule (3^ end of passenger strand / 5^ end of guide strand) and a two nucleotide 3^-guide strand overhang on the left side of the molecule (5^ end of the passenger strand / 3^ end of the guide strand). In such molecules, there is a 21 bp duplex region. See, e.g., US Patent Nos.9,012,138; 9,012,621; 9,193,753; 8,420,391; and, 8,552,171 all to Tuschl et al. Such patents also indicate a lack of activity with regard to double overhang constructs. In some embodiments, the RNAi oligonucleotides conjugates disclosed herein comprise sense and antisense strands that are both in the range of about 17 to 26 (e.g., 17 to 26, 20 to 25 or 21-23) nucleotides in length. In some embodiments, the RNAi oligonucleotides disclosed herein comprise a sense and antisense strand that are both in the range of about 19- 22 nucleotides in length. In some embodiments, the sense and antisense strands are of equal length. In some embodiments, the RNAi oligonucleotides disclosed herein comprise sense and antisense strands, such that there is a 3^-overhang on either the sense strand or the antisense strand, or both the sense and antisense strand. In some embodiments, for RNAi oligonucleotides that have sense and antisense strands that are both in the range of about 21- 23 nucleotides in length, a 3^ overhang on the sense, antisense, or both sense and antisense strands is 1 or 2 nucleotides in length. In some embodiments, an RNAi oligonucleotide has a guide strand of 22 nucleotides and a passenger strand of 20 nucleotides, where there is a blunt end on the right side of the molecule (3^ end of passenger strand / 5^ end of guide strand) and a 2 nucleotide 3^-guide strand overhang on the left side of the molecule (5^ end of the passenger strand / 3^ end of the guide strand). In such molecules, there is a 20 bp duplex region. Other RNAi oligonucleotide designs for use with the compositions and methods herein include: 16-mer siRNAs (see, e.g., Nucleic Acids in Chemistry and Biology, Blackburn (ed.), ROYALSOCIETY OFCHEMISTRY, 2006), shRNAs (e.g., having 19 bp or shorter stems; see, e.g., Moore et al. (2010) METHODSMOL. BIOL.629:141-58), blunt siRNAs (e.g., of 19 bps inFH12501620.1 Attorney Docket: DCY-13025 length; see, e.g., Kraynack & Baker (2006) RNA 12:163-76), asymmetrical siRNAs (aiRNA; see, e.g., Sun et al. (2008) NAT. BIOTECHNOL.26:1379-82), asymmetric shorter-duplex siRNA (see, e.g., Chang et al. (2009) MOL. THER.17:725-32), fork siRNAs (see, e.g., Hohjoh (2004) FEBS Lett. 557:193-98), and small internally segmented interfering RNA (siRNA; see, e.g., Bramsen et al. (2007) NUCLEIC ACIDS RES.35:5886-97). Further non-limiting examples of an oligonucleotide structure that may be used in some embodiments to reduce or inhibit the expression of a target gene are microRNA (miRNA), short hairpin RNA (shRNA) and short siRNA (see, e.g., Hamilton et al. (2002) EMBO J.21:4671-79; see also, US Patent Application Publication No.2009 / 0099115). Antisense Strands In some embodiments, an antisense strand of an RNAi oligonucleotide is referred to as a “guide strand.” For example, an antisense strand that engages with RNA-induced silencing complex (RISC) and binds to an Argonaute protein such as Ago2, or engages with or binds to one or more similar factors, and directs silencing of a target gene, the antisense strand is referred to as a guide strand. In some embodiments, a sense strand complementary to a guide strand is referred to as a “passenger strand.” In some embodiments, an RNAi oligonucleotide herein comprises an antisense strand of up to about 50 nucleotides in length (e.g., up to 50, up to 40, up to 35, up to 30, up to 27, up to 25, up to 21, up to 19, up to 17, up to 15, or up to 8 nucleotides in length). In some embodiments, an RNAi oligonucleotide herein comprises an antisense strand of at least about 12 nucleotides in length (e.g., at least 12, at least 15, at least 19, at least 21, at least 22, at least 25, at least 27, at least 30, at least 35 or at least 38 nucleotides in length). In some embodiments, a herein comprises an antisense strand in a range of about 8 to about 40 (e.g., 8 to 40, 8 to 36, 8 to 32, 8 to 28, 15 to 40, 15 to 36, 15 to 32, 15 to 30, 15 to 28, 17 to 22, 17 to 25, 19 to 27, 19 to 30, 20 to 40, 22 to 40, 25 to 40 or 32 to 40) nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises an antisense strand of 15 to 30 nucleotides in length. In some embodiments, an antisense strand of any one of the RNAi oligonucleotide disclosed herein is of 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 or 40 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises an antisense strand of 19-23 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises an antisense strand of 19 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises an antisense strand of 20 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises an antisense 76FH12501620.1 Attorney Docket: DCY-13025 strand of 21 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises an antisense strand of 22 nucleotides in length. In some embodiments, an RNAi oligonucleotide comprises an antisense strand of 23 nucleotides in length. Sense Strands In some embodiments, an RNAi oligonucleotide disclosed herein comprises a sense strand (or passenger strand) of up to about 50 nucleotides in length (e.g., up to 50, up to 40, up to 36, up to 30, up to 27, up to 25, up to 21, up to 19, up to 17 or up to 12 nucleotides in length). In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of at least about 12 nucleotides in length (e.g., at least 12, at least 15, at least 19, at least 21, at least 25, at least 27, at least 30, at least 36 or at least 38 nucleotides in length). In some embodiments, an RNAi oligonucleotide herein comprises a sense strand in a range of about 12 to about 50 (e.g., 12 to 50, 12 to 40, 12 to 36, 12 to 32, 12 to 28, 15 to 40, 15 to 36, 15 to 32, 15 to 28, 17 to 21, 17 to 25, 19 to 27, 19 to 30, 20 to 40, 22 to 40, 25 to 40 or 32 to 40) nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand 15 to 50 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand 18 to 38 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 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, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 12-21 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 12 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 13 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 14 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 15 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 16 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 17 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 18 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 19 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 20 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 21 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 22 nucleotides in length. In some embodiments, an RNAiFH12501620.1 Attorney Docket: DCY-13025 oligonucleotide herein comprises a sense strand of 23 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 24 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 25 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 26 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 27 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 28 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 29 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 30 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 31 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 32 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 33 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 34 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 35 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 36 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 37 nucleotides in length. In some embodiments, an RNAi oligonucleotide herein comprises a sense strand of 38 nucleotides in length. In some embodiments, a sense strand comprises a stem-loop structure at its 3^ end. In some embodiments, a sense strand comprises a stem-loop structure at its 5^ end. In some embodiments, the stem-loop is formed by intrastrand base pairing. In some embodiments, a sense strand comprises a stem-loop structure at its 5^ end. In some embodiments, a stem is a duplex of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 1 nucleotide in length. In some embodiments, the stem of the stem-loop comprises a duplex of 2 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 3 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 4 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 5 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 6 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 7 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 8 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 9 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 10 nucleotides in length. InFH12501620.1 Attorney Docket: DCY-13025 some embodiments, the stem of the stem-loop comprises a duplex of 11 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 12 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 13 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 14 nucleotides in length. In some embodiments, a stem-loop provides the RNAi oligonucleotide protection against degradation (e.g., enzymatic degradation), facilitates or improves targeting and / or delivery to a target cell, tissue, or organ, or both. For example, in some embodiments, the loop of a stem-loop provides nucleotides comprising one or more modifications that facilitate, improve, or increase targeting to a target mRNA (e.g., a target mRNA expressed in extrahepatic tissue), inhibition of target gene expression, and / or delivery to a target cell, tissue, or organ (e.g., extrahepatic tissue), or a combination thereof. In some embodiments, the stem-loop itself or modification(s) to the stem-loop do not substantially affect the inherent gene expression inhibition activity of the RNAi oligonucleotide, but facilitates, improves, or increases stability (e.g., provides protection against degradation) and / or delivery of the RNAi oligonucleotide to a target cell, tissue, or organ (e.g., extrahepatic tissue ). In some embodiments, an RNAi oligonucleotide herein comprises a sense strand comprising (e.g., at its 3^ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a single-stranded loop between S1 and S2 of up to about 10 nucleotides in length (e.g., 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides in length). In some embodiments, the loop (L) is 3 nucleotides in length. In some embodiments, the loop (L) is 4 nucleotides in length. In some embodiments, the tetraloop comprises the sequence 5’-GAAA-3’. In some embodiments, the tetraloop comprises the sequence 5’-UNCG-3’. In some embodiments, the tetraloop comprises the sequence 5’-UACG-3’. In some embodiments, the stem loop comprises the sequence 5’-GCAGCCGAAAGGCUGC-3’ (SEQ ID NO: 11). In some embodiments, a loop (L) of a stem-loop having the structure S1-L-S2 as described above is a triloop. In some embodiments, the triloop comprises ribonucleotides, deoxyribonucleotides, modified nucleotides, delivery ligands, and combinations thereof. In some embodiments, a loop (L) of a stem-loop having the structure S1-L-S2 as described above is a tetraloop (e.g., within a nicked tetraloop structure). In some embodiments, the tetraloop comprises ribonucleotides, deoxyribonucleotides, modified nucleotides, delivery ligands, and combinations thereof.FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, a loop (L) of a stem-loop having the structure S1-L-S2 as described above is a tetraloop as described in US Patent No. 10,131,912, incorporated herein by reference (e.g., within a nicked tetraloop structure). Duplex Length In some embodiments, a duplex formed between a sense and antisense strand is at least 8 (e.g., at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16) nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is at least 12 (e.g., at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21) nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is in the range of 12-30 nucleotides in length (e.g., 12 to 30, 12 to 27, 12 to 22, 15 to 25, 18 to 30, 18 to 22, 18 to 25, 18 to 27, 18 to 30, 19 to 30 or 21 to 30 nucleotides in length). In some embodiments, a duplex formed between a sense and antisense strand is 12, 13, 14, 15, 16, 17, 18, 19, 29, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 10-18 base pairs in length. In some embodiments, a duplex formed between a sense and antisense strand is 15- 30 base pairs in length. In some embodiments, a duplex formed between a sense and antisense strand is 17-21 base pairs in length. In some embodiments, a duplex formed between a sense and antisense strand is 12 base pairs in length. In some embodiments, a duplex formed between a sense and antisense strand is 13 base pairs in length. In some embodiments, a duplex formed between a sense and antisense strand is 14 base pairs in length. In some embodiments, a duplex formed between a sense and antisense strand is 15 base pairs in length. In some embodiments, a duplex formed between a sense and antisense strand is 16 base pairs in length. In some embodiments, a duplex formed between a sense and antisense strand is 17 base pairs in length. In some embodiments, a duplex formed between a sense and antisense strand is 18 base pairs in length. In some embodiments, a duplex formed between a sense and antisense strand is 19 base pairs in length. In some embodiments, a duplex formed between a sense and antisense strand is 20 base pairs in length. In some embodiments, a duplex formed between a sense and antisense strand is 21 base pairs in length. In some embodiments, a duplex formed between a sense and antisense strand does not span the entire length of the sense strand and / or antisense strand. In some embodiments, a duplex between a sense and antisense strand spans the entire length of either the sense or antisense strands. In some embodiments, a duplex between a sense and antisense strand spans the entire length of both the sense strand and the antisense strand.FH12501620.1 Attorney Docket: DCY-13025 Oligonucleotide Ends In some embodiments, an RNAi oligonucleotide disclosed herein comprises sense and antisense strands, such that there is a 3’-overhang on either the sense strand or the antisense strand, or both the sense and antisense strand. In some embodiments, an RNAi oligonucleotide herein has one 5’end that is thermodynamically less stable compared to the other 5’ end. In some embodiments, an asymmetric RNAi oligonucleotide is provided that includes a blunt end at the 3’end of a sense strand and overhang at the 3’ end of the antisense strand. In some embodiments, a 3’ overhang on an antisense strand is 1-4 nucleotides in length (e.g., 1, 2, 3, or 4 nucleotides in length). In some embodiments, the 3’-overhang is about one to twenty nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length). In some embodiments, the 3’ overhang is about one to nineteen, one to eighteen, one to seventeen, one to sixteen, one to fifteen, one to fourteen, one to thirteen, one to twelve, one to eleven, one to ten, one to nine, one to eight, one to seven, one to six, one to five, one to four, one to three, or about one to two nucleotides in length. In some embodiments, the 3’-overhang is nucleotide in length. In some embodiments, the 3’-overhang is two nucleotides in length. In some embodiments, the 3’-overhang is three nucleotides in length. In some embodiments, the 3’-overhang is four nucleotides in length. In some embodiments, the 3’-overhang is five nucleotides in length. In some embodiments, the 3’- overhang is six nucleotides in length. In some embodiments, the 3’-overhang is seven nucleotides in length. In some embodiments, the 3’-overhang is eight nucleotides in length. In some embodiments, the 3’-overhang is nine nucleotides in length. In some embodiments, the 3’-overhang is ten nucleotides in length. In some embodiments, the 3’-overhang is eleven nucleotides in length. In some embodiments, the 3’-overhang is twelve nucleotides in length. In some embodiments, the 3’-overhang is thirteen nucleotides in length. In some embodiments, the 3’-overhang is fourteen nucleotides in length. In some embodiments, the 3’-overhang is fifteen nucleotides in length. In some embodiments, the 3’-overhang is sixteen nucleotides in length. In some embodiments, the 3’-overhang is seventeen nucleotides in length. In some embodiments, the 3’-overhang is eighteen nucleotides in length. In some embodiments, the 3’-overhang is nineteen nucleotides in length. In some embodiments, the 3’-overhang is twenty nucleotides in length. Typically, an oligonucleotide for RNAi has a two nucleotide overhang on the 3’ end of the antisense (guide) strand. However, other overhangs are possible. In some embodiments, an overhang is a 3’ overhang comprising a length of between one and four nucleotides,FH12501620.1 Attorney Docket: DCY-13025 optionally one to four, one to three, one to two, two to four, two to three, or one, two, three, or four nucleotides. In some embodiments, the overhang is a 5’ overhang comprising a length of between one and four nucleotides, optionally one to four, one to three, one to two, two to four, two to three, or one, two, three, or four nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the 5’ terminus of either or both strands comprise a 5’-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the sense strand comprises a 5’- overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 5’-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein both the sense strand and the antisense strand comprises a 5’-overhang comprising one or more nucleotides. In some embodiments, the 5’-overhang is about one to twenty nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length). In some embodiments, the 5’ overhang is about one to nineteen, one to eighteen, one to seventeen, one to sixteen, one to fifteen, one to fourteen, one to thirteen, one to twelve, one to eleven, one to ten, one to nine, one to eight, one to seven, one to six, one to five, one to four, one to three, or about one to two nucleotides in length. In some embodiments, the 5’-overhang is nucleotide in length. In some embodiments, the 5’-overhang is two nucleotides in length. In some embodiments, the 5’-overhang is three nucleotides in length. In some embodiments, the 5’-overhang is four nucleotides in length. In some embodiments, the 5’-overhang is five nucleotides in length. In some embodiments, the 5’- overhang is six nucleotides in length. In some embodiments, the 5’-overhang is seven nucleotides in length. In some embodiments, the 5’-overhang is eight nucleotides in length. In some embodiments, the 5’-overhang is nine nucleotides in length. In some embodiments, the 5’-overhang is ten nucleotides in length. In some embodiments, the 5’-overhang is eleven nucleotides in length. In some embodiments, the 5’-overhang is twelve nucleotides in length. In some embodiments, the 5’-overhang is thirteen nucleotides in length. In some embodiments, the 5’-overhang is fourteen nucleotides in length. In some embodiments, the 5’-overhang is fifteen nucleotides in length. In some embodiments, the 5’-overhang is sixteen nucleotides in length. In some embodiments, the 5’-overhang is seventeen nucleotides in length. In some embodiments, the 5’-overhang is eighteen nucleotides in length. In someFH12501620.1 Attorney Docket: DCY-13025 embodiments, the 5’-overhang is nineteen nucleotides in length. In some embodiments, the 5’-overhang is twenty nucleotides in length. In some embodiments, one or more (e.g., 2, 3, or 4) terminal nucleotides of the 3’ end or 5’ end of a sense and / or antisense strand are modified. For example, in some embodiments, one or two terminal nucleotides of the 3’ end of the antisense strand are modified. In some embodiments, the last nucleotide at the 3’ end of an antisense strand is modified, e.g., comprises 2’ modification, e.g., a 2’-O-methoxyethyl. In some embodiments, the last one or two terminal nucleotides at the 3’ end of an antisense strand are complementary with the target. In some embodiments, the last one or two nucleotides at the 3’ end of the antisense strand are not complementary with the target. In some embodiments, an RNAi oligonucleotide disclosed herein comprises a stem- loop structure at the 3’ end of the sense strand and comprises two terminal overhang nucleotides at the 3’ end of the antisense strand. In some embodiments, an RNAi oligonucleotide herein comprises a nicked tetraloop structure, wherein the 3’ end of the sense strand comprises a stem- tetraloop structure and comprises two terminal overhang nucleotides at the 3’ end of the antisense strand. In some embodiments, an RNAi oligonucleotide disclosed herein comprises a stem- loop structure at the 5’ end of the sense strand and comprises an overhang nucleotides at the 3’ end of the antisense strand. In some embodiments, an RNAi oligonucleotide herein comprises a nicked tetraloop structure, wherein the 5’ end of the sense strand comprises a stem-tetraloop structure and comprises two terminal overhang nucleotides at the 3’ end of the antisense strand. In some embodiments, an RNAi oligonucleotide disclosed herein comprises a stem- loop structure at the 5’ end of the sense strand and comprises a blunt end at the 5’ end of the antisense strand. In some embodiments, an RNAi oligonucleotide disclosed herein comprises an overhang of 1-8 nucleotides at the 5’ end of the sense strand and comprises an overhang of 1- 8 nucleotides at the 5’ end of the antisense strand. In some embodiments, the overhang is selected from AA, GG, AG, and GA. In some embodiments, the overhang is AA. In some embodiments, the overhang is AG. In some embodiments, the overhang is GA. In some embodiments, the two terminal overhang nucleotides are GG. Typically, one or both of the two terminal GG nucleotides of the antisense strand are not complementary with the target. In some embodiments, the 5’ end and / or the 3’end of a sense or antisense strand has an inverted cap nucleotide.FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, one or more (e.g., 2, 3, 4, 5, 6) modified internucleotide linkages are provided between terminal nucleotides of the 3’ end or 5’ end of a sense and / or antisense strand. In some embodiments, modified internucleotide linkages are provided between overhang nucleotides at the 3’ end or 5’ end of a sense and / or antisense strand. Oligonucleotide Modifications In some embodiments, an RNAi oligonucleotide disclosed herein comprises one or more modifications. Oligonucleotides (e.g., RNAi oligonucleotides) may be modified in various ways to improve or control specificity, stability, delivery, bioavailability, resistance from nuclease degradation, immunogenicity, base-pairing