Glycolipid compositions

Abstract

Provided herein are particles and compositions comprising one or more glycolipids and a nucleic acid, wherein the one or more glycolipids are represented by, for example, formula I or a pharmaceutically acceptable salt thereof.

Description

[0001] Glycolipid Compositions

[0002] DESCRIPTION

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to International Patent Application No. PCT / EP23 / 85641 , filed December 13, 2023, the entirety of which is incorporated herein by reference.

[0005] BACKGROUND

[0006] Targeted delivery and expression of therapeutic and / or prophylactic agents such as nucleic acids present certain challenges due to the instability of nucleic acids and their inability to permeate the cell membrane. Certain approaches, including use of lipid or polymer-based systems, exhibit promise but suffer from drawbacks related to manufacturing difficulties, poor structural definition, and high polydispersity. Still further, many such compositions lack satisfactory safety and efficacy for use in delivery of therapeutic agents.

[0007] SUMMARY

[0008] The present disclosure provides, among other things, compositions comprising particles that are useful for the delivery of therapeutics agents, such as nucleic acids, that overcome certain deficiencies associated with previous compositions.

[0009] In some embodiments, the present disclosure provides a particle comprising one or more glycolipids and a nucleic acid, wherein the one or more glycolipids are represented by formula I:

[0010] G1-G2-G3

[0011] I or a pharmaceutically acceptable salt thereof, wherein

[0012] G1is a glycodendron or a carbohydrate moiety;

[0013] G2is a polymer-linker moiety comprising units selected from ethylene glycol, 2-(2-(2- aminoethoxy)ethoxy)acetic acid, and sarcosine, or is an optionally substituted C2-C175aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, - N(RZ)C(O)N(RZ)-, -OC(O)O-, -O-, -S-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1 -3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1 -4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted Ce- C12aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20aliphatic, or C3-C12cycloaliphatic; and G3is a lipid or phospholipid tail.

[0014] In some embodiments, the present disclosure provides a compound that is a glycolipid, or a particle comprising one or more glycolipids and a nucleic acid, wherein the one or more glycolipids are represented by formula II: or a pharmaceutically acceptable salt thereof, wherein:

[0015] R1is -A, -M1-M2-A, or -M3-N(-M1-M2-A)2;

[0016] R2is -H, -A, -M1-M2-A, or -M3-N(-M1-M2-A)2; each M1is independently an optionally substituted C2-C12aliphatic or 2- to 12-membered heteroaliphatic; each M2is independently -NHC(S)NH-, -NHS(O)2-, -NHC(O)-, -C(O)NH-, -C(O)O-, or - OC(O)-; each M3is independently an optionally substituted C2-C12aliphatic or 2- to 12-membered heteroaliphatic;

[0017] A is -A1-X-A2; each A1is independently a bond, optionally substituted C2-C12aliphatic, 2- to 12- membered heteroaliphatic, optionally substituted C6-C12aryl, optionally substituted C3- C12cycloaliphatic, optionally substituted 4- to 12-membered heterocycle, or optionally substituted 5- to 12-membered heteroaryl; each X is independently a bond, -(CH2)1 -6-, -NH-, -S-, -S(O)2-, or -O-; each A2is independently a monosaccharide, a disaccharide, an oligosaccharide, a fluorescent tag, or a moiety of formula J: wherein at least one instance of A2is a monosaccharide, a disaccharide, an oligosaccharide, or a moiety of formula J; each of R3, R4, and R5is each independently at each occurrence a monosaccharide, a disaccharide, or an oligosaccharide; each of X’ is independently a bond, -Cy’-O-, -O-Cy’-, -NH-, -S-, -S(O)2-, or -O-, wherein each Cy’ is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1 -3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1 -4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted C6-C12aryl; each A3is independently, at each occurrence, a bond, optionally substituted C2-C12aliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 12- membered heterocycle, or optionally substituted 5- to 12-membered heteroaryl;

[0018] M4is optionally substituted C2-C6aliphatic-NHC(S)NH-, or optionally substituted 2- to 12- membered heteroaliphatic-NHC(S)NH-;