properties, RNA distribution and cellular uptake and other features relevant to therapeutic research use. In some embodiments, the modification is a modified sugar. In some embodiments, the modification is a 5’-terminal phosphate group. In some embodiments, the modification is a modified internucleoside linkage. In some embodiments, the modification is a modified base. In some embodiments, an oligonucleotide described herein can comprise any one of the modifications described herein or any combination thereof. For example, in some embodiments, an oligonucleotide described herein comprises at least one modified sugar, a 5’- terminal phosphate group, at least one modified internucleoside linkage, and at least one modified base. The number of modifications on an oligonucleotide (e.g., an RNAi oligonucleotide) and the position of those nucleotide modifications may influence the properties of an oligonucleotide. For example, oligonucleotides may be delivered in vivo by conjugating them to or encompassing them in a lipid nanoparticle (LNP) or similar carrier. However, when an oligonucleotide is not protected by an LNP or similar carrier, it may be advantageous for at least some of the nucleotides to be modified. Accordingly, in some embodiments, all or substantially all of the nucleotides of an oligonucleotides are modified. In some embodiments, more than half of the nucleotides are modified. In some embodiments, less than half of the nucleotides are modified. In some embodiments, the sugar moiety of all nucleotides comprising the oligonucleotide is modified at the 2’ position. In some embodiments, the sugar moiety of all nucleotides comprising the oligonucleotide is modified at the 2’ position, except for the nucleotide conjugated to a ligand (e.g., the 5’-terminal nucleotide of the sense strand). The modifications may be reversible or irreversible. In some embodiments, an oligonucleotide as disclosed herein has a number and type of modified nucleotides sufficient to cause the desiredFH12501620.1 Attorney Docket: DCY-13025 characteristics (e.g., protection from enzymatic degradation, capacity to target a desired cell after in vivo administration, and / or thermodynamic stability). Sugar Modifications In some embodiments, a nucleotide modification in a sugar comprises a 2^- modification. In some embodiments, a 2^-modification may be 2^-O-propargyl, 2^-O- propylamin, 2^-amino, 2^-ethyl, 2^-fluoro (2^-F), 2^-aminoethyl (EA), 2^-O-methyl (2^-OMe), 2^- O-methoxyethyl (2^-MOE), 2^-O-[2-(methylamino)-2-oxoethyl] (2^-O-NMA) or 2^-deoxy-2^- fluoro-^-d-arabinonucleic acid (2^-FANA). In some embodiments, the modification is 2^-F, 2^- OMe or 2^-MOE. In some embodiments, a modification in a sugar comprises a modification of the sugar ring, which may comprise modification of one or more carbons of the sugar ring. For example, a modification of a sugar of a nucleotide may comprise a 2^-oxygen of a sugar is linked to a 1^-carbon or 4^-carbon of the sugar, or a 2^-oxygen is linked to the 1^-carbon or 4^- carbon via an ethylene or methylene bridge. In some embodiments, a modified nucleotide has an acyclic sugar that lacks a 2^-carbon to 3^-carbon bond. In some embodiments, a modified nucleotide has a thiol group, e.g., in the 4^ position of the sugar. In some embodiments, an RNAi oligonucleotide described herein comprises at least about 1 modified nucleotide (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, or more). In some embodiments, the sense strand of the RNAi oligonucleotide comprises at least about 1 modified nucleotide (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, or more). In some embodiments, the antisense strand of the RNAi oligonucleotide comprises at least about 1 modified nucleotide (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, or more). In some embodiments, all the nucleotides of the sense strand of the RNAi oligonucleotide are modified. In some embodiments, all the nucleotides of the antisense strand of the RNAi oligonucleotide are modified. In some embodiments, all the nucleotides of the RNAi oligonucleotide, both the sense strand and the antisense strand) are modified. In some embodiments, the modified nucleotide comprises a 2^-modification (e.g., a 2^-F or 2^-OMe, 2^- MOE, and 2^-deoxy-2^-fluoro-^-d-arabinonucleic acid). In some embodiments, the disclosure provides RNAi oligonucleotides having different modification patterns. In some embodiments, the modified RNAi oligonucleotides comprise a sense strand sequence having a modification pattern as set forth in the Examples and SequenceFH12501620.1 Attorney Docket: DCY-13025 Listing and an antisense strand having a modification pattern as set forth in the Examples and Sequence Listing. In some embodiments, an RNAi oligonucleotide disclosed herein comprises an antisense strand having nucleotides that are modified with 2^-F. In some embodiments, an RNAi oligonucleotide disclosed herein comprises an antisense strand comprises nucleotides that are modified with 2^-F and 2^-OMe. In some embodiments, an RNAi oligonucleotide disclosed herein comprises a sense strand having nucleotides that are modified with 2^-F. In some embodiments, an RNAi oligonucleotide disclosed herein comprises a sense strand comprising nucleotides that are modified with 2^-F and 2^-OMe. In some embodiments, an RNAi oligonucleotide disclosed herein comprises a sense strand comprising nucleotides that are modified with 2^-F and 2^-OMe, provided that a nucleotide conjugated to a ligand is not modified with 2’-F or 2’-OMe. In some embodiments, an oligonucleotide described herein comprises a sense strand with about 10-25%, 10%, 11%, 12%, 13%, 14% 15%, 16%, 17%, 18%, 19% or 20% of the nucleotides of the sense strand comprising a 2’-fluoro modification. In some embodiments, about 11% of the nucleotides of the sense strand comprise a 2-fluoro modification. In some embodiments, about 40% of the nucleotides of the sense strand comprise a 2-fluoro modification. In some embodiments, about 20% of the nucleotides of the sense strand comprise a 2-fluoro modification. In some embodiments, an oligonucleotide described herein comprises an antisense strand with about 25-45%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34% 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, or 45% of the nucleotides of the antisense strand comprising a 2’-fluoro modification. In some embodiments, an oligonucleotide described herein comprises an antisense strand with about 25-35%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34% or 35% of the nucleotides of the antisense strand comprising a 2’-fluoro modification. In some embodiments, about 32% of the nucleotides of the antisense strand comprise a 2’-fluoro modification. In some embodiments, about 40% of the nucleotides of the antisense strand comprise a 2’-fluoro modification. In some embodiments, the oligonucleotide has about 15-30%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% of its nucleotides comprising a 2’-fluoro modification. In some embodiments, the oligonucleotide has about 15-25%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of its nucleotides comprising a 2’-fluoro modification. In some embodiments, about 19% of the nucleotides in the oligonucleotide comprise a 2’-fluoro modification. In some embodiments, about 26% of the nucleotides in theFH12501620.1 Attorney Docket: DCY-13025 oligonucleotide comprise a 2’-fluoro modification. In some embodiments, about 29% of the nucleotides in the oligonucleotide comprise a 2’-fluoro modification. In some embodiments, one or more of positions 8, 9, 10 or 11 of the sense strand is modified with a 2^-F group. In some embodiments, one or more nucleotides forming a base pair with a nucleotide at one or more of positions 10-13 of the antisense strand, is modified with a 2^-F group. In some embodiments, the sugar moiety at each of nucleotides not modified with a 2’-F group or conjugated to a ligand in the sense strand is modified with a 2^-OMe. In some embodiments, the sugar moiety at each of nucleotides at positions 1-7 and 12-20 in the sense strand is modified with a 2^-OMe. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand 22 nucleotides in length, with positions 1-22 numbered 5’ to 3’, and a sense strand having a 2’-fluoro modification at each of the nucleotides forming a base pair with nucleotides at one or more of positions 10, 11, 12, and 13 of the antisense strand. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand 22 nucleotides in length, with positions 1-22 numbered 5’ to 3’, and a sense strand having a 2’- fluoro modification at each of the nucleotides forming a base pair with nucleotides at positions 10, 11, 12, 13, or any combination thereof, of the antisense strand. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand 22 nucleotides in length, with positions 1-22 numbered 5’ to 3’, and a sense strand having a 2’-fluoro modification at each of the nucleotides forming a base pair with nucleotides at positions 10, 11, 12, and 13 of the antisense strand. In some embodiments, one or more of positions 4, 6, 9, 11, 13, 14, 16, and 18 of the sense strand is modified with a 2^-F group. In some embodiments, one or more nucleotides forming a base pair with a nucleotide at one or more of positions 4, 6, 8, 9, 11, 13, 16, or 18 of the antisense strand, is modified with a 2^-F group. In some embodiments, the sugar moiety at each of nucleotides not modified with a 2’-F group or conjugated to a ligand in the sense strand is modified with a 2^-OMe. In some embodiments, the sugar moiety at each of nucleotides at positions 2, 3, 5, 7, 8, 10, 12, 15, 17, 19, 20, and 21 in the sense strand is modified with a 2^- OMe. In some embodiments, one or more of positions 3, 5, 8, 10, 12, 13, 15, and 17 of the sense strand is modified with a 2^-F group. In some embodiments, one or more nucleotides forming a base pair with a nucleotide at one or more of positions 4, 6, 8, 9, 11, 13, 16, or 18 of the antisense strand, is modified with a 2^-F group. In some embodiments, the sugar moiety at each of nucleotides not modified with a 2’-F group or conjugated to a ligand in the sense strandFH12501620.1 Attorney Docket: DCY-13025 is modified with a 2^-OMe. In some embodiments, the sugar moiety at each of nucleotides at positions 1, 2, 4, 6, 7, 9, 11, 14, 16, 18, 19, and 20 in the sense strand is modified with a 2^- OMe. In some embodiments, the sense strand comprises at least one 2’-F modified nucleotide wherein the remaining nucleotides not modified with a 2’-F group or conjugated to a ligand are modified with a 2’-OMe. In some embodiments, at least one internal position (e.g., a position other than the 5’ and 3’ terminal nucleotides) of the sense strand is modified with a 2^-F group. In some embodiments, there is no 2^-F group at a terminal nucleotide of the sense strand. In some embodiments, at least one internal position (e.g., a position other than the 5’ and 3’ terminal nucleotides) of the antisense strand is modified with a 2^-F group. In some embodiments, there is no 2^-F group at a terminal nucleotide of the antisense strand. In some embodiments, the antisense strand has 7 nucleotides that are modified at the 2’ position of the sugar moiety with a 2’-F. In some embodiments, the sugar moiety at positions 2, 3, 4, 5, 7, 10, and 14 of the antisense strand are modified with a 2’-F. In some embodiments, the antisense strand has 14 nucleotides that are modified at the 2’ position of the sugar moiety with a 2’-OMe. In some embodiments, the sugar moiety at positions 6, 8, 9, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, and 22 of the antisense strand are modified with a 2’-OMe. In some embodiments, antisense strand has 9 nucleotides that are modified at the 2’ position of the sugar moiety with a 2’-F. In some embodiments, the sugar moiety at positions 2, 3, 4, 5, 7, 10, 14, 16, and 19 of the antisense strand are modified with a 2’-F. In some embodiments, the antisense strand has 12 nucleotides that are modified at the 2’ position of the sugar moiety with a 2’-OMe. In some embodiments, the sugar moiety at positions 6, 8, 9, 11, 12, 13, 15, 17, 18, 20, 21, and 22 of the antisense strand are modified with a 2’-OMe. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 10, and 14 of the antisense strand modified with 2^-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2^-O-propargyl, 2^-O-propylamin, 2^-amino, 2^-ethyl, 2^-aminoethyl (EA), 2’-O- methyl (2^-OMe), 2’-O-methoxyethyl (2^-MOE), 2^-O-[2-(methylamino)-2-oxoethyl] (2^-O- NMA), and 2’-deoxy-2’-fluoro-^-d-arabinonucleic acid (2^-FANA). In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 7, 10,FH12501620.1 Attorney Docket: DCY-13025 14, 16 and 19 of the antisense strand modified with 2^-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2^-O-propargyl, 2^-O-propylamin, 2^-amino, 2^-ethyl, 2^-aminoethyl (EA), 2’-O-methyl (2^-OMe), 2’-O-methoxyethyl (2^-MOE), 2^-O-[2-(methylamino)-2-oxoethyl] (2^- O-NMA), and 2’-deoxy-2’-fluoro-^-d-arabinonucleic acid (2^-FANA). In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, or position 22 modified with 2^-F. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, or position 22 modified with 2^-OMe. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, or position 22 modified with a modification selected from the group consisting of 2^-O-propargyl, 2^-O-propylamin, 2^-amino, 2^-ethyl, 2’-aminoethyl (EA), 2^-O-methyl (2^- OMe), 2^-O-methoxyethyl (2^-MOE), 2^-O-[2-(methylamino)-2-oxoethyl] (2^-O-NMA), and 2^-deoxy-2^-fluoro-^-d-arabinonucleic acid (2^-FANA). In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 8-11 modified with 2^-F. In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 4, 6, 9, 11, 13, 14, 16, and 18 modified with 2^-F. In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 3, 5, 8, 10, 12, 13, 15, and 17 modified with 2^-F. In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 1-7 and 12-20 modified with 2’OMe. In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 2-7 and 12-20 modified with 2’OMe. In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 2-7 and 12-19 modified with 2’OMe. In someFH12501620.1 Attorney Docket: DCY-13025 embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 3-7 and 12-20 modified with 2’OMe. In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 1, 2, 4, 6, 7, 9, 11, 14, 16, 18, 19, and 20 modified with 2’OMe. In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 2, 3, 5, 7, 8, 10, 12, 15, 17, 19, 20, and 21 modified with 2’OMe. In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety of each of the nucleotides at positions 1-7 and 12-20 of the sense strand modified with a modification selected from the group consisting of 2^-O- propargyl, 2^-O-propylamin, 2^-amino, 2^-ethyl, 2’-aminoethyl (EA), 2^-O-methyl (2^-OMe), 2^- O-methoxyethyl (2^-MOE), 2^-O-[2-(methylamino)-2-oxoethyl] (2^-O-NMA), and 2^-deoxy-2^- fluoro-^-d-arabinonucleic acid (2^-FANA). In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety of each of the nucleotides at positions 2-7 and 12-20 of the sense strand modified with a modification selected from the group consisting of 2^-O- propargyl, 2^-O-propylamin, 2^-amino, 2^-ethyl, 2’-aminoethyl (EA), 2^-O-methyl (2^-OMe), 2^- O-methoxyethyl (2^-MOE), 2^-O-[2-(methylamino)-2-oxoethyl] (2^-O-NMA), and 2^-deoxy-2^- fluoro-^-d-arabinonucleic acid (2^-FANA). In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety of each of the nucleotides at positions 2-7 and 12-19 of the sense strand modified with a modification selected from the group consisting of 2^-O- propargyl, 2^-O-propylamin, 2^-amino, 2^-ethyl, 2’-aminoethyl (EA), 2^-O-methyl (2^-OMe), 2^- O-methoxyethyl (2^-MOE), 2^-O-[2-(methylamino)-2-oxoethyl] (2^-O-NMA), and 2^-deoxy-2^- fluoro-^-d-arabinonucleic acid (2^-FANA). In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety of each of the nucleotides at positions 3-7 and 12-20 of the sense strand modified with a modification selected from the group consisting of 2^-O- propargyl, 2^-O-propylamin, 2^-amino, 2^-ethyl, 2’-aminoethyl (EA), 2^-O-methyl (2^-OMe), 2^- O-methoxyethyl (2^-MOE), 2^-O-[2-(methylamino)-2-oxoethyl] (2^-O-NMA), and 2^-deoxy-2^- fluoro-^-d-arabinonucleic acid (2^-FANA). In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 5, 7, 8, 10, 12, 15, 17, 19, 20, and 12-17 or 12-20 of the sense strand modified with a modification selected from the group consisting of 2^-O-propargyl, 2^-O-propylamin, 2^-amino, 2^-ethyl, 2’-aminoethylFH12501620.1 Attorney Docket: DCY-13025 (EA), 2^-O-methyl (2^-OMe), 2^-O-methoxyethyl (2^-MOE), 2^-O-[2-(methylamino)-2- oxoethyl] (2^-O-NMA), and 2^-deoxy-2^-fluoro-^-d-arabinonucleic acid (2^-FANA). In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 1, 2, 4, 6, 7, 9, 11, 14, 16, 18, 19, and 20of the sense strand modified with a modification selected from the group consisting of 2^-O-propargyl, 2^- O-propylamin, 2^-amino, 2^-ethyl, 2’-aminoethyl (EA), 2^-O-methyl (2^-OMe), 2^-O- methoxyethyl (2^-MOE), 2^-O-[2-(methylamino)-2-oxoethyl] (2^-O-NMA), and 2^-deoxy-2^- fluoro-^-d-arabinonucleic acid (2^-FANA). In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, or position 36 modified with 2^-F. In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, position 36, position 37 or position 38 modified with 2^-F. In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, or position 36 modified with 2^-OMe. In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28,FH12501620.1 Attorney Docket: DCY-13025 position 29, position 30, position 31, position 32, position 33, position 34, position 35, position 36, position 37 or position 38 modified with 2^-OMe. In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, or position 36 modified with a modification selected from the group consisting of 2^-O-propargyl, 2^-O-propylamin, 2^-amino, 2^-ethyl, 2’-aminoethyl (EA), 2^-O-methyl (2^-OMe), 2^-O- methoxyethyl (2^-MOE), 2^-O-[2-(methylamino)-2-oxoethyl] (2^-O-NMA), and 2^-deoxy-2^- fluoro-^-d-arabinonucleic acid (2^-FANA). In some embodiments, an RNAi oligonucleotide provided herein comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, position 36, position 37 or position 38 modified with a modification selected from the group consisting of 2^-O-propargyl, 2^-O-propylamin, 2^-amino, 2^-ethyl, 2’-aminoethyl (EA), 2^-O-methyl (2^- OMe), 2^-O-methoxyethyl (2^-MOE), 2^-O-[2-(methylamino)-2-oxoethyl] (2^-O-NMA), and 2^-deoxy-2^-fluoro-^-d-arabinonucleic acid (2^-FANA). 5’-Terminal Phosphate In some embodiments, an RNAi oligonucleotide described herein comprises a 5’- terminal phosphate. In some embodiments, the 5^-terminal phosphate groups of the RNAi oligonucleotide enhance the interaction with Ago2. However, oligonucleotides comprising a 5^-phosphate group may be susceptible to degradation via phosphatases or other enzymes, which can limit their bioavailability in vivo. In some embodiments, an RNAi oligonucleotide herein comprises analogs of 5^ phosphates that are resistant to such degradation. In some embodiments, the phosphate analog is oxymethyl phosphonate, vinyl phosphonate or malonyl phosphonate, or a combination thereof. In some embodiments, the 5^ end of an RNAi oligonucleotide strand is attached to chemical moiety that mimics the electrostatic and steric properties of a natural 5^-phosphate group (“phosphate mimic”).FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, an RNAi oligonucleotide herein has a phosphate analog at a 4^- carbon position of the sugar (referred to as a “4^-phosphate analog”). See, e.g., Intl. Patent Application Publication No. WO 2018 / 045317. In some embodiments, an RNAi oligonucleotide herein comprises a 4^-phosphate analog at a 5^-terminal nucleotide. In some embodiments, a phosphate analog is an oxymethyl phosphonate, in which the oxygen atom of the oxymethyl group is bound to the sugar moiety (e.g., at its 4^-carbon) or analog thereof. In other embodiments, a 4^-phosphate analog is a thiomethyl phosphonate or an aminomethyl phosphonate, in which the sulfur atom of the thiomethyl group or the nitrogen atom of the amino methyl group is bound to the 4^-carbon of the sugar moiety or analog thereof. In some embodiments, a 4^-phosphate analog is an oxymethyl phosphonate. In some embodiments, an oxymethyl phosphonate is represented by the formula –O–CH2–PO(OH)2,–O–CH2–PO(OR)2, or -O-CH2-POOH(R), in which R is independently selected from H, CH3, an alkyl group, CH2CH2CN, CH2OCOC(CH3)3, CH2OCH2CH2Si (CH3)3or a protecting group. In some embodiments, the alkyl group is CH2CH3. More typically, R is independently selected from H, CH3or CH2CH3. In some embodiment, R is CH3. In some embodiments, the 4’-phosphate analog is 5’-methoxyphosphonate-4’-oxy. In some embodiments, the 4’-phosphate analog is 4’-oxymethyl phosphonate. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand comprising a phosphorylated nucleotide at the 5’ terminus. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand comprising a phosphorylated nucleotide at the 5’ terminus, wherein the phosphorylated nucleotide is selected from uridine and adenosine. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand comprising a phosphorylated nucleotide at the 5’ terminus, wherein the phosphorylated nucleotide is uridine. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand comprising a phosphorylated nucleotide at the 5’ terminus, wherein the phosphorylated nucleotide is adenosine. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand comprising a 4^-phosphate analog at the 5^-terminal nucleotide. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand comprising a 4^-phosphate analog at the 5^-terminal nucleotide, wherein the phosphorylated nucleotide is selected from uridine and adenosine. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand comprising a 4^-phosphate analog at the 5^-terminal nucleotide, wherein the phosphorylated nucleotide is uridine. In someFH12501620.1 Attorney Docket: DCY-13025 embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand comprising a 4^-phosphate analog at the 5^-terminal nucleotide, wherein the phosphorylated nucleotide is adenosine. In some embodiments, an RNAi oligonucleotide provided herein comprises an antisense strand comprising a 4^-phosphate analog at the 5^-terminal nucleotide, wherein 5’-terminal nucleotide comprises the following structure (Chem 1): 4’-O-monomethylphosphonate-2’-O-methyluridine phosphorothioate [MePhosphonate-4O-mUs, alternatively referred to as “MeMOP”] Chem 1 Modified Internucleotide Linkage In some embodiments, an RNAi oligonucleotide herein comprises a modified internucleoside linkage. In some embodiments, phosphate modifications or substitutions result in an oligonucleotide that comprises at least about 1 (e.g., at least 1, at least 2, at least 3 or at least 5) modified internucleotide linkage. In some embodiments, any one of the oligonucleotides disclosed herein comprises about 1 to about 10 (e.g., 1 to 10, 2 to 8, 4 to 6, 3 to 10, 5 to 10, 1 to 5, 1 to 3 or 1 to 2) modified internucleotide linkages. In some embodiments, any one of the oligonucleotides disclosed herein comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 modified internucleotide linkages. A modified internucleotide linkage may be a phosphorodithioate linkage, a phosphorothioate linkage, a phosphotriester linkage, a thionoalkylphosphonate linkage, a thionalkylphosphotriester linkage, a phosphoramidite linkage, a phosphonate linkage or a boranophosphate linkage. In some embodiments, at least one modified internucleotide linkage of any one of the oligonucleotides as disclosed herein is a phosphorothioate linkage.FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, an RNAi oligonucleotide provided herein has a phosphorothioate linkage between one or more of positions 1 and 2 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 3 and 4 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand. In some embodiments, the oligonucleotide described herein has a phosphorothioate linkage between each of positions 1 and 2 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand. In some embodiments, the oligonucleotide described herein has a phosphorothioate linkage between each of positions 1 and 2 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 3 and 4 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand. In some embodiments, the oligonucleotide described herein has a phosphorothioate linkage between each of positions 1 and 2 of the sense strand, positions 18 and 19 of the sense strand, positions 19 and 20 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 3 and 4 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand. In some embodiments, the oligonucleotide described herein has a phosphorothioate linkage between each of positions 1 and 2 of the sense strand, the third to last position and penultimate position of the sense strand, and the penultimate position and ultimate position of the sense strand. In some embodiments, the oligonucleotide comprises phosphodiester linkages between nucleotides that do not comprise a phosphorothioate linkage. In some embodiments, an oligonucleotide conjugate described herein comprises a peptide nucleic acid (PNA). PNAs are oligonucleotide mimics in which the sugar-phosphate backbone has been replaced by a pseudopeptide skeleton, composed of N-(2- aminoethyl)glycine units. Nucleobases are linked to this skeleton through a two-atom carboxymethyl spacer. In some embodiments, an oligonucleotide conjugate described herein comprises a morpholino oligomer (PMO) comprising an internucleotide linkage backbone of methylene morpholine rings linked through phosphorodiamidate groups. Base Modifications In some embodiments, an RNAi oligonucleotide herein comprises one or more modified nucleobases. In some embodiments, modified nucleobases (also referred to herein asFH12501620.1 Attorney Docket: DCY-13025 base analogs) are linked at the 1^ position of a nucleotide sugar moiety. In some embodiments, a modified nucleobase is a nitrogenous base. In some embodiments, a modified nucleobase does not contain nitrogen atom. See, e.g., US Patent Application Publication No. 2008 / 0274462. In some embodiments, a modified nucleotide comprises a universal base. In some embodiments, a modified nucleotide does not contain a nucleobase (abasic). In some embodiments, a universal base is a heterocyclic moiety located at the 1^ position of a nucleotide sugar moiety in a modified nucleotide, or the equivalent position in a nucleotide sugar moiety substitution, that, when present in a duplex, can be positioned opposite more than one type of base without substantially altering structure of the duplex. In some embodiments, compared to a reference single-stranded nucleic acid (e.g., oligonucleotide) that is fully complementary to a target nucleic acid, a single-stranded nucleic acid containing a universal base forms a duplex with the target nucleic acid that has a lower Tm than a duplex formed with the complementary nucleic acid. In some embodiments, when compared to a reference single-stranded nucleic acid in which the universal base has been replaced with a base to generate a single mismatch, the single-stranded nucleic acid containing the universal base forms a duplex with the target nucleic acid that has a higher Tmthan a duplex formed with the nucleic acid comprising the mismatched base. Non-limiting examples of universal-binding nucleotides include, but are not limited to, inosine, 1-^-D-ribofuranosyl-5-nitroindole and / or 1-^-D-ribofuranosyl-3-nitropyrrole (see, US Patent Application Publication No.2007 / 0254362; Van Aerschot et al. (1995) NUCLEIC ACIDS RES.23:4363-70; Loakes et al. (1995) NUCLEICACIDSRES.23:2361-66; and Loakes & Brown (1994) NUCLEICACIDSRES.22:4039-43). Tm-Increasing Nucleotides In some embodiments, the oligonucleotide described herein comprises at least one Tm- increasing nucleotide in the sense strand. In some embodiments, the oligonucleotide has one Tm-increasing nucleotide in the sense strand. In some embodiments, the oligonucleotide has up to two Tm-increasing nucleotides in the sense strand. In some embodiments, the oligonucleotide has up to three Tm-increasing nucleotides in the sense strand. In some embodiments, the oligonucleotide has up to four Tm-increasing nucleotides in the sense strand. In some embodiments, the oligonucleotide has up to five Tm-increasing nucleotides in the sense strand. In some embodiments, the oligonucleotide has up to six Tm-increasing nucleotides in the sense strand. In some embodiments, the oligonucleotide has up to seven Tm- increasing nucleotides in the sense strand. In some embodiments, the oligonucleotide has up toFH12501620.1 Attorney Docket: DCY-13025 eight Tm-increasing nucleotides in the sense strand. In some embodiments, the oligonucleotide has up to nine Tm-increasing nucleotides in the sense strand. In some embodiments, the oligonucleotide has up to ten Tm-increasing nucleotides in the sense strand. In some embodiments, the oligonucleotide has 1 to 2 Tm-increasing nucleotides in the sense strand. In some embodiments, the oligonucleotide has 1 to 3 Tm-increasing nucleotides in the sense strand. In some embodiments, the oligonucleotide has 1 to 4 Tm-increasing nucleotides in the sense strand. In some embodiments, the oligonucleotide has 1 to 5 Tm- increasing nucleotides in the sense strand. In some embodiments, an oligonucleotide comprising a stem-loop comprises a Tm- increasing nucleotide in the stem. In some embodiments, an oligonucleotide comprising a stem-loop comprises Tm-increasing nucleotides in at least one base pair of the stem. In some embodiments, an oligonucleotide comprising a stem-loop comprises Tm-increasing nucleotides in one base pair of the stem. In some embodiments, an oligonucleotide comprising a stem-loop comprises Tm-increasing nucleotides in two base pairs of the stem. In some embodiments, an oligonucleotide comprising a stem-loop comprises Tm-increasing nucleotides in three base pairs of the stem. In some embodiments, an oligonucleotide comprising a stem-loop comprises Tm-increasing nucleotides in four base pairs of the stem. In some embodiments, an oligonucleotide comprising a stem-loop comprises Tm-increasing nucleotides in five base pairs of the stem. In some embodiments, an oligonucleotide comprising a stem-loop comprises Tm-increasing nucleotides in six base pairs of the stem. Tm-increasing nucleotides include, but are not limited to, bicyclic nucleotides, tricyclic nucleotides, a G-clamp, and analogues thereof, hexitol nucleotides, or a modified nucleotide. In some embodiments, the Tm-increasing nucleotide is a bicyclic nucleotide. In some embodiments, the Tm-increasing nucleotide is a locked nucleic acid (LNA). In some embodiments, the disclosure provides an RNAi oligonucleotide for reducing target gene expression by the RNAi pathway comprising a combination of one or more Tm- increasing nucleotides and one or more nucleotides (e.g., a modified nucleotide) having a lower binding affinity, wherein the duplex region comprising the RNAi oligonucleotide is maintained under physiological conditions and the ability of the RNAi oligonucleotide to inhibit or reduce target gene expression is maintained. Bicyclic Nucleotides In some embodiments, the oligonucleotide-ligand conjugates of the disclosure (e.g., Formula (AI), (AII), (BI), (BII), (CI), or (CII)) comprise are bicyclic nucleotides. For example,FH12501620.1 Attorney Docket: DCY-13025 the monocyclic sugar moiety shown in Formula (AI), (AII), (BI), (BII), (CI), or (CII) may be replaced by a bicyclic sugar as discussed below. Bicyclic nucleotides typically have a sugar moiety with a 4 to 7 membered ring (including but not limited to a furanosyl) comprising a bridge connecting two atoms of the 4 to 7 membered ring to form a second ring, resulting in a bicyclic structure. Such bicyclic nucleotides have various names including BNA's and LNA's for bicyclic nucleic acids and locked nucleic acids, respectively. The synthesis of bicyclic nucleotides and their incorporation into nucleic acid compounds has also been reported in the literature, including, for example, Singh et al., Chem. Commun., 1998, 4, 455-56; Koshkin et al., TETRAHEDRON, 1998, 54, 3607- 30; Wahlestedt et al., PROC. NATL. ACAD. SCI. U.S.A., 2000, 97, 5633-38; Kumar et al., BIOORG. MED. CHEM. LETT., 1998, 8, 2219-22; Singh et al., J. ORG. CHEM., 1998, 63, 10035- 039; U.S. Patent Nos. 7,427,672, 7,053,207, 6,794,499, 6,770,748, 6,268,490 and 6,794,499; and published U.S. applications 20040219565, 20040014959, 20030207841, 20040192918, 20030224377, 20040143114 and 20030082807; each of which is incorporated by reference herein, in its entirety. In some embodiments, the Tm-increasing nucleotide is a bicyclic nucleotide that comprises a bicyclic sugar moiety. In certain embodiments, the bicyclic sugar moiety comprises a first ring of 4 to 7 members and a bridge forming a North-type sugar confirmation that connects any two atoms of the first ring of the sugar moiety to form a second ring. In some embodiments, the bridge connects the 2^-carbon and the 4^-carbon of the first ring to form a second ring. Typically, the bridge contains 2 to 8 atoms. In some embodiments, the bridge contains 3 atoms. In some embodiments, the bridge contains 4 atoms. In some embodiments, the bridge contains 5 atoms. In some embodiments, the bridge contains 6 atoms. In some embodiments, the bridge contains 7 atoms. In some embodiments, the bridge contains 8 atoms. In some embodiments, the bridge contains more than 8 atoms. In some embodiments, the bicyclic sugar moiety is a substituted furanosyl comprising a bridge that connects the 2^-carbon and the 4^-carbon of the furanosyl to form the second ring. In some embodiments, the bicyclic nucleotide has the structure of Formula I:FH12501620.1 Attorney Docket: DCY-13025 wherein B is a nucleobase; wherein G is H, OH, NH2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, substituted C1-C6alkyl, substituted C2-C6alkenyl, substituted C2-C6alkynyl, acyl, substituted acyl, substituted amide, thiol, or substituted thio; wherein X is O, S, or NR1, wherein R1is H, C1-C6alkyl, C1-C6alkoxy, benzene or pyrene; and wherein Wa and Wb are each independently, H, OH, a hydroxyl protecting group, a phosphorous moiety, or an internucleotide linking group attaching the nucleotide represented by Formula I to another nucleotide or to an oligonucleotide and wherein at least one of War or Wb is an internucleotide linking group attaching the nucleotide represented by Formula I to an oligonucleotide. In some embodiments of Formula I, G is H and X is NR1, wherein R1 is benzene or pyrene. In some embodiments, of Formula I, G is H and X is S. In some embodiments of Formula I, G is H and X is O: Formula Ia In some embodiments of Formula I, G is H and X is NR1, wherein R1is H, CH3, or OCH3:FH12501620.1 Attorney Docket: DCY-13025 Formula Ib In some embodiments of Formula I, G is OH or NH2 and X is O. In some embodiments of Formula I, G is OH and X is O: In some embodiments of Formula I, G is NH2and X is O: In some embodiments, of Formula I, G is CH3or CH2OCH3and X is O. In some embodiments, of Formula I, G is CH3and X is O: In some embodiments, of Formula I, G is CH2OCH3and X is O:FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, the bicyclic nucleotide has the structure of Formula II: Formula II wherein B is a nucleobase; wherein Q1is CH2or O; wherein X is CH2, O, S, or NR1, wherein R1is H, C1-C6alkyl, C1-C6alkoxy, benzene or pyrene; wherein if Q1 is O, X is CH2; wherein if Q1 is CH2, X is CH2, O, S, or NR1, wherein R1 is H, C1-C6 alkyl, C1-C6 alkoxy, benzene or pyrene; wherein Wa and Wb are each independently, H, OH, a hydroxyl protecting group, a phosphorous moiety, or an internucleotide linking group attaching the nucleotide represented by Formula II to another nucleotide or to an oligonucleotide and wherein at least one of Wa or Wb is an internucleotide linking group attaching the nucleotide represented by Formula II to an oligonucleotide. In some embodiments of Formula II, Q1is O and X is CH2: Formula IIa In some embodiments of Formula II, Q1is CH2and X is O:FH12501620.1 Attorney Docket: DCY-13025 Formula IIb In some embodiments of Formula II, Q1 is CH2 and X is NR1, wherein R1 is H, CH3 or OCH3: In some embodiments of Formula II, Q1is CH2and X is NH: Formula IId In some embodiments, the bicyclic nucleotide has the structure of Formula III: Formula III wherein B is a nucleobase; wherein Q2 is O or NR1, wherein R1 is H, C1-C6 alkyl, C1-C6 alkoxy, benzene or pyrene;FH12501620.1 Attorney Docket: DCY-13025 wherein X is CH2, O, S, or NR1, wherein R1is H, C1-C6alkyl, C1-C6alkoxy, benzene or pyrene; wherein if Q2is O, X is NR1; wherein if Q2is NR1, X is O or S; wherein Wa and Wb are each independently, H, OH, a hydroxyl protecting group, a phosphorous moiety, or an internucleotide linking group attaching the nucleotide represented by Formula III to another nucleotide or to an oligonucleotide and wherein at least one of Wa or Wb is an internucleotide linking group attaching the nucleotide represented by Formula III to an oligonucleotide. In some embodiments of Formula III, Q2 is O and X is NR1. In some embodiments of Formula III, Q2 is O and X is NR1, wherein R1 is C1-C6 alkyl. In some embodiments of Formula III, Q2 is O and X is NR1 and R1 is H or CH3. In some embodiments of Formula III, Q2is O and X is NR1and R1is CH3: Formula IIIa In some embodiments of Formula III, Q2is NR1and X is O. In some embodiments of Formula III, Q2is NR1, wherein R1is C1-C6alkyl and X is O. In some embodiments of Formula III, Q2is NCH3and X is O: Formula IIIb In some embodiments, the bicyclic nucleotide has the structure of Formula IV:FH12501620.1 Attorney Docket: DCY-13025 Formula IV wherein B is a nucleobase; wherein P1and P3are CH2, P2is CH2or O and P4is O; and wherein Waand Wbare each independently, H, OH, a hydroxyl protecting group, a phosphorous moiety, or an internucleotide linking group attaching the nucleotide represented by Formula IV to another nucleotide or to an oligonucleotide and wherein at least one of Waor Wb is an internucleotide linking group attaching the nucleotide represented by Formula IV to an oligonucleotide. In some embodiments of Formula IV, P1, P2, and P3 are CH2, and P4 is O: In some embodiments of Formula IV, P1 and P3 are CH2, P2 is O and P4 is O: Formula IVb In some embodiments, the bicyclic nucleotide has the structure of Formula Va or Vb:FH12501620.1 Attorney Docket: DCY-13025 wherein B is a nucleobase; wherein r1, r2, r3, and r4 are each independently H, halogen, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl; substituted C2-C12 alkynyl; C1-C12 alkoxy; substituted C1-C12 alkoxy, OT1, ST1, SOT1, SO2T1, NT1T2, N3, CN, C(^O)OT1, C(^O)NT1T2,C(^O)T1,O^C(^O)NT1T2, N(H)C(^NH)NT1T2, N(H)C(^O)NT1T2or N(H)C(^S)NT1T2, wherein each of T1 and T2 is independently H, C1- C6alkyl, or substituted C1-C16alkyl; or r1 and r2 or r3 and r4 together are ^C(r5)(r6), wherein r5 and r6 are each independently H, halogen, C1-C12alkyl, or substituted C1-C12alkyl; and wherein Wa and Wb are each independently, H, OH, a hydroxyl protecting group, a phosphorous moiety, or an internucleotide linking group attaching the nucleotide represented by Formula V to another nucleotide or to an oligonucleotide and wherein at least one of Wa or Wb is an internucleotide linking group attaching the nucleotide represented by Formula V to an oligonucleotide. In some embodiments, the bicyclic sugar moiety is a substituted furanosyl comprising a bridge that connects the 2^-carbon and the 4^-carbon of the furanosyl to form the second ring, wherein the bridge that connects the 2^-carbon and the 4^-carbon of the furanosyl includes, but is not limited to: a) 4^-CH2-O-N(R)-2^ and 4^-CH2-N(R)-O-2^, wherein R is H, C1-C12alkyl, or a protecting group, including, for example, 4^-CH2-NH-O-2^ (also known as BNANC), 4^-CH2-N(CH3)-O-2^ (also known as BNANC[NMe]), (as described in U.S. Patent No. 7,427,672, which is hereby incorporated by reference in its entirety); b) 4^-CH2-2^; 4^-(CH2)2-2^; 4^-(CH2)3-2^; 4^-(CH2)-O-2^ (also known as LNA); 4^-(CH2)-S-2^; 4^-(CH2)2-O-2^ (also known as ENA); 4^-CH(CH3)-O-2^FH12501620.1 Attorney Docket: DCY-13025 (also known as cEt); and 4^-CH(CH2OCH3)-O-2^ (also known as cMOE), and analogs thereof (as described in U.S. Patent No. 7,399,845, which is hereby incorporated by reference in its entirety); c) 4^-C(CH3)(CH3)-O-2^ and analogs thereof (as described in U.S. Patent No. 8,278,283, which is hereby incorporated by reference in its entirety); d) 4^-CH2-N(OCH3)-2^ and analogs thereof (as described in U.S. Patent No. 8,278,425, which is hereby incorporated by reference in its entirety); e) 4^-CH2-O-N(CH3)-2^ and analogs thereof (as described in U.S. Patent Publication No.2004 / 0171570, which is hereby incorporated by reference in its entirety); f) 4^-CH2-C(H)(CH3)-2^ and analogs thereof (as described in Chattopadhyaya et al., J. ORG. CHEM., 2009, 74, 118-34, which is hereby incorporated by reference in its entirety); and g) 4^-CH2-C(^CH2)-2^ and analogs thereof as described in U.S. Patent No. 8,278,426, which is hereby incorporated by reference in its entirety). In some embodiments, the bicyclic nucleotide (BN) is one or more of the following: (a) methyleneoxy BN, (b) ethyleneoxy BN, (c) aminooxy BN; (d) oxyamino BN, (e) methyl(methyleneoxy) BN (also known as constrained ethyl or cET), (f) methylene-thio BN, (g) methylene amino BN, (h) methyl carbocyclic BN, and (i) propylene carbocyclic BN, as shown below. FH12501620.1 Attorney Docket: DCY-13025 FH12501620.1 Attorney Docket: DCY-13025 In the bicyclic nucleotides of (a) to (i) above, B is a nucleobase, R2is H or CH3and Waand Wbare each independently, H, OH, a hydroxyl protecting group, a phosphorous moiety, or an internucleotide linking group attaching the bicyclic nucleotide to another nucleotide or to an oligonucleotide and wherein at least one of Wa or Wb is an internucleotide linking group attaching the bicyclic nucleotide to an oligonucleotide. In one embodiment of the oxyamino BN (d), R2 is CH3, as follows (also known as BNANC[NMe]): . In some embodiments, bicyclic sugar moieties and bicyclic nucleotides incorporating such bicyclic sugar moieties are further defined by isomeric configuration. In some embodiments, the bicyclic sugar moiety or nucleotide is in the ^-L configuration. In some embodiments, the bicyclic sugar moiety or nucleotide is in the ^-D configuration. For example, in some embodiments, the bicyclic sugar moiety or nucleotide comprises a 2^O,4^-C-methylene bridge (2^-O-CH2-4^) in the ^-L configuration (^-L LNA). In some embodiments, the bicyclic sugar moiety or nucleotide is in the R configuration. In some embodiments, the bicyclic sugarFH12501620.1 Attorney Docket: DCY-13025 moiety or nucleotide is in the S configuration. For example, in some embodiments, the bicyclic sugar moiety or nucleotide comprises a 4^-CH(CH3)-O-2^ bridge (i.e., cEt) in the S- configuration. Tricyclic Nucleotides In some embodiments, the Tm-increasing nucleotide is a tricyclic nucleotide. The synthesis of tricyclic nucleotides and their incorporation into nucleic acid compounds has also been reported in the literature, including, for example, Steffens et al., J. AM. CHEM. SOC. 1997;119:11548-549; Steffens et al., J. ORG. CHEM. 1999;121(14):3249-55; Renneberg et al., J. AM. CHEM. SOC. 2002;124:5993-6002; Ittig et al., NUCLEICACIDSRES.2004;32(1):346-53; Scheidegger et al., CHEMISTRY2006;12:8014-23; Ivanova et al., OLIGONUCLEOTIDES2007;17:54-65; each of which is each hereby incorporated by reference in its entirety. In some embodiments, the tricyclic nucleotide is a tricyclo nucleotide (also called tricyclo DNA) in which the 3^-carbon and 5^-carbon centers are connected by an ethylene that is fused to a cyclopropane ring, as discussed for example in Leumann CJ, BIOORG. MED. CHEM. 2002;10:841-54 and published U.S. Applications 2015 / 0259681 and 2018 / 0162897, which are each hereby incorporated by reference. In some embodiments, the tricyclic nucleotide comprises a substituted furanosyl ring comprising a bridge that connects the 2^-carbon and the 4^-carbon of the furanosyl to form a second ring, and a third fused ring resulting from a group connecting the 5^-carbon to the methylene group of the bridge that connects the 2^-carbon and the 4^-carbon of the furanosyl, as discussed, for example, in published U.S. Application 2015 / 0112055, which is hereby incorporated by reference. Other Tm-increasing nucleotides In addition to bicyclic and tricyclic nucleotides, other Tm-increasing nucleotides can be used in the RNAi oligonucleotides described herein. For example, in some embodiments, the Tm-increasing nucleotide is a G-clamp, guanidine G-clamp or analogue thereof (Wilds et al., CHEM, 2002;114:123 and Wilds et al., CHIM ACTA 2003;114:123), a hexitol nucleotide (Herdewijn, CHEM. BIODIVERSITY 2010;7:1-59), or a modified nucleotide. The modified nucleotide can have a modified nucleobase, as described herein, including for example, 5- bromo-uracil, 5-iodo-uracil, 5-propynyl-modified pyrimidines, or 2-amino adenine (also called 2,6-diaminopurine) (Deleavey et al., CHEM. & BIOL.2012;19:937-54) or 2-thio uridine, 5 Me- thio uridine, and pseudo uridine. The modified nucleotide can also have a modified sugar moiety, as described for example, in U.S. Patent No. 8,975,389, which is hereby incorporatedFH12501620.1 Attorney Docket: DCY-13025 by reference, or as described herein, except that the Tm-increasing nucleotide is not modified at the 2^-carbon of the sugar moiety with a 2^-F or a 2^-OMe. In some embodiments, the Tm-increasing nucleotide is a bicyclic nucleotide. In some embodiments, the Tm-increasing nucleotide is a tricyclic nucleotide. In some embodiments, the Tm-increasing nucleotide a G-clamp, guanidine G-clamp or analogue thereof. In some embodiments, the Tm-increasing nucleotide is a hexitol nucleotide. In some embodiments, the Tm-increasing nucleotide is a bicyclic or tricyclic nucleotide. In some embodiments, the Tm- increasing nucleotide is a bicyclic nucleotide, a tricyclic nucleotide, or a G-clamp, guanidine G-clamp or analogue thereof. In some embodiments, the Tm-increasing nucleotide is a bicyclic nucleotide, a tricyclic nucleotide, a G-clamp, guanidine G-clamp or analogue thereof, or a hexitol nucleotide. In some embodiments, the Tm-increasing nucleotide increases the Tm of the nucleic acid inhibitor molecule by at least 2 °C per incorporation. In some embodiments, the Tm-increasing nucleotide increases the Tmof nucleic acid inhibitor molecule by at least 3 °C per incorporation. In some embodiments, the Tm-increasing nucleotide increases the Tmof nucleic acid inhibitor molecule by at least 4 °C per incorporation. In some embodiments, the Tm-increasing nucleotide increases the Tm of nucleic acid inhibitor molecule by at least 5 °C per incorporation. mRNA Target Sequences In some embodiments, the RNAi oligonucleotide is targeted to a target sequence comprising a target mRNA. In some embodiments, the RNAi oligonucleotide is targeted to a target sequence within a target mRNA. In some embodiments, the RNAi oligonucleotide, or a portion, fragment, or strand thereof (e.g., an antisense strand or a guide strand of a double- stranded oligonucleotide) binds or anneals to a target sequence comprising a target mRNA, thereby reducing target gene expression. In some embodiments, the RNAi oligonucleotide is targeted to a target sequence comprising target mRNA for the purpose of reducing expression of a target gene in vivo. In some embodiments, the amount or extent of reduction of target gene expression by an RNAi oligonucleotide targeted to a specific target sequence correlates with the potency of the RNAi oligonucleotide. In some embodiments, the amount or extent of reduction of target gene expression by an RNAi oligonucleotide targeted to a specific target sequence correlates with the amount or extent of therapeutic benefit in a subject or patient having a disease, disorder or condition associated with target gene expression treated with the RNAi oligonucleotide.FH12501620.1 Attorney Docket: DCY-13025 Through examination of the nucleotide sequence of mRNAs encoding target genes, including mRNAs of multiple different species (e.g., human, cynomolgus monkey, mouse, and rat) and as a result of in vitro and in vivo testing, it has been discovered that certain nucleotide sequences and certain systemic modifications to those oligonucleotides are more amenable than others to RNAi oligonucleotide-mediated reduction and are thus useful as part of oligonucleotides that are otherwise targeted to specific gene target sequences. In some embodiments, a sense strand of an RNAi oligonucleotide, or a portion or fragment thereof, described herein, comprises a nucleotide sequence that is similar (e.g., having no more than 4 mismatches) or is identical to a target sequence comprising a target mRNA. In some embodiments, a portion or region of the sense strand of a double-stranded oligonucleotide described herein comprises a target sequence comprising a target mRNA. In some embodiments, the target mRNA is expressed in hepatic tissue, adipose tissue, cardiac tissue, adrenal tissue, or skeletal muscle tissue. In some embodiments, the target mRNA is expressed in extrahepatic tissue. In some embodiments, the target mRNA is expressed in cardiac tissue, adipose tissue, adrenal tissue, the central nervous system, or skeletal muscle tissue. In some embodiments, the target mRNA is expressed in cardiac tissue. In some embodiments, the target mRNA is expressed in adipose tissue. In some embodiments, the target mRNA is expressed in gonadal white adipose tissue. In some embodiments, the target mRNA is expressed in subcutaneous white adipose tissue. In some embodiments, the target mRNA is expressed in skeletal muscle tissue. In some embodiments, the target mRNA is expressed in adrenal tissue. In some embodiments, the target mRNA is expressed in the central nervous system. Targeting Ligands In some embodiments, it is desirable to target the oligonucleotides of the disclosure (e.g., RNAi oligonucleotide) to one or more cells or tissues of extrahepatic tissue. In some embodiments, it is desirable to target the oligonucleotides of the disclosure (e.g., RNAi oligonucleotide) to one or more cells or tissues of the liver. In some embodiments, it is desirable to target the oligonucleotides of the disclosure (e.g., RNAi oligonucleotide) to one or more cells or tissues of extrahepatic tissue. In some embodiments, it is desirable to target the oligonucleotides of the disclosure (e.g., RNAi oligonucleotide) to one or more cells or tissues of the heart. In some embodiments, it is desirable to target the oligonucleotides of the disclosure (e.g., RNAi oligonucleotide) to one or more cells or tissues of the skeletal muscle. In some embodiments, it is desirable to target the oligonucleotides of the disclosure (e.g., RNAi 111FH12501620.1 Attorney Docket: DCY-13025 oligonucleotide) to one or more cells or tissues of the adrenal gland. In some embodiments, it is desirable to target the oligonucleotides of the disclosure (e.g., RNAi oligonucleotide) to one or more cells of adipose tissue. In some embodiments, it is desirable to target the oligonucleotides of the disclosure (e.g., RNAi oligonucleotide) to one or more cells of gonadal white adipose tissue. In some embodiments, it is desirable to target the oligonucleotides of the disclosure (e.g., RNAi oligonucleotide) to one or more cells of subcutaneous white adipose tissue. In some embodiments, it is desirable to target the oligonucleotides of the disclosure (e.g., RNAi oligonucleotide) to one or more cells or tissues of the central nervous system. Such a strategy can help to avoid undesirable effects in other organs or avoid undue loss of the oligonucleotide to cells, tissue or organs that would not benefit from the oligonucleotide. Accordingly, in some embodiments, an RNAi oligonucleotide disclosed herein is modified to facilitate targeting and / or delivery to a particular tissue, cell, or organ (e.g., to facilitate delivery of the conjugate to extrahepatic tissue). In some embodiments, an RNAi oligonucleotide comprises at least one nucleotide (e.g., 1, 2, 3, 4, 5, 6 or more nucleotides) conjugated to one or more targeting ligand(s). In some embodiments, an RNAi oligonucleotide herein does not have a GalNAc conjugated thereto. In some embodiments, 1 or more (e.g., 1, 2, 3, 4, 5 or 6) nucleotides of an RNAi oligonucleotide disclosed herein are each conjugated to a separate targeting ligand. In some embodiments, 1 nucleotide of an RNAi oligonucleotide herein is conjugated to a separate targeting ligand. In some embodiments, 2 to 4 nucleotides of an RNAi oligonucleotide herein are each conjugated to a separate targeting ligand. In some embodiments, 2 nucleotides of an RNAi oligonucleotide herein are each conjugated to a separate targeting ligand. In some embodiments, the 5’ terminal nucleotide of the sense strand and the 3’ terminal nucleotide of the sense strand are conjugated to a targeting ligand described herein. In some embodiments, the 5’ terminal nucleotide of the sense strand and the 3’ terminal nucleotide of the sense strand are conjugated to the same targeting ligand. In some embodiments, the 5’ terminal nucleotide of the sense strand and the 3’ terminal nucleotide of the sense strand are conjugated to different targeting ligands. In some embodiments, nucleotides at position 1 and position 2 of the sense strand are conjugated to the same targeting ligand. In some embodiments, nucleotides at position 1 and position 2 of the sense strand are conjugated to different targeting ligands. In some embodiments, targeting ligands are conjugated to 2 to 4 nucleotides at either ends of the sense or antisense strand (e.g., targeting ligands are conjugated to a 2 to 4 nucleotide overhang or extension on the 5^ or 3^ end of the sense or antisense strand) such that the targeting ligands resemble bristles of a toothbrush and the RNAi oligonucleotide resembles a toothbrush. ForFH12501620.1 Attorney Docket: DCY-13025 example, an RNAi oligonucleotide may comprise a stem-loop at either the 5^ or 3^ end of the sense strand and 1, 2, 3 or 4 nucleotides of the loop of the stem may be individually conjugated to a targeting ligand. In some embodiments, an RNAi oligonucleotide provided by the disclosure comprises a stem-loop at the 3^ end of the sense strand, wherein the loop of the stem- loop comprises a triloop or a tetraloop, and wherein the 3 or 4 nucleotides comprising the triloop or tetraloop, respectfully, are individually conjugated to a targeting ligand. Appropriate methods or chemistry (e.g., click chemistry) can be used to link a targeting ligand to a nucleotide. In some embodiments, a targeting ligand is conjugated to a nucleotide using a click linker. In some embodiments, an acetal-based linker is used to conjugate a targeting ligand to a nucleotide of any one of the oligonucleotides described herein. Acetal- based linkers are disclosed, for example, in Intl. Patent Application Publication No. WO 2016 / 100401. In some embodiments, the linker is a labile linker. However, in other embodiments, the linker is stable. As mentioned, various appropriate methods or chemistry synthetic techniques (e.g., click chemistry) can be used to link a targeting ligand to a nucleotide. In some embodiments, a targeting ligand is conjugated to a nucleotide using a click linker. In some embodiments, an acetal-based linker is used to conjugate a targeting ligand to a nucleotide of any one of the oligonucleotides described herein. Acetal-based linkers are disclosed, for example, in Intl. Patent Application Publication No. WO 2016 / 100401. In some embodiments, the linker is a labile linker. However, in other embodiments, the linker is a stable linker. In some embodiments, the linker is In some embodiments, the linker is In some embodiments, a duplex extension (e.g., of up to 3, 4, 5 or 6 bp in length) is provided between a targeting ligand and an RNAi oligonucleotide. Ligand ConjugatesFH12501620.1 Attorney Docket: DCY-13025 In some embodiments, any of the ligands described herein are conjugated to a nucleotide of the sense strand of the oligonucleotide. In some embodiments, a ligand is conjugated to a terminal position of the oligonucleotide (e.g., as shown in Formula (BI), (BII), (CI) or (CII)). In some embodiments, the ligand is conjugated to the 5’ terminal nucleotide of the sense strand (e.g., as shown in Formula (BI) or (BII)). In some embodiments, the ligand is conjugated to the 3’ terminal nucleotide of the sense strand (e.g., as shown in Formula (CI) or (CII)). In some embodiments, the ligand is conjugated to an internal nucleotide on the sense strand (e.g., as shown in Formula (AI)-(AV)). An internal position is any nucleotide position other than the two terminal positions from each end of the sense strand. In some embodiments, the ligand is conjugated to one or more internal positions of the sense strand. In some embodiments, the ligand is conjugated to position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, position 36, position 37 or position 38 of a sense strand. In some embodiments, the ligand is conjugated to position 1 of the sense strand. In some embodiments, the ligand is conjugated to position 28 of the sense strand. In some embodiments, two ligands are conjugated to the sense strand of the oligonucleotide. In some embodiments, the two ligands conjugated to the sense strand of the oligonucleotide are the same ligand. In some embodiments, the two ligands conjugated to the sense strand of the oligonucleotide are different ligands. In some embodiments, the two ligands conjugated to the sense strand are conjugated to position 1 and to a nucleotide in the stem loop. In some embodiments, the two ligands conjugated the sense strand are conjugated to position 1 and position and position 28. In some embodiments, the two ligands conjugated to the sense strand are conjugated at position 2 and position 29. In some embodiments, the two ligands conjugated to the sense strand are conjugated at the 5’ terminal nucleotide and the 3’ terminal nucleotide. In some embodiments, an RNAi oligonucleotide described herein comprises at least one nucleotide conjugated with one or more ligands. In some embodiments, the one or more ligands are conjugated to the same nucleotide. In some embodiments, the one or more ligands are conjugated to different nucleotides. In some embodiments, 1, 2, 3, 4, 5, 6, or more ligands are conjugated to the oligonucleotide. In some embodiments, one or more ligands are conjugated to an adenine nucleotide. In some embodiments, one or more ligands are conjugatedFH12501620.1 Attorney Docket: DCY-13025 to a guanine nucleotide. In some embodiments, one or more ligands are conjugated to a cytosine nucleotide. In some embodiments, one or more ligands are conjugated to a thymine nucleotide. In some embodiments, one or more ligands are conjugated to a uracil nucleotide. In some embodiments, the ligand comprises one or more -COOH groups and a hydrocarbon chain. In some embodiments, the hydrocarbon chain is saturated. In some embodiments, the hydrocarbon chain is unsaturated. In some embodiments, the hydrocarbon chain comprises at least 6 (e.g., at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, or at least 26) carbon atoms. In some embodiments, the hydrocarbon chain comprises from 6-26 carbon atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26). In some embodiments, the ligand comprises a C8:0, C10:0, C11:0, C12:0, C14:0, C16:0, C17:0, C18:0, C18:1, C18:2, C22:5, C22:0, C24:0, C26:0, C22:6, C24:1, diacyl C16:0 or diacyl C18:1 hydrocarbon chain. In some embodiments of the RNAi oligonucleotide of the present disclosure, Y-COOH is:FH12501620.1 Attorney Docket: DCY-13025 , FH12501620.1 Attorney Docket: DCY-13025 FH12501620.1 Attorney Docket: DCY-13025 . In some embodiments, the oligonucleotide of the oligonucleotide-ligand conjugate is a double-stranded molecule. In some embodiments, the oligonucleotide is an RNAi molecule. In some embodiments, the double stranded oligonucleotide comprises a stem loop. In some embodiments, the stem loop is set forth as S1-L-S2, wherein S1 is complementary to S2, and wherein L forms a loop between S1 and S2. In some embodiments, the ligand is conjugated to any of the nucleotides in the loop of the stem loop. In some embodiments, the ligand is conjugated to any of the nucleotides in the stem of the stem loop. In some embodiments, the ligand is conjugated to the first nucleotide from 5’ to 3’ in the loop. In some embodiments, the ligand is conjugated to the second nucleotide from 5’ to 3’ in the loop. In some embodiments, the ligand is conjugated to the third nucleotide from 5’ to 3’ in the loop. In some embodiments, the ligand is conjugated to the fourth nucleotide from 5’ to 3’ in the loop. In some embodiments, the ligand is conjugated to one, two, three, or four of the nucleotides in the loop. In some embodiments, the ligand is conjugated to three of the nucleotides in the stem loop. In some embodiments, the stem loop is 16 nucleotides in length. In some embodiments, the ligand is conjugated to the third nucleotide from 5’ to 3’ in the stem loop. In some embodiments, the ligand is conjugated to the eighth nucleotide from 5’ to 3’ in the stem loop. In some embodiments, the ligand is conjugated to the ninth nucleotide from 5’ to 3’ in the stem loop. In some embodiments, the ligand is conjugated to the tenth nucleotide from 5’ to 3’ in the stem loop. Exemplary Oligonucleotides In some embodiments, RNAi oligonucleotides comprise a nucleotide conjugated with a ligand comprising Y-(CO2H)ngroups, or a charged form thereof, wherein Y is alkylene, alkenylene, or alkynylene, and q is 1, 2, 3, 4, 5, or 6. In some embodiments, the oligonucleotide of the RNAi oligonucleotide is conjugated to a ligand comprising: FH12501620.1 Attorney Docket: DCY-13025 . In some embodiments, the 3’ end of the sense strand is a blunt end. In some embodiments, the 5’ end of the antisense strand is a blunt end. In some embodiments, the 3’ end of the antisense strand comprises an overhang. In some embodiments, the 5’ end of the antisense strand comprises an overhang. In some embodiments, the 5’ and 3’ ends of the antisense strand each comprise an overhang. In some embodiments, the RNAi oligonucleotide comprises one or more 2’ modifications. In some embodiments, the 2’ modifications are selected from 2’-fluoro and 2’- methyl. In some embodiments, a lipid-conjugated RNAi oligonucleotide for reducing expression of a target gene comprises one or more of the following sequences: STEM-LOOP Sense Strand: 5’-[G][G][U][G][G][A][U][G][A][A][A][C][U][C] [A][G][U][U][U][A][G][C][A][G][C] [C][G][A][A][A][G][G][C][U][G][C]-3’ (SEQ ID NO: 12) Antisense Strand A: 5’-[U][A][A][A][C][U][G][A][G][U][U][U][C][A][U][C][C][A][C][C][G][G]-3’ (SEQ ID NO: 13) BLUNT Sense Strand 5’- [G][G][U][G][G][A][U][G][A][A][A][C][U][C][A][G][U][U][U][A]- 3’ (SEQ ID NO: 14) ^ Antisense B: 5’- [U][A][A][A][C][U][G][A][G][U][U][U][C][A][U][C][C][A][C][C][G][G]- 3’ (SEQ ID NO: 13)FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 15 to 30 nucleotides in length, a sense strand of 13 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue; and (ii) one or more ligands. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 15 to 30 nucleotides in length, a sense strand of 13 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more -L-Y-(CO2H)n groups, or a charged form thereof, wherein L is a linker, Y is alkylene, alkenylene, or alkynylene, and n is 1-6, wherein when Y is alkylene, L comprises -O(CH2)a(OCH2CH2)bNH-, wherein a is 1- 6 and b is 0-5, and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 15 to 30 nucleotides in length, a sense strand of 15 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra- hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more C6-24 alkylene-(CO2H)n, or a charged form thereof, conjugated to a nucleotide of the sense strand, wherein n is 1-6, wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 15 to 30 nucleotides in length, a sense strand of 13 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is , and wherein the ligand is conjugated to a nucleotide of the sense strand.FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 15 to 30 nucleotides in length, a sense strand of 15 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra- hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is , and wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 15 to 30 nucleotides in length, a sense strand of 13 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is , and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 15 to 30 nucleotides in length, a sense strand of 15 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra- hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is FH12501620.1 Attorney Docket: DCY-13025 wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 15 to 30 nucleotides in length, a sense strand of 13 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is selected from , and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 15 to 30 nucleotides in length, a sense strand of 15 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra- hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; andFH12501620.1 Attorney Docket: DCY-13025 (ii) one or more ligands, wherein the ligand is selected from wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 22 nucleotides in length, a sense strand of 36 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more -L-Y-(CO2H)n groups, or a charged form thereof, wherein L is a linker, Y is alkylene, alkenylene, or alkynylene, and n is 1-6, wherein when Y is alkylene, L comprises -O(CH2)a(OCH2CH2)bNH-, wherein a is 1- 6 and b is 0-5, and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 22 nucleotides in length, a sense strand of 36 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; andFH12501620.1 Attorney Docket: DCY-13025 (ii) one or more ligands, each ligand comprising one or more C6-24 alkylene-(CO2H)n, or a charged form thereof, conjugated to a nucleotide of the sense strand, wherein n is 1-6, wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 22 nucleotides in length, a sense strand of 36 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is , and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 22 nucleotides in length, a sense strand of 36 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is , wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 22 nucleotides in length, a sense strand of 36 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand isFH12501620.1 Attorney Docket: DCY-13025 , and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 22 nucleotides in length, a sense strand of 36 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is , wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 22 nucleotides in length, a sense strand of 36 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is selected fromFH12501620.1 Attorney Docket: DCY-13025 , and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 22 nucleotides in length, a sense strand of 36 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; andFH12501620.1 Attorney Docket: DCY-13025 (ii) one or more ligands, wherein the ligand is selected from , wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 22 nucleotides in length, a sense strand of 37 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more -L-Y-(CO2H)n groups, or a charged form thereof, wherein L is a linker, Y is alkylene, alkenylene, or alkynylene, and n is 1-6, wherein when Y is alkylene, L comprises -O(CH2)a(OCH2CH2)bNH-, wherein a is 1- 6 and b is 0-5, and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 22 nucleotides in length, a sense strand of 37 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; andFH12501620.1 Attorney Docket: DCY-13025 (ii) one or more ligands, each ligand comprising one or more C6-24 alkylene-(CO2H)n, or a charged form thereof, conjugated to a nucleotide of the sense strand, wherein n is 1-6, wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 22 nucleotides in length, a sense strand of 37 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is , and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 22 nucleotides in length, a sense strand of 37 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is ,wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 22 nucleotides in length, a sense strand of 37 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is FH12501620.1 Attorney Docket: DCY-13025 , and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 22 nucleotides in length, a sense strand of 37 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is ,wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 22 nucleotides in length, a sense strand of 37 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is selected fromFH12501620.1 Attorney Docket: DCY-13025 , and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 22 nucleotides in length, a sense strand of 37 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is selected fromFH12501620.1 Attorney Docket: DCY-13025 ,wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 22 nucleotides in length, a sense strand of 20 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more -L-Y-(CO2H)n groups, or a charged form thereof, wherein L is a linker, Y is alkylene, alkenylene, or alkynylene, and n is 1-6, wherein when Y is alkylene, L comprises -O(CH2)a(OCH2CH2)bNH-, wherein a is 1- 6 and b is 0-5, and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 20 nucleotides in length, a sense strand of 36 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; andFH12501620.1 Attorney Docket: DCY-13025 (ii) one or more ligands, each ligand comprising one or more C6-24 alkylene-(CO2H)n, or a charged form thereof, conjugated to a nucleotide of the sense strand, wherein n is 1-6, wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 22 nucleotides in length, a sense strand of 20 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is , and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 20 nucleotides in length, a sense strand of 36 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is ,wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 22 nucleotides in length, a sense strand of 20 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is FH12501620.1 Attorney Docket: DCY-13025 , and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 20 nucleotides in length, a sense strand of 36 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, wherein the ligand is ,wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises: (i) an antisense strand of 22 nucleotides in length, a sense strand of 20 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; andFH12501620.1 Attorney Docket: DCY-13025 (ii) one or more ligands, wherein the ligand is selected from , and wherein the ligand is conjugated to a nucleotide of the sense strand. In some embodiments, an RNAi oligonucleotide comprises: (i) a double-stranded oligonucleotide comprising an antisense strand of 20 nucleotides in length, a sense strand of 36 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extra-hepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; andFH12501620.1 Attorney Docket: DCY-13025 (ii) one or more ligands, wherein the ligand is selected from ,wherein knock down of the target mRNA in the extra-hepatic tissue is greater than knock down of the target mRNA in liver tissue. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand is 20 nucleotides in length, and the antisense strand is 22 nucleotides in length, wherein the sense strand comprises at least one oligonucleotide-ligand conjugate, and wherein the oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII). In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand is 36 nucleotides in length, and the antisense strand is 22 nucleotides in length, wherein the sense strand comprises at least one oligonucleotide-ligand conjugate, and wherein the oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII). In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand is 37 nucleotides in length, and the antisense strand is 22 nucleotides in length, wherein the sense strand comprises at least oneFH12501620.1 Attorney Docket: DCY-13025 oligonucleotide-ligand conjugate, and wherein the oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII). In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand is 20 nucleotides in length, and the antisense strand is 22 nucleotides in length, wherein the sense strand comprises at least one oligonucleotide-ligand conjugate, wherein the oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), and wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand is 20 nucleotides in length, and the antisense strand is 22 nucleotides in length, wherein the sense strand comprises at least one oligonucleotide-ligand conjugate, wherein the oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), and wherein the nucleobase (B) is the nucleobase at position 20 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand is 36 nucleotides in length, and the antisense strand is 22 nucleotides in length, wherein the sense strand comprises at least one oligonucleotide-ligand conjugate, wherein the oligonucleotide- ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), and wherein the nucleobase (B) is the nucleobase at position 28 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand is 37 nucleotides in length, and the antisense strand is 22 nucleotides in length, wherein the sense strand comprises at least one oligonucleotide-ligand conjugate, wherein the oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), and wherein the nucleobase (B) is the nucleobase at position 29 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand is 36 nucleotides in length, and the antisense strand is 22 nucleotides in length, wherein the sense strand comprises at least one oligonucleotide-ligand conjugate, wherein the oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), and wherein the nucleobase (B) is the nucleobase in the tetraloop of the sense strand. In some embodiments, an RNAi oligonucleotide comprises an oligonucleotide-ligand conjugate of any one of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII). In some embodiments, an RNAi oligonucleotide comprises at least one oligonucleotide-ligand conjugate of any of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII). In some embodiments, an RNAi oligonucleotide comprises at least two oligonucleotide-ligandFH12501620.1 Attorney Docket: DCY-13025 conjugates selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII). In some embodiments, an RNAi oligonucleotide comprises at least two oligonucleotide-ligand conjugates selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the at least two oligonucleotide-ligand conjugates are selected from the same Formula. In some embodiments, an RNAi oligonucleotide comprises at least two oligonucleotide-ligand conjugates selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the at least two oligonucleotide-ligand conjugates are selected from a different Formula. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any one of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any one of Formulas (AI), (AII), (AIII), (AIV), or (AV), wherein the nucleobase (B) is the nucleobase at position 2 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any one of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 20 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any one of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 28 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any one of Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 29 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any one of Formulas (AI), (AII), (AIII), (AIV), or (AV), wherein the nucleobase (B) is a nucleobase in the tetraloop of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises a first and a second oligonucleotide-ligand conjugate, wherein:FH12501620.1 Attorney Docket: DCY-13025 (i) the first oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand; and (ii) the second oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), or (AV), wherein the nucleobase (B) is the nucleobase at position 2 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises a first and a second oligonucleotide-ligand conjugate, wherein: (i) the first oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand; and (ii) the second oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), or (AV), wherein the nucleobase (B) is the nucleobase at position 20 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises a first and a second oligonucleotide-ligand conjugate, wherein: (i) the first oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand; and (ii) the second oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is a nucleobase in the tetraloop of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises a first and a second oligonucleotide-ligand conjugate, wherein: (i) the first oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand; and (ii) the second oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 28 of the sense strand.FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises a first and a second oligonucleotide-ligand conjugate, wherein: (i) the first oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand; and (ii) the second oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 29 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises a first and a second oligonucleotide-ligand conjugate, wherein: (i) the first oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand; and (ii) the second oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), or (AV), wherein the nucleobase (B) is the nucleobase at position 2 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand comprises a first and a second oligonucleotide-ligand conjugate, wherein: (i) the first oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand; and (ii) the second oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 20 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand is 20 nucleotides in length and the antisense strand is 22 nucleotides in length, wherein the sense strand comprises a first and a second oligonucleotide- ligand conjugate, and wherein: (i) the first oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand; andFH12501620.1 Attorney Docket: DCY-13025 (ii) the second oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), or (AV), wherein the nucleobase (B) is the nucleobase at position 2 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand is 20 nucleotides in length and the antisense strand is 22 nucleotides in length, wherein the sense strand comprises a first and a second oligonucleotide- ligand conjugate, and wherein: (i) the first oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand; and (ii) the second oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 20 of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand is 36 nucleotides in length and the antisense strand is 22 nucleotides in length, wherein the sense strand comprises a first and a second oligonucleotide- ligand conjugate, and wherein: (i) the first oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand; and (ii) the second oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), or (AV), wherein the nucleobase (B) is a nucleobase in the tetraloop of the sense strand. In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand is 36 nucleotides in length and the antisense strand is 22 nucleotides in length, wherein the sense strand comprises a first and a second oligonucleotide- ligand conjugate, and wherein: (i) the first oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand; and (ii) the second oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), or (AV), wherein the nucleobase (B) is the nucleobase at position 28 of the sense strand.FH12501620.1 Attorney Docket: DCY-13025 In some embodiments, an RNAi oligonucleotide comprises a sense and antisense strand, wherein the sense strand is 37 nucleotides in length and the antisense strand is 22 nucleotides in length, wherein the sense strand comprises a first and a second oligonucleotide- ligand conjugate, and wherein: (i) the first oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), (AV), (BI), (BII), (CI), or (CII), wherein the nucleobase (B) is the nucleobase at position 1 of the sense strand; and (ii) the second oligonucleotide-ligand conjugate is selected from Formulas (AI), (AII), (AIII), (AIV), or (AV), wherein the nucleobase (B) is the nucleobase at position 29 of the sense strand. General Methods of Providing the Nucleic Acids and Analogues Thereof The nucleic acids and analogues thereof comprising an oligonucleotide-ligand conjugate described herein can be made using a variety of synthetic methods known in the art, including standard phosphoramidite methods. Any phosphoramidite synthesis method can be used to synthesize the provided nucleic acids of this disclosure. In some embodiments, phosphoramidites are used in a solid phase synthesis method to yield reactive intermediate phosphite compounds, which are subsequently oxidized using known methods to produce phosphonate-modified oligonucleotides, typically with a phosphodiester or phosphorothioate internucleotide linkages. The oligonucleotide synthesis of the present disclosure can be performed in either direction: from 5^ to 3^ or from 3^ to 5^ using art known methods. In some embodiments, the method for synthesizing a provided nucleic acid comprises (a) attaching a nucleoside or analogue thereof to a solid support via a covalent linkage; (b) coupling a nucleoside phosphoramidite or analogue thereof to a reactive hydroxyl group on the nucleoside or analogue thereof of step (a) to form an internucleotide bond there between, wherein any uncoupled nucleoside or analogue thereof on the solid support is capped with a capping reagent; (c) oxidizing said internucleotide bond with an oxidizing agent; and (d) repeating steps (b) to (c) iteratively with subsequent nucleoside phosphoramidites or analogue thereof to form a nucleic acid or analogue thereof, wherein at least the nucleoside or analogue thereof of step (a), the nucleoside phosphoramidite or analogue thereof of step (b) or at least one of the subsequent nucleoside phosphoramidites or analogues thereof of step (d) comprises a hydrocarbon chain bearing one or more carboxyl groupsas described herein. Typically, the coupling, capping / oxidizing steps and optionally, the deprotecting steps, are repeated until the oligonucleotide reaches the desired length and / or sequence, after which it is cleaved from theFH12501620.1 Attorney Docket: DCY-13025 solid support. In some embodiments, an oligonucleotide is prepared comprising 1-3 nucleic acid or analogues thereof comprising hydrocarbon chain bearing one or more carboxyl groups on a tetraloop. In Scheme A below, where a particular protecting group, leaving group, or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Certain reactive functional groups (e.g., -N(H)-, -OH, etc.) envisioned in the genera in Scheme A requiring additional protection group strategies are also contemplated and is appreciated by those having ordinary skill in the art. Such groups and transformations are described in detail in MARCH'SADVANCEDORGANICCHEMISTRY: REACTIONS, MECHANISMS,ANDSTRUCTURE, M. B. Smith and J. March, 5thEdition, John Wiley & Sons, 2001, COMPREHENSIVEORGANICTRANSFORMATIONS, (R. C. Larock, 2ndEdition, John Wiley & Sons, 1999), and PROTECTING GROUPS IN ORGANIC SYNTHESIS, (T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999), the entirety of each of which is hereby incorporated herein by reference. In some embodiments, nucleic acids, and analogues thereof of the present disclosure are generally prepared according to Scheme A, Scheme A1 and Scheme B set forth below:FH12501620.1 Attorney Docket: DCY-13025 Scheme A: Synthesis of Ligand Conjugated Oligonucleotides of the Disclosure Scheme A1: Synthesis of Conjugated Oligonucleotides of the DisclosureFH12501620.1 Attorney Docket: DCY-13025 FH12501620.1 Attorney Docket: DCY-13025 As depicted in Scheme A and Scheme A1 above, a nucleic acid or analogue thereof of formula I-1 is conjugated with one or more ligand / lipophilic compound to form a compound of formula I or Ia comprising one more ligand conjugates. Typically, conjugation is performed through an esterification or amidation reaction between a nucleic acid or analogue thereof of formula I-1 or I-1a and one or more hydrocarbon bearing carboxylic acid in series or in parallel by known techniques in the art. Nucleic acid or analogue thereof of formula I or Ia can then be deprotected to form a compound of formula I-2 or I-2a and protected with a suitable hydroxyl protecting group (e.g., DMTr) to form a compound of formula I-3 or I-3a. In one aspect, nucleic acid-ligand conjugates of formula I-3 or I-3a can be covalently attached to a solid support (e.g., through a succinic acid linking group) to form a solid support nucleic acid- ligand conjugate or analogue thereof of formula I-4 or I-4a comprising one or more hydrocarbon with carboxylic acid. In another aspect, a nucleic acid- ligand conjugates of formula I-3 or I-3a can react with a P(III) forming reagent (e.g., 2-cyanoethyl N,N-di- isopropylchlorophosphoramidite) to form a nucleic acid or analogue thereof of formula I-5 or I-5a comprising a P(III) group. A nucleic acid-ligand conjugate or analogue thereof of formula I-5 or I-5a can then be subjected to oligomerization forming conditions preformed using known and commonly applied processes to prepare oligonucleotides in the art. For example, the compound of formula I-5 or I-5a is coupled to a solid supported nucleic acid-ligand conjugate or analogue thereof bearing a 5’-hydroxyl group. Further steps can comprise one or more deprotections, couplings, phosphite oxidation, and / or cleavage from the solid support to provide an oligonucleotide of various nucleotide lengths, including one or more conjugate nucleotide units represented by a compound of formula II-1 or II-Ia. Each of B, L, R1, R2, and Z is as defined above and in Formula (AI), (BI), or (CI) or as described herein. X, as provided in formula I-1, is a reactive functional group or leaving group. In some embodiments, PG1and PG2comprise silyl ethers or cyclic silylene derivatives that can be removed under acidic conditions or with fluoride anion. In some embodiments, PG1and PG2are taken together with their intervening atoms to form a cyclic diol protecting group, such as a cyclic acetal or ketal. PG3used for protection of the 5’-hydroxyl group includes an acid labile protecting group such as trityl, 4-methyoxytrityl, 4,4’-dimethyoxytrityl, 4,4’,4’’-trimethyoxytrityl, 9-phenyl-xanthen- 9-yl, 9-(p-tolyl)-xanthen-9-yl, pixyl, 2,7-dimethylpixyl, and the like. E is 2-cyanoethyl when 2-cyanoethyl N,N-diisopropylchlorophosphoramidite or 2-cyanoethyl phosphorodichloridate is used as a P(III) forming reagent. X3is O-, -S-, or a covalent bond. R3is hydrogen or a suitable protecting group. n is 1, 2, or 3.FH12501620.1 Attorney Docket: DCY-13025 Scheme B: Post-Synthetic Conjugation of Oligonucleotides of the Disclosure As depicted in Scheme B above, a nucleic acid or analogue thereof of formula I-1 can be deprotected to form a compound of formula I-6, protected with a suitable hydroxyl protecting group (e.g., DMTr) to form a compound of formula I-7, and reacted with a P(III) forming reagent (e.g., 2-cyanoethyl N,N-di-isopropylchlorophosphoramidite) to form a nucleic acid or analogue thereof of formula I-8 comprising a P(III) group. Next, a nucleic acid or analogue thereof of formula I-8 is subjected to oligomerization forming conditions preformed using known and commonly applied processes to prepare oligonucleotides in the art. For example, the compound of formula I-8 is coupled to a solid supported nucleic acid or analogue thereof bearing a 5’-hydroxyl group. Further steps can comprise one or more deprotections, couplings, phosphite oxidation, and / or cleavage from the solid support to provide an oligonucleotide of various nucleotide lengths represented by a compound of formula II-2. An oligonucleotide of formula II-2 can then be conjugated with one or more ligands e.g., hydrocarbon bearing carboxylic acid to form a compound of formula II-1 comprising one ligand conjugate (n=1). Typically, conjugation is performed through an esterification or amidation reaction between a nucleic acid or analogue thereof of formula II-2 and one or more hydrocarbon bearing carboxylic acid in series or in parallel by known techniques in the art. Each of B, E, L, ligand, LC, n, PG1, PG2, PG3, R1, R2, R3, X3, and Z is as defined above. In some embodiments, nucleic acids, and analogues thereof of the present disclosureFH12501620.1 Attorney Docket: DCY-13025 are prepared according to Scheme C and Scheme D set forth below: Scheme C: Synthesis of Conjugated Oligonucleotides of the Disclosure As depicted in Scheme C above, a nucleic acid or analogue thereof of formula C1 is protected to form a compound of formula C2. Nucleic acid or analogue thereof of formula C2 is then alkylated (e.g., using DMSO and acetic acid via the Pummerer rearrangement) to form a monothioacetal compound of formula C3. Next, nucleic acid or analogue thereof of formula C3 is coupled with C4 under appropriate conditions (e.g., mild oxidizing conditions) to form a nucleic acid or analogue thereof of formula C5. Nucleic acid or analogue thereof of formula C5 can then be deprotected to form a compound of formula C6 and coupled with a ligand (adamantyl or lipophilic compound (e.g., a fatty acid)) of formula C7 under appropriate amide forming conditions (e.g., HATU, DIPEA), to form a nucleic acid-ligand conjugate or analogue thereof of formula I-b comprising a hydrocarbon chain bearing one or more carboxyl groupsFH12501620.1 Attorney Docket: DCY-13025 of the disclosure. Nucleic acid-ligand conjugate or analogue thereof of formula I-b can then be deprotected to form a compound of formula C8 and protected with a suitable hydroxyl protecting group (e.g., DMTr) to form a compound of formula C9. In one aspect, nucleic acid, or analogue thereof of formula C9 can be covalently attached to a solid support (e.g., through a succinic acid linking group) to form a solid support nucleic acid-ligand conjugate or analogue thereof of formula C10 comprising a ligand conjugate of the disclosure. In another aspect, a nucleic acid-ligand conjugate or analogue thereof of formula C9 can reacted with a P(III) forming reagent (e.g., 2-cyanoethyl N,N-di-isopropylchlorophosphoramidite) to form a nucleic acid-ligand conjugate or analogue thereof of formula C11 comprising a P(III) group. A nucleic acid-ligand conjugate or analogue thereof of formula C11 can then be subjected to oligomerization forming conditions preformed using known and commonly applied processes to prepare oligonucleotides in the art. For example, the compound of formula C11 is coupled to a solid supported nucleic acid-ligand conjugate or analogue thereof bearing a 5’-hydroxyl group. Further steps can comprise one or more deprotections, couplings, phosphite oxidation, and / or cleavage from the solid support to provide an oligonucleotide of various nucleotide lengths, including one or more conjugate nucleotide units represented by a compound of formula II...