[0019] L is a polymeric moiety that comprises monomers of ethylene glycol, sarcosine, 2-(2-(2- aminoethoxy)ethoxy)acetic acid, or a combination thereof, a bond, or L is an optionally substituted C20-C100aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, - OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1 -3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1 -4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted C6- C12aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20aliphatic, or C3-C12cycloaliphatic;

[0020] M5is a bond, -OC(O)NH-, -NHC(O)O-, -NHC(O)-, -C(O)-NH-, - C1-C6aliphatic-C(O)NH-, or -NHC(O)-CI-C6aliphatic;

[0021] T is optionally substituted C10-C20aliphatic, or a moiety of formula B or B”: each R7is independently -(CH2)x2-M6-R8; each M6is independently a bond, -OC(O)-, -C(O)O-, -C(O)-, -C(S)-, -NHC(O)-, - C(O)NH-, -S-, -S-S-, and -S(O)2-; each R8is optionally substituted C10-C20aliphatic or 10- to 20-membered heteroaliphatic; n is 0 or 1 ; x1 is an integer selected from 1 to 6; and each x2 is independently selected from 0, 1 , and 2.

[0022] In some embodiments, the present disclosure provides a composition comprising a particle comprising glycolipids described herein.

[0023] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition comprising administering to a subject a composition described herein.

[0024] In some embodiments, the present disclosure provides a method of increasing or causing increased expression of RNA in a target in a subject comprising administering to the subject a composition described herein.

[0025] BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1A is a bar graph illustrating the size and PDI of particles comprising example glycolipids. FIG. 1 B illustrates RNA encapsulation of particles comprising example glycoplipids.

[0027] FIG. 2 is a plot illustrating the dose-inhibition profile for HRP-ConA binding to mannan with example glycolipids.

[0028] FIG. 3 is a plot illustrating the effect of formulation glycolipid concentration on ligand potency.

[0029] FIG. 4 illustrates detection of micelles formed by example glycolipids for various concentrations of glycolipid.

[0030] FIG. 5A is a bar graph illustrating transfection efficiency of example glycolipids compared to benchmark.

[0031] FIG.5B is a bar graph illustrating luciferase expression for LNPs containing 3 mol% of example glycolipids.

[0032] FIG. 6 is a bar graph illustrating transfection efficacy of LNPs functionalized with example glycolipids relative to benchmark.

[0033] FIG. 7 is a bar graph illustrating CD14+-specific transfection efficacy of LNPs functionalized with example glycolipids relative to benchmark.

[0034] FIG. 8A illustrates transfection efficacy of LNPs functionalized with example glycolipids in cell line expressing huCD209 relative to control.

[0035] FIG. 8B illustrates transfection efficacy of LNPs functionalized with example glycolipids in cell line expressing huCD301 relative to control.

[0036] FIG. 9A is a bar graph illustrating the impact of LNPs functionalized with example glycolipids on IL- iβ secretion.

[0037] FIG. 9B is a bar graph illustrating the impact of LNPs functionalized with example glycolipids on IL-6 secretion.

[0038] FIG. 9C is a bar graph illustrating the impact of LNPs functionalized with example glycolipids on TNF-a secretion.

[0039] FIG. 10A is a bar graph illustrating the impact of LNPs functionalized with example glycolipids on the body weight of mice relative to control.

[0040] FIG. 10B illustrates in vivo bioluminescence imaging of mice after intramuscular injection of LNPs functionalized with example glycolipids relative to control.

[0041] FIG. 10C is a bar graph illustrating the bioluminescence signal intensities in the liver and the muscle injection site of mice relative to control. FIG. 11 illustrates the immunization and analysis schedule for in vivo mouse immunogenicity study.

[0042] FIG. 12A is a bar graph illustrating humoral immune responses in mice 7 days before delivery of first injection of LNPs functionalized with example glycolipids relative to control.

[0043] FIG. 12B are bar graphs illustrating humoral immune responses induced in mice 14 days after delivery of first injection of LNPs functionalized with example glycolipids relative to control and 7 days after delivery of second injection (day 28) of LNPs functionalized with example glycolipids relative to control.

[0044] FIG. 13A is a bar graph illustrating the impact of LNPs functionalized with example glycolipids on IFNy secretion by splenocytes relative to control.

[0045] FIG. 13B are bar graphs illustrating the impact of LNPs functionalized with example glycolipids on IFNy, TNF-D, and IL-2 secretion by T cells relative to control.