Claims

Attorney Docket: DCY-13025 CLAIMS 1. A double-stranded oligonucleotide comprising: (i) an antisense strand of 15 to 30 nucleotides in length, a sense strand of 13 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in an extrahepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more -L-Y-Wn groups, or a charged form thereof, wherein: L is a linker selected from -O(CH2)a(OCH2CH2)bNH- , -O(CH2)a(OCH2CH2)b(NH)(CO)-, -O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-, -OP(=O)(OH)O(CH2)a(OCH2CH2)bNH-, -OP(=O)(OH)O(CH2)a(OCH2CH2)b(NH)(CO)-, -OP(=O)(OH)O(CH2)aM, - OP(=O)(OH)O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-, Y is alkylene, alkenylene, alkynylene, or (CH2)e(OCH2CH2)f; each W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substituted aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N (H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; M is absent, -NHC(O)-, -N(alkyl)C(O)-, or heteroarylene; R^ is H or methyl; n is an integer from 1-6; a is an integer from 1-6; b is an integer from 0-8; c is an integer from 0-6; d is an integer from 0-20; e is an integer from 1-6; f is an integer from 1-20; and wherein the ligand is conjugated to a nucleotide of the sense strand.

2. A double-stranded oligonucleotide comprising:FH12501620.1Attorney Docket: DCY-13025 (i) a double-stranded oligonucleotide comprising an antisense strand of 15 to 30 nucleotides in length, a sense strand of 15 to 40 nucleotides in length, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extrahepatic tissue, and wherein the region of complementarity is at least 15 contiguous nucleotides in length; and (ii) one or more ligands, each ligand comprising one or more -L-(C6-24 alkylene)-Wn, or a charged form thereof, conjugated to a nucleotide of the sense strand, wherein: L is a linker selected from -O(CH2)a(OCH2CH2)bNH- , -O(CH2)a(OCH2CH2)b(NH)(CO)-, -O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-, -OP(=O)(OH)O(CH2)a(OCH2CH2)bNH-, -OP(=O)(OH)O(CH2)a(OCH2CH2)b(NH)(CO)-, -OP(=O)(OH)O(CH2)aM, and -OP(=O)(OH)O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-, each W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substituted aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N(H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; M is absent, -NHC(O)-, -N(alkyl)C(O)-, or heteroarylene; R^ is H or methyl; n is an integer from 1-6; a is an integer from 1-6; b is an integer from 0-8; c is an integer from 0-6; d is an integer from 0-20; wherein knock down of the target mRNA in the extrahepatic tissue is greater than knock down of the target mRNA in liver tissue.