[0046] Detailed Description of Certain Embodiments

[0047] The present disclosure provides, among other things, compositions comprising particles that are useful for the delivery of therapeutics agents, such as nucleic acids, that overcome certain deficiencies associated with previous compositions.

[0048] Definitions

[0049] Compounds of this disclosure include those described generally above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001 , the entire contents of which are hereby incorporated by reference.

[0050] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some cases, Tables 1 -5 (i.e., Tables 1 , 2, 3, 4, 5, as well as tables in the various Examples within) show one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and / or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.

[0051] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0052] About or approximately: As used herein, the term "approximately" or "about," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In general, those skilled in the art, familiar within the context, will appreciate the relevant degree of variance encompassed by "about" or "approximately" in that context. For example, in some embodiments, the term "approximately" or "about" may encompass a range of values that are within (i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, or less of the referred value.

[0053] Administering: As used herein, the term "administering" or "administration" typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some particular embodiments, administration may be intravenous. In some particular embodiments, administration may be subcutaneous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. In some embodiments, administration may comprise a prime-and-boost protocol. A prime-and-boost protocol can include administration of a first dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine) followed by, after an interval of time, administration of a second or subsequent dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine). In the case of an immunogenic composition, a prime-and-boost protocol can result in an increased immune response in a patient.

[0054] Aliphatic: The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point or more than one points of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1 -12 aliphatic carbon atoms. As used herein, it is understood that an aliphatic group can also be bivalent (e.g., encompass a bivalent hydrocarbon chain that is saturated or contains one or more units of unsaturation, such as, for example, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, and so on). In some embodiments, aliphatic groups contain 1 -6 aliphatic carbon atoms (e.g., C1-e). In some embodiments, aliphatic groups contain 1 -5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1 -3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1 -2 aliphatic carbon atoms (e.g., C1-2). In some embodiments, “cycloaliphatic” refers to a monocyclic C3-8hydrocarbon or a bicyclic C7-10hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups and hybrids thereof. A preferred aliphatic group is C1-6alkyl.

[0055] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched chain hydrocarbon group having (unless otherwise specified) 1 -12, 1 -10, 1-8, 1 -6, 1 -4, 1 -3, or 1 -2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0056] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms(e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0057] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3) . Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0058] Analog: As used herein, the term “analog” refers to a substance that shares one or more particular structural features, elements, components, or moieties with a reference substance. Typically, an “analog” shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete ways. In some embodiments, an analog is a substance that can be generated from the reference substance, e.g., by chemical manipulation of the reference substance. In some embodiments, an analog is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference substance. In some embodiments, an analog is or can be generated through performance of a synthetic process different from that used to generate the reference substance.

[0059] Aryl: The term “aryl” refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members (e.g., C5-C14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., C6-C12). The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. In some embodiments, an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused include

[0060] Associated: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level and / or form of one is correlated with that of the other. For example, a particular entity (e.g., polypeptide, genetic signature, metabolite, microbe, etc) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and / or form correlates with incidence of and / or susceptibility to the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and / or remain in physical proximity with one another. In some embodiments, two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof.

[0061] Biological sample: As used herein, the term “biological sample” typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids (e.g., sperm, sweat, tears), secretions, and / or excretions; and / or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or include cells from an individual from whom the sample is obtained. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and / or by adding one or more agents to) a primary sample. For example, filtering using a semi- permeable membrane. Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of certain components, etc.

[0062] Carrier: As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.

[0063] Combination therapy: As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents or modality(ies)). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0064] Comparable'. As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison therebetween so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.

[0065] Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form - e.g., gas, gel, liquid, solid, etc.

[0066] Cycloaliphatic. As used herein, the term “cycloaliphatic” refers to a monocyclic C3-8hydrocarbon or a bicyclic C7-10hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule.

[0067] Cycloalky . As used herein, the term “cycloalkyl” refers to an optionally substituted saturated ring monocyclic or polycyclic system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0068] Deoxyribonucleic Acid (DNA) As used herein, the term “DNA” refers to a polymeric molecule of nucleotides that are typically double-stranded and comprise adenine, cytosine, guanine and thymine, and a deoxyribose sugar backbone structure as specified in the definition “Nucleic Acid / Polynucleotide.” In some embodiments, DNA is linear DNA, plasmid DNA, minicircle DNA, nanoplasmid DNA, doggybone DNA, or a transposon.

[0069] Deoxyribonucleotide: As used herein, the term “deoxyribonucleotide” refers to unmodified and modified deoxyribonucleotides. For example, unmodified deoxyribonucleotides include the purine bases adenine (A) and guanine (G), and the pyrimidine bases cytosine (C) and thymine (T). Modified deoxyribonucleotides may include one or more modifications including, but not limited to, for example, (a) end modifications, e.g., 5' end modifications (e.g., phosphorylation, dephosphorylation, conjugation, inverted linkages, etc.), 3' end modifications (e.g., conjugation, inverted linkages, etc.), (b) base modifications, e.g. , replacement with modified bases, stabilizing bases, destabilizing bases, or bases that base pair with an expanded repertoire of partners, or conjugated bases, (c) sugar modifications (e.g., at the 2' position or 4' position) or replacement of the sugar, and (d) internucleoside linkage modifications, including modification or replacement of the phosphodiester linkages.

[0070] Dosage form or unit dosage form: Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population ( / .e., with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.

[0071] Dosing regimen or therapeutic regimen: Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population ( / .e., is a therapeutic dosing regimen). Excipient: As used herein, the term “excipient” refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0072] Heteroaliphatic'. The term “heteroaliphatic” or “heteroaliphatic group”, as used herein, denotes an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight-chain (i.e., unbranched), branched, or cyclic (“heterocyclic”) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. The term “nitrogen” also includes a substituted nitrogen. Unless otherwise specified, heteroaliphatic groups contain 1-10 carbon atoms wherein 1-3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1-4 carbon atoms, wherein 1-2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroaliphatic groups contain 1-3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups. For example, a 2- to 12-atom heteroaliphatic group includes the following exemplary groups: -O-CH3, -CH2-O-CH3, -O-CH2-CH2-O-CH2-CH2-O-CH3, and the like.

[0073] Heteroaryl: The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 12 ring atoms (e.g., 5- to 6- membered monocyclic heteroaryl or 9- to 12-membered bicyclic heteroaryl); having 6, 10, or 14 ir-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1 ,2-a]pyrimidinyl, imidazo[1 ,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5- c]pyridyl, pyrrolopyridyl, pyrrolopyrazinyl, thienopyrimidinyl, triazolopyridyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 / - / — quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1 ,4-oxazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, and benzoisoxazolyl. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0074] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0075] Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8- membered monocyclic, a 7- to 12-membered bicyclic, or a 10- to 16-membered polycyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+(as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1 ,3- dihydroisobenzof uranyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11 -membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). A bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11 -membered bridged heterocyclic ring having one, two, or three bridging atoms.

[0076] Nanoparticle: As used herein, the term “nanoparticle” refers to a discrete entity of small size, e.g., typically having a longest dimension that is shorter than about 1000 nanometers (nm) and often is shorter than 500 nm, or even 100 nm or less. In many embodiments, a nanoparticle may be characterized by a longest dimension between about 1 nm and about 100 nm, or between about 1 μm and about 500 nm, or between about 1 nm and 1000 nm. In many embodiments, a population of microparticles is characterized by an average size (e.g., longest dimension) that is below about 1000 nm, about 500 nm, about 100 nm, about 50 nm, about 40 nm, about 30 nm, about 20 nm, or about 10 nm and often above about 1 nm. In many embodiments, a microparticle may be substantially spherical (e.g., so that its longest dimension may be its diameter). In some embodiments, a nanoparticle has a diameter of less than 100 nm as defined by the National Institutes of Health. In some embodiments, nanoparticles are micelles in that they comprise an enclosed compartment, separated from the bulk solution by a micellar membrane, typically comprised of amphiphilic entities which surround and enclose a space or compartment (e.g., to define a lumen). In some embodiments, a micellar membrane is comprised of at least one polymer, such as for example a biocompatible and / or biodegradable polymer.