3. The double-stranded oligonucleotide of claim 1 or 2, wherein L is a linker selected from -O(CH2)a(OCH2CH2)bNH-, -O(CH2)a(OCH2CH2)b(NH)(CO)-, and -O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-.FH12501620.1Attorney Docket: DCY-13025 4. The double-stranded oligonucleotide of any one of claims 1-3, wherein L is -O(CH2)a(OCH2CH2)b(NH)(CO)(CH2)c(OCH2CH2)dM-.

5. The double-stranded oligonucleotide of claim 4, wherein M is heteroarylene.

6. The double-stranded oligonucleotide of claim 4 or 5, wherein the heteroarylene is a triazolylene.

7. The double-stranded oligonucleotide of claim 6, wherein the triazolylene is.

8. The double-stranded oligonucleotide of claim 4, wherein M is -NHC(O)-.

9. The double-stranded oligonucleotide of any one of claims 1 and 3-8, wherein Y is an C6-24 alkylene, C6-24 alkenylene, or C6-24 alkynylene.

10. The double-stranded oligonucleotide of any one of claims 1 and 3-9, wherein Y is an C6-24 alkylene or C6-24 alkenylene.

11. The double-stranded oligonucleotide of any one of claims 1 and 3-10, wherein Y is a C6-24 alkenylene.

12. The double-stranded oligonucleotide of any one of claims 1 and 3-10, wherein Y is a C6-20alkylene.

13. The double-stranded oligonucleotide of any one of claims 1 and 3-9, wherein the alkenylene comprises from 1-6 olefinic bonds; and the alkynylene comprises from 1-6 acetylenic bonds.

14. The double-stranded oligonucleotide of claim 1,wherein when Y is alkylene, L comprises -O(CH2)a(OCH2CH2)bNH- or -O(CH2)a(OCH2CH2)b(NH)(CO)-.

15. The double-stranded oligonucleotide of any one of claims 0-14, wherein n is 1.FH12501620.1Attorney Docket: DCY-13025 16. The double-stranded oligonucleotide of any one of claims 1-15, wherein W is -CO2H,, , , - OH, -N(H)SO2(methyl), -N(H)SO2(ethyl), -N(H)SO2(n-propyl), -N(H)SO2(i-propyl), -N( H)SO2(sec-propyl), -N(H)SO2(n-butyl), -N(H)SO2(i-butyl), -N(H)SO2(sec- butyl), -N(H)SO2(t-butyl), -N(H)SO2(n- pentyl), -N(H)SO2(cyclopropyl), -N(H)SO2(cyclobutyl), -N(H)SO2(cyclopentyl), -N(H)SO2(cyclohexyl), -N(H)SO2(cycloheptyl),-N(H)SO2(cyclooctyl), -N(H)SO2([1.1.1]propellane), ,17. The double-stranded oligonucleotide of any one of claims 1-15, wherein W is piperazinyl or piperidinyl.

18. The double-stranded oligonucleotide of 1-17, wherein a is 1.

19. The double-stranded oligonucleotide of 1-18, wherein b is 0 or 1.

20. The double-stranded oligonucleotide of 1-18, wherein b is 2.FH12501620.1Attorney Docket: DCY-13025 21. The double-stranded oligonucleotide of any one of claims 4-8, wherein c is 2.

22. The double-stranded oligonucleotide of any one of claims 4-8 and 21, wherein d is 4.

23. The double-stranded oligonucleotide of claim 1 or 2, wherein the -L-Y-(W)ngroup is:wherein g is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

24. The double-stranded oligonucleotide of claim 23, wherein M is -NHC(O)-.

25. The double-stranded oligonucleotide of claim 23, wherein M is -N(methyl)C(O).

26. The double-stranded oligonucleotide of claim 23, wherein M is heteroarylene.

27. The double-stranded oligonucleotide of claim 26, wherein the heteroaryl is triazolylene.

28. The double-stranded oligonucleotide of claim 27, wherein the triazolylene is.

29. The double-stranded oligonucleotide of claim 23, wherein M is absent.

30. The double-stranded oligonucleotide of any one of claims 23-29, wherein W is -CO2H,, , , - OH, -N(H)SO2(methyl), -N(H)SO2(ethyl), -N(H)SO2(n-propyl), -N(H)SO2(i-propyl), -N( H)SO2(sec-propyl), -N(H)SO2(n-butyl), -N(H)SO2(i-butyl), -N(H)SO2(sec- butyl), -N(H)SO2(t-butyl), -N(H)SO2(n- pentyl), -N(H)SO2(cyclopropyl), -N(H)SO2(cyclobutyl), -N(H)SO2(cyclopentyl), -N(H)SO2(cyclohexyl), -N(H)SO2(cycloheptyl),FH12501620.1Attorney Docket: DCY-13025-N(H)SO2(cyclooctyl), -N(H)SO2([1.1.1]propellane), ,31. The double-stranded oligonucleotide of any one of claims 23-29, wherein W is piperazinyl or piperidinyl.

32. The double-stranded oligonucleotide of any one of claims 23-31, wherein c is 1.

33. The double-stranded oligonucleotide of any one of claims 23-31, wherein c is 2.

34. The double-stranded oligonucleotide of any one of claims 23-33, wherein d is 0 to 12.

35. The double-stranded oligonucleotide of any one of claims 23-33, wherein d is 4 to 12.

36. The double-stranded oligonucleotide of any one of claims 23-33, wherein d is 4.

37. The double-stranded oligonucleotide of any one of claims 23-36, wherein g is 12 to 23.

38. The double-stranded oligonucleotide of any one of claims 23-36, wherein g is 11, 14, 15, 20, or 21.FH12501620.1Attorney Docket: DCY-13025 39. The double-stranded oligonucleotide of any one of claims 1-38, wherein the extrahepatic tissue is adipose tissue, heart tissue, skeletal muscle, or adrenal gland tissue.

40. The double-stranded oligonucleotide of any one of claims 1-39, wherein the extrahepatic tissue is adipose tissue.

41. The double-stranded oligonucleotide of any one of claims 1-40, wherein the antisense strand is 22 nucleotides.

42. The double-stranded oligonucleotide of any one of claims 1-41, wherein the antisense strand comprises a 3’ overhang of 2 to 6 nucleotides.

43. The double-stranded oligonucleotide of any one of claims 1-42, wherein the sense strand and / or antisense strand comprises at least one modified internucleotide linkage.

44. The double-stranded oligonucleotide of claim 43, wherein the at least one modified internucleotide linkage is a phosphorothioate linkage.

45. The double-stranded oligonucleotide of any one of claims 1-44, wherein the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5’ to 3’.

46. The double-stranded oligonucleotide of any one of claims 43-45, wherein the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5^ to 3^.

47. The double-stranded oligonucleotide of any one of claims 43-46, wherein the sense strand comprises a phosphorothioate linkage (i) between positions 1 and 2; (ii) between positions 2 and 3; (iii) between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20; or, (iv) between positions 2 and 3, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^.FH12501620.1Attorney Docket: DCY-13025 48. The double-stranded oligonucleotide of any one of claims 43-46, wherein the sense strand is 36 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, wherein positions are numbered 1-36 from 5^ to 3^.

49. The double-stranded oligonucleotide of any one of claims 43-45, wherein the sense strand is 20 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^.

50. The double-stranded oligonucleotide of any one of claims 1-49, wherein the oligonucleotide comprises a stem-loop comprising a tetraloop.

51. The double-stranded oligonucleotide of claim 50, wherein the tetraloop comprises a 5’- GAAA-3’ sequence.

52. The double-stranded oligonucleotide of any one of claims 1-51, wherein the sense strand and / or antisense strand comprises one or more modified nucleotides.

53. The double-stranded oligonucleotide of claim 52, wherein the modified nucleotide comprises a modified sugar.

54. The double-stranded oligonucleotide of claim 53, wherein the modified sugar comprises a 2’-OMe group.

55. The double-stranded oligonucleotide of claim 53, wherein the modified sugar comprises a 2’-F substituent.

56. The double-stranded oligonucleotide of any one of claims 1-55, wherein the antisense strand comprises up to 4 contiguous nucleotides with a 2’-F modified sugar.

57. The double-stranded oligonucleotide of any one of claims 1-56, wherein the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, and 14, numbered 5^ to 3^ comprise a 2’-F modification.FH12501620.1Attorney Docket: DCY-13025 58. The double-stranded oligonucleotide of any one of claims 1-56, wherein the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, 14, 16, and 19, numbered 5^ to 3^, comprise a 2’-F modification.

59. The double-stranded oligonucleotide of any one of claims 1-57, wherein the sense strand comprises 20 nucleotides, wherein nucleotides at each of positions 8, 9, 10, and 11 numbered 5^ to 3^, comprise a 2’-F modification.

60. The double-stranded oligonucleotide of any one of claims 1-58, wherein the sense strand comprises 36 nucleotides, wherein nucleotides at each of positions 3, 5, 8, 10, 12, 13, 15, and 17, numbered 5^ to 3^, comprise a 2’-F modification.

61. The double-stranded oligonucleotide of any one of claims 1-60, wherein the antisense strand comprises a 4’-O-monomethylphosphonate-2’-O-methyl modified nucleotide.

62. The double-stranded oligonucleotide of any one of claims 1-60, wherein the antisense strand comprises a phosphorylated nucleotide at the 5’ terminus, and wherein the phosphorylated nucleotide is selected from uridine and adenosine.

63. The double-stranded oligonucleotide of any one of claims 1-60, wherein the 4^-carbon of the sugar of the 5^-nucleotide of the antisense strand comprises a phosphate analog.

64. The double-stranded oligonucleotide of claim 63, wherein the phosphate analog is oxymethyl phosphonate, vinyl phosphonate or malonyl phosphonate.

65. The double-stranded oligonucleotide of any one of claims 62-64, wherein the phosphorylated nucleotide is 4’-O-monomethylphosphonate-2’-O-methyl uridine.

66. The double-stranded oligonucleotide of any one of claims 1-65, wherein the one or more ligands is conjugated to a ribose of the sense strand at the 3’- or 5’-position.

67. The double-stranded oligonucleotide of any one of claims 1-65, wherein the one or more ligands is conjugated to a ribose of the sense strand at the 2’-position.FH12501620.1Attorney Docket: DCY-13025 68. The double-stranded oligonucleotide of any one of claims 1-67, wherein one ligand is conjugated to position one of the sense strand, numbered 5^ to 3^.

69. The double-stranded oligonucleotide of any one of claims 1-67, comprising at least two ligands.

70. The double-stranded oligonucleotide of claim 69, wherein the at least two ligands are conjugated to different nucleotides of the sense strand.

71. The double-stranded oligonucleotide of claim 70, wherein the at least two ligands are the same ligand.

72. The double-stranded oligonucleotide of claim 70, wherein the at least two ligands are different ligands.

73. The double-stranded oligonucleotide of claim 71 or 72, wherein the at least two ligands are conjugated to position 1, numbered 5^ to 3^, and a nucleotide within a tetraloop.

74. The double-stranded oligonucleotide of claim 71 or 72, wherein (a) at least one ligand is conjugated to position 1 and at least one ligand is conjugated to position 29; (b) at least one ligand is conjugated to position 1 and at least one ligand is conjugated to position 28; (c) at least one ligand is conjugated to position 1 and at least one ligand is conjugated to position 2; or (d) at least one ligand is conjugated to position 1 and at least one ligand is conjugated to position 20, numbered 5^ to 3^, of the sense strand.

75. The double-stranded oligonucleotide of any one of claims 1-74, wherein the region of complementarity is fully complementary to the mRNA target sequence.

76. The double-stranded oligonucleotide of any one of claims 1-74, wherein the region of complementarity is partially complementary to the mRNA target sequence.FH12501620.1Attorney Docket: DCY-13025 77. The double-stranded oligonucleotide of claim 76, wherein the region of complementarity comprises no more than four mismatches to the mRNA target sequence.

78. An oligonucleotide-ligand conjugate of Formula (AI):or a pharmaceutically acceptable salt or charged form thereof; wherein: A and A’ are each independently H or one or more nucleotides; B is a nucleobase; Z is O or S; M is absent, -NRC(O)-, or heteroarylene, wherein R is H or alkyl; each W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substituted aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N(H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; a is 1, 2, 3, 4, 5, or 6; b is 1, 2, 3, 4, 5, 6, 7, or 8; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23; and f is 0, 1, 2, 3, 4, 5, or 6.

79. The oligonucleotide-ligand conjugate of claim 78, wherein M is -NRC(O)-.FH12501620.1Attorney Docket: DCY-13025 80. The oligonucleotide-ligand conjugate of claim 78 or 79, wherein R is H or C1-5 alkyl.

81. The oligonucleotide-ligand conjugate of any one of claims 78-80, wherein R is H or methyl.

82. The oligonucleotide-ligand conjugate of any one of claims 78-81, wherein R is H.

83. The oligonucleotide-ligand conjugate of any one of claims 78-82, wherein W is -CO2H,, , , - OH, -N(H)SO2(methyl), -N(H)SO2(ethyl), -N(H)SO2(n-propyl), -N(H)SO2(i-propyl), -N( H)SO2(sec-propyl), -N(H)SO2(n-butyl), -N(H)SO2(i-butyl), -N(H)SO2(sec- butyl), -N(H)SO2(t-butyl), -N(H)SO2(n- pentyl), -N(H)SO2(cyclopropyl), -N(H)SO2(cyclobutyl), -N(H)SO2(cyclopentyl), -N(H)SO2(cyclohexyl), -N(H)SO2(cycloheptyl),-N(H)SO2(cyclooctyl), -N(H)SO2([1.1.1]propellane), ,FH12501620.1Attorney Docket: DCY-13025 84. The oligonucleotide-ligand conjugate of any one of claims 78-82, wherein W is piperazinyl or piperidinyl.

85. The oligonucleotide-ligand conjugate of any one of claims 78-84, wherein c is 1 or 2.

86. The oligonucleotide-ligand conjugate of any one of claims 78-85, having a structure of Formula (AII)or a pharmaceutically acceptable salt or charged form thereof.

87. The oligonucleotide-ligand conjugate of claim 78, wherein M is heteroarylene.

88. The oligonucleotide-ligand conjugate of claim 87, wherein the heteroarylene is triazolylene.

89. The oligonucleotide-ligand conjugate of claim 88, wherein the triazolylene is .

90. The oligonucleotide-ligand conjugate of any one of claims 78 and 87-89, having a structure of Formula (AIII)FH12501620.1Attorney Docket: DCY-13025 or a pharmaceutically acceptable salt or charged form thereof.

91. The oligonucleotide-ligand conjugate of any one of claims 78-90, wherein d is 0 to 12.

92. The oligonucleotide-ligand conjugate of any one of claims 78-91, wherein d is 4 to 12.

93. The oligonucleotide-ligand conjugate of any one of claims 78-92, wherein d is 4.

94. The oligonucleotide-ligand conjugate of any one of claims 78 and 87-91, having a structure of Formula (AIV)or a pharmaceutically acceptable salt or a charged form thereof.

95. The oligonucleotide-ligand conjugate of claims 78, wherein M is absent.

96. The oligonucleotide-ligand conjugate of claims 78 or 95, having a structure of Formula (AV)or a pharmaceutically acceptable salt or a charged form thereof.

97. The oligonucleotide-ligand conjugate of any one of claims 78-96, wherein a is 1 or 2.FH12501620.1Attorney Docket: DCY-13025 98. The oligonucleotide-ligand conjugate of any one of claims 78-97, wherein a is 1.

99. The oligonucleotide-ligand conjugate of any one of claims 78-98, wherein b is 1 or 2.

100. The oligonucleotide-ligand conjugate of any one of claims 78-99, wherein b is 2.

101. The oligonucleotide-ligand conjugate of any one of claims 78-100, wherein e is 11 to 22.

102. The oligonucleotide-ligand conjugate of any one of claims 78-101, wherein e is 11, 15, or 21.

103. The oligonucleotide-ligand conjugate of any one of claims 78-102, wherein f is 0, 1, or 2.

104. The oligonucleotide-ligand conjugate of any one of claims 78-103, wherein f is 0.

105. The oligonucleotide-ligand conjugate of any one of claims 78-104, wherein B is106. The oligonucleotide-ligand conjugate of any one of claims 78-105, wherein B is.

107. The oligonucleotide-ligand conjugate of any one of claims 78-106, wherein A is H.

108. The oligonucleotide-ligand conjugate of any one of claims 78-107, wherein Z is S.FH12501620.1Attorney Docket: DCY-13025 109. A double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises the oligonucleotide-ligand conjugate of any one of claims 78-108, and wherein the sense strand and antisense strand form a duplex region.

110. The double-stranded oligonucleotide of claim 109, wherein the antisense strand is 15 to 30 nucleotides in length.

111. The double-stranded oligonucleotide of any one of claims 109-110, wherein the sense strand and / or antisense strand comprises at least one modified internucleotide linkage.

112. The oligonucleotide-ligand conjugate of claim 111, wherein the at least one modified internucleotide linkage is a phosphorothioate linkage.

113. The double-stranded oligonucleotide of any one of claims 109-112, wherein A is H and A^ is 12 to 40 nucleotides.

114. The double-stranded oligonucleotide of any one of claims 109-113, wherein the nucleotides of A^ comprise at least one modified internucleotide linkage.

115. The double-stranded oligonucleotide of any one of claims 109-112, wherein A is 12- 29 nucleotides and A^ is 1-10 nucleotides.

116. The double stranded oligonucleotide of claim 115, wherein the nucleotides of A comprise at least one modified internucleotide linkage.

117. The double-stranded oligonucleotide of any one of claims 109-116, wherein the oligonucleotide-ligand conjugate and at least 14 nucleotides of A’ form the duplex region with the antisense strand.

118. The double-stranded oligonucleotide of any one of claims 109-117, wherein the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5’ to 3’.FH12501620.1Attorney Docket: DCY-13025 119. The double-stranded oligonucleotide of any one of claims 109-117, wherein the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5^ to 3^.

120. The double-stranded oligonucleotide of any one of claims 109-119, wherein the sense strand comprises a phosphorothioate linkage (i) between positions 1 and 2; (ii) between positions 2 and 3; (iii) between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20; or, (iv) between positions 2 and 3, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^.

121. The double-stranded oligonucleotide of any one of claims 109-119, wherein the sense strand is 36 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, wherein positions are numbered 1- 36 from 5^ to 3^.

122. The double-stranded oligonucleotide of any one of claims 109-119, wherein the sense strand is 20 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^.

123. The double-stranded oligonucleotide of any one of claims 109-122, wherein the duplex region comprises 20 to 30 base pairs.

124. The double-stranded oligonucleotide of any one of claims 109-123, wherein the sense strand comprises a stem-loop comprising a tetraloop.

125. The double-stranded oligonucleotide of claim 124, wherein the tetraloop comprises a 5’-GAAA-3’ sequence.

126. The double-stranded oligonucleotide of claim 124, wherein the oligonucleotide-ligand conjugate is a nucleotide of the tetraloop.FH12501620.1Attorney Docket: DCY-13025 127. The double-stranded oligonucleotide of any one of claims 109-126, wherein the sense and antisense strand comprise one or more modified nucleotides.

128. The double-stranded oligonucleotide of claim 127, wherein the modified nucleotide comprises a modified sugar.

129. The double-stranded oligonucleotide of claim 128, wherein the modified sugar comprises a 2’-OMe group.

130. The double-stranded oligonucleotide of claim 128, wherein the modified sugar comprises a 2’-F substituent.

131. The double-stranded oligonucleotide of any one of claims 109-130, wherein the sense strand comprises 20 nucleotides, wherein nucleotides at each of positions 8, 9, 10, and 11 comprise a 2’-F modification.

132. The double-stranded oligonucleotide of any one of claims 109-130, wherein the sense strand comprises 36 nucleotides, wherein nucleotides at each of positions 3, 5, 8, 10, 12, 13, 15, and 17 comprise a 2’-F modification.

133. The double-stranded oligonucleotide of any one of claims 109-130, wherein the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, and 14 comprise a 2’-F modification.

134. The double-stranded oligonucleotide of any one of claims 109-130, wherein the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, 14, 16, and 19 comprise a 2’-F modification.

135. The double-stranded oligonucleotide of claim 109-134, wherein the modified nucleotide comprises a modified nucleobase.

136. The double-stranded oligonucleotide of any one of claims 109-135 comprising a 4’- O-monomethylphosphonate-2’-O-methyl modified nucleotide.FH12501620.1Attorney Docket: DCY-13025 137. The double-stranded oligonucleotide of any one of claims 109-136, wherein the antisense strand comprises a phosphorylated nucleotide at the 5’ terminus, and wherein the phosphorylated nucleotide is selected from uridine and adenosine.

138. The double-stranded oligonucleotide of any one of claims 109-136, wherein the 4^- carbon of the sugar of the 5^-nucleotide of the antisense strand comprises a phosphate analog.

139. The double-stranded oligonucleotide of claim 138, wherein the phosphate analog is oxymethyl phosphonate, vinyl phosphonate or malonyl phosphonate.

140. The double-stranded oligonucleotide of any one of claims 137-139, wherein the phosphorylated nucleotide is 4’-O-monomethylphosphonate-2’-O-methyl uridine.

141. An oligonucleotide-ligand conjugate of Formula (BI):or a pharmaceutically acceptable salt or charged form thereof, wherein: B is a nucleobase; A is a one or more nucleotides; Z1and Z2are each independently O or S; M is absent, -NRC(O)-, or heteroarylene, wherein R is H or alkyl; W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substitutedFH12501620.1Attorney Docket: DCY-13025 aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N(H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23; and f is 0, 1, 2, 3, 4, 5, or 6.

142. An oligonucleotide-ligand conjugate of Formula (BII):or a salt or charged form thereof, wherein: B is a nucleobase; A is a one or more nucleotides ; Z is O or S; M is absent, NRC(O), or heteroarylene, wherein R is H or alkyl; W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substituted aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N(H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 23; andFH12501620.1Attorney Docket: DCY-13025 f is 0, 1, 2, 3, 4, 5, or 6.

143. An oligonucleotide-ligand conjugate of Formula (CI)or a pharmaceutically acceptable salt or charged form thereof, wherein: B is a nucleobase; A is one or more nucleotides; Z1and Z2are each independently O or S; M is absent, NRC(O), or heteroarylene, wherein R is H or alkyl; W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substituted aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N(H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 23; and f is 0, 1, 2, 3, 4, 5, or 6.

144. An oligonucleotide-ligand conjugate of Formula (CII)or a salt or charged form thereof, wherein:FH12501620.1Attorney Docket: DCY-13025 B is a nucleobase; A is one or more nucleotides; Z is O or S; M is absent, NRC(O), or heteroarylene, wherein R is H or alkyl; W is independently -C(O)OH, -CR^(C(O)OH)2, -CR^(C(O)O(alkyl))2, -SO2OH, tetrazolyl, -OH, -N(H)SO2(alkyl), -N(H)SO2(cycloalkyl), -N(H)SO2(optionally substituted aryl), -N(H)SO2(heterocyclyl), -N(H)SO2(optionally substituted heteroaryl), -O(optionally substituted aryl), -N(H)C(O)N(H)SO2(alkyl), -C(O)NH(hydroxyphenyl), -N(H)C(O)(hydroxyphenyl), -N(H)(hydroxyphenyl), hydroxyphenyl, or heterocyclyl; a is 1, 2, 3, 4, or 5; c is 0, 1, 2, 3, 4, 5, or 6; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; e is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 23; and f is 0, 1, 2, 3, 4, 5, or 6.

145. A double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises an oligonucleotide-ligand conjugate of any one of claims 141-144 and wherein the sense strand and antisense strand form a duplex region.

146. The double-stranded oligonucleotide of claim 145, wherein the antisense strand is 15 to 30 nucleotides in length.

147. The double-stranded oligonucleotide of claim 146, wherein A is 12 to 40 nucleotides.

148. The double-stranded oligonucleotide of any one of claims 145-147, wherein the sense strand and / or antisense strand comprises at least one modified internucleotide linkage.

149. The double-stranded oligonucleotide of claim 148, wherein the at least one modified internucleotide linkage is a phosphorothioate linkage.

150. The double-stranded oligonucleotide of any one of claims 145-149, wherein the duplex region includes one or more phosphorothioate linkages.FH12501620.1Attorney Docket: DCY-13025 151. The double-stranded oligonucleotide of claim 150, wherein two phosphorothioate linkages are adjacent to each other.

152. The double-stranded oligonucleotide of any one of claims 145-151, wherein the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5’ to 3’.

153. The double-stranded oligonucleotide of any one of claims 145-152, wherein the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5^ to 3^.

154. The double-stranded oligonucleotide of any one of claims 145-153, wherein the sense strand comprises a phosphorothioate linkage (i) between positions 1 and 2; (ii) between positions 2 and 3; (iii) between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20; or, (iv) between positions 2 and 3, between positions 18 and 19, and between positiosn 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^.

155. The double-stranded oligonucleotide of any one of claims 145-153, wherein the sense strand is 36 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, wherein positions are numbered 1- 36 from 5^ to 3^.

156. The double-stranded oligonucleotide of any one of claims 145-153, wherein the sense strand is 20 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20, wherein positions are numbered 1-20 from 5^ to 3^.

157. The double-stranded oligonucleotide of any one of claims 145-156, wherein the duplex region comprises 20 to 30 base pairs.FH12501620.1Attorney Docket: DCY-13025 158. The double-stranded oligonucleotide of any one of claims 145-156, wherein the sense strand comprises a loop region that includes a tetraloop region.

159. The double-stranded oligonucleotide of claim 158, wherein the tetraloop region comprises a 5’-GAAA-3’ sequence.

160. The double-stranded oligonucleotide of any one of claims 145-159, wherein the sense and antisense strand comprise one or more modified nucleotides.

161. The double-stranded oligonucleotide of claim 160, wherein the modified nucleotide comprises a modified sugar.

162. The double-stranded oligonucleotide of claim 161, wherein the modified sugar comprises a 2’-OMe group.

163. The double-stranded oligonucleotide of claim 161, wherein the modified sugar comprises a 2’-F substituent.

164. The double-stranded oligonucleotide of any one of claims 145-163, wherein the sense strand comprises 20 nucleotides, wherein nucleotides at each of positions 8, 9, 10, and 11 comprise a 2’-F modification.

165. The double-stranded oligonucleotide of any one of claims 145-163, wherein the sense strand comprises 36 nucleotides, wherein nucleotides at each of positions 3, 5, 8, 10, 12, 13, 15, and 17 comprise a 2’-F modification.

166. The double-stranded oligonucleotide of any one of claims 145-163, wherein the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, and 14 comprise a 2’-F modification.

167. The double-stranded oligonucleotide of any one of claims 145-163, wherein the antisense strand comprises 22 nucleotides, wherein nucleotides at each of positions 2, 3, 4, 5, 7, 10, 14, 16, and 19 comprise a 2’-F modification.FH12501620.1Attorney Docket: DCY-13025 168. The double-stranded oligonucleotide of claim 160-167, wherein the modified nucleotide comprises a modified nucleobase.

169. The double-stranded oligonucleotide of any one of claims 145-168 comprising a 4’- O-monomethylphosphonate-2’-O-methyl modified nucleotide.

170. The double-stranded oligonucleotide of any one of claims 145-169, wherein the antisense strand comprises a phosphorylated nucleotide at the 5’ terminus, and wherein the phosphorylated nucleotide is selected from uridine and adenosine.

171. The double-stranded oligonucleotide of any one of claims 145-169, wherein the 4^- carbon of the sugar of the 5^-nucleotide of the antisense strand comprises a phosphate analog.

172. The double-stranded oligonucleotide of claim 171, wherein the phosphate analog is oxymethyl phosphonate, vinyl phosphonate or malonyl phosphonate.

173. The double-stranded oligonucleotide of any one of claims 170-172, wherein the phosphorylated nucleotide is 4’-O-monomethylphosphonate-2’-O-methyl uridine.

174. The double-stranded oligonucleotide of any one of claims 109-173, wherein the sense strand comprises a second oligonucleotide-ligand conjugate.

175. The double-stranded oligonucleotide of claim 174, wherein the second oligonucleotide-ligand conjugate is selected from the oligonucleotide-ligand conjugate of any one of claims 109 and 141-144.

176. The double-stranded oligonucleotide of any one of claims 109-140 and 145-175, wherein the antisense strand has a region of complementarity to a target sequence in a target mRNA in extrahepatic tissue, wherein the region of complementarity is at least 15 contiguous nucleotides in length.

177. The double-stranded oligonucleotide of claim 176, wherein the region of complementarity is fully complementary to the mRNA target sequence.FH12501620.1Attorney Docket: DCY-13025 178. The double-stranded oligonucleotide of claim 176, wherein the region of complementarity is partially complementary to the mRNA target sequence.

179. The double-stranded oligonucleotide of claim 178, wherein the region of complementarity comprises no more than four mismatches to the mRNA target sequence.

180. The double-stranded oligonucleotide of any one of claims 176-179, wherein the extrahepatic tissue is adipose tissue, heart tissue, skeletal muscle, or adrenal gland tissue.

181. The double-stranded oligonucleotide of any one of claims 176-180, wherein the extrahepatic tissue is adipose tissue.

182. A double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises two or more oligonucleotide-ligand conjugates of (i), (ii), or (iii): (i) Formula (AI), (AII), (AIII), (AIV), or (AV); (ii) Formula (BI) or (BII); and (iii) Formula (CI) or (CII).

183. The double-stranded oligonucleotide of claim 182, wherein the two or more oligonucleotide ligand conjugates are conjugated to different nucleotides of the sense strand.

184. The double-stranded oligonucleotide of claim 182 or 183, wherein the two or more oligonucleotide ligand conjugates are the same.

185. The double-stranded oligonucleotide of claim 182 or 183, wherein the two or more oligonucleotide ligand conjugates are different.

186. The double-stranded oligonucleotide of claim 182, wherein the sense strand comprises a first oligonucleotide-ligand conjugate and a second oligonucleotide-ligand conjugate.FH12501620.1Attorney Docket: DCY-13025 187. The double-stranded oligonucleotide of claim 186, wherein the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand and the nucleobase (B) of the second oligonucleotide-ligand conjugate is a nucleobase within a tetraloop of the sense strand.

188. The double-stranded oligonucleotide of claim 186, wherein (a) the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand, and the nucleobase (B) of the second oligonucleotide-ligand conjugate is the nucleobase at position 29 of the sense strand; (b) the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand, and the nucleobase (B) of the second oligonucleotide-ligand conjugate is the nucleobase at position 28 of the sense strand; (c) the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand, and the nucleobase (B) of the second oligonucleotide-ligand conjugate is the nucleobase at position 20 of the sense strand; or (d) the nucleobase (B) of the first oligonucleotide-ligand conjugate is the nucleobase at position 1 of the sense strand, and the nucleobase (B) of the second oligonucleotide-ligand conjugate is the nucleobase at position 2 of the sense strand.

189. The double-stranded oligonucleotide of any one of the proceeding claims, wherein the oligonucleotide-ligand conjugate reduces expression of the target mRNA in an extrahepatic tissue, provided the oligonucleotide-ligand conjugate does not reduce expression of the mRNA target in the liver.

190. A pharmaceutical composition comprising the double-stranded oligonucleotide of any one of claims 1-77, 109-140, and 145-175, and a pharmaceutically acceptable carrier, delivery agent, or excipient.

191. A method of inhibiting target mRNA expression in an extrahepatic cell or tissue in a subject, comprising administering to the subject the double-stranded oligonucleotide of any one of claims 1-77, 109-140, and 145-175, or the pharmaceutical composition of claim 190, thereby inhibiting target mRNA expression in the cell of the extrahepatic tissue.FH12501620.1Attorney Docket: DCY-13025 192. The method of claim 191, wherein the extrahepatic cell or tissue is selected from skeletal muscle, adipose tissue, adrenal tissue, heart tissue, and any combination thereof.

193. The method of claim 191 or 192, wherein reduction of the target mRNA in the extrahepatic cell or tissue is increased compared to reduction in liver cells or tissue, optionally wherein reduction of the target mRNA is increased by at least 10%.

194. The method of claim 193, wherein reduction of the target mRNA is increased by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50%.

195. The double-stranded oligonucleotide of any one of claims 1-189 in the manufacture of a medicament for inhibiting target mRNA expression in an extrahepatic cell or tissue in a subject.

196. Use of the double-stranded oligonucleotide of any one of claims 1-189 for inhibiting target mRNA expression in a cell of an extrahepatic tissue in a subject.

197. A kit comprising a container comprising the double-stranded oligonucleotide of any one of claims 1-77, 109-140, and 145-175, and optionally a pharmaceutically acceptable carrier, and instructions for administering the oligonucleotide-ligand conjugate to a subject in need thereof, wherein the oligonucleotide-ligand conjugate inhibits target mRNA expression in an extrahepatic cell or tissue in the subject.

198. The double-stranded oligonucleotide of claim 195, the use of claim 196, or the kit of claim 197, wherein the extrahepatic cell or tissue is selected from skeletal muscle, adipose tissue, adrenal tissue, heart tissue, and any combination thereof.

199. The double-stranded oligonucleotide of claim 195, the use of claim 196, or the kit of claim 197, wherein the cell of the extrahepatic cell or tissue is selected from a cardiomyocyte, a cell of skeletal muscle, a cell of adipose tissue, a cell of adrenal tissue, and any combination thereof.FH12501620.1Attorney Docket: DCY-13025 200. The double-stranded oligonucleotide, use, or kit of any one of claims 195-198, wherein reduction of the target mRNA in the extrahepatic cell or tissue is increased compared to reduction in a cell of the liver, optionally wherein reduction of the target mRNA is increased by at least 10%.

201. The double-stranded oligonucleotide, use, or kit of claim 200, wherein reduction of the target mRNA is increased by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50%.

202. A method for treating a subject having a disease, disorder or condition associated with expression of an mRNA in an extrahepatic cell or tissue, the method comprising administering to the subject a therapeutically effective amount of the double-stranded oligonucleotide of any one of claims 1-77, 109-140, and 145-175, or the pharmaceutical composition of claim 190.

203. A method of delivering a double-stranded oligonucleotide to a cell or population of cells in extrahepatic tissue, the method comprising administering the pharmaceutical composition of claim 190.FH12501620.1

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