[0077] Nucleic acid / Polynucleotide: As used herein, the term “nucleic acid” refers to a polymer of at least 10 nucleotides or more. In some embodiments, a nucleic acid is or comprises DNA. In some embodiments, a nucleic acid is or comprises RNA. In some embodiments, a nucleic acid is or comprises peptide nucleic acid (PNA). In some embodiments, a nucleic acid is or comprises a single stranded nucleic acid. In some embodiments, a nucleic acid is or comprises a double-stranded nucleic acid. In some embodiments, a nucleic acid comprises both single and double-stranded portions. In some embodiments, a nucleic acid comprises a backbone that comprises one or more phosphodiester linkages. In some embodiments, a nucleic acid comprises a backbone that comprises both phosphodiester and non-phosphodiester linkages. For example, in some embodiments, a nucleic acid may comprise a backbone that comprises one or more phosphorothioate or 5'-N-phosphoramidite linkages and / or one or more peptide bonds, e.g., as in a “peptide nucleic acid”. In some embodiments, a nucleic acid comprises one or more, or all, natural residues (e.g., adenine, cytosine, deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymidine, guanine, thymine, uracil). In some embodiments, a nucleic acid comprises on or more, or all, non-natural residues. In some embodiments, a non-natural residue comprises a nucleoside analog (e.g., 2- aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3 -methyl adenosine, 5- methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5- bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5 -propynyl- cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 6-O-methylguanine, 2-thiocytidine, methylated bases, intercalated bases, and combinations thereof). In some embodiments, a non-natural residue comprises one or more modified sugars (e.g., 2'-fluororibose, ribose, 2'- deoxyribose, arabinose, and hexose) as compared to those in natural residues. In some embodiments, a nucleic acid has a nucleotide sequence that encodes a functional gene product such as an RNA or polypeptide. In some embodiments, a nucleic acid has a nucleotide sequence that comprises one or more introns. In some embodiments, a nucleic acid may be prepared by isolation from a natural source, enzymatic synthesis (e.g., by polymerization based on a complementary template, e.g., in vivo or in vitro, reproduction in a recombinant cell or system, or chemical synthesis. In some embodiments, a nucleic acid is at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11 ,000, 11 ,500, 12,000, 12,500, 13,000,

[0078] 13.500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000,

[0079] 18.500, 19,000, 19,500, or 20,000 or more residues or nucleotides long.

[0080] Nucleic acid particle: A “nucleic acid particle” can be used to deliver nucleic acid to a target site of interest (e.g., cell, tissue, organ, and the like). A nucleic acid particle may be formed from at least one cationic or cationically ionizable lipid or lipid-like material, at least one cationic polymer such as protamine, or a mixture thereof and nucleic acid. Nucleic acid particles include lipid nanoparticle (LNP)-based and lipoplex (LPX)-based formulations.

[0081] Nucleotide: As used herein, the term “nucleotide” refers to its art-recognized meaning. When a number of nucleotides is used as an indication of size, e.g., of a polynucleotide, a certain number of nucleotides refers to the number of nucleotides on a single strand, e.g., of a polynucleotide.

[0082] Parenteral: The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0083] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.

[0084] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0085] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0086] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0087] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations. Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

[0088] Physiological conditions: as used herein, has its art-understood meaning referencing conditions under which cells or organisms live and / or reproduce. In some embodiments, the term refers to conditions of the external or internal mileu that may occur in nature for an organism or cell system. In some embodiments, physiological conditions are those conditions present within the body of a human or non-human animal, especially those conditions present at and / or within a surgical site. Physiological conditions typically include, e.g., a temperature range of 20 - 40°C, atmospheric pressure of 1 , pH of 6-8, glucose concentration of 1 -20 mM, oxygen concentration at atmospheric levels, and gravity as it is encountered on earth. In some embodiments, conditions in a laboratory are manipulated and / or maintained at physiologic conditions. In some embodiments, physiological conditions are encountered in an organism.

[0089] Polycyclic: As used herein, the term “polycyclic” refers to a saturated or unsaturated ring system having two or more rings (for example, heterocyclyl rings, heteroaryl rings, cycloalkyl rings, or aryl rings), having between 7 and 20 atoms, in which one or more carbon atoms are common to two adjacent rings. For example, in some embodiments, a polycyclic ring system refers to a saturated or unsaturated ring system having three or more rings (for example, heterocyclyl rings, heteroaryl rings, cycloalkyl rings, or aryl rings), having between 14 and 20 atoms, in which one or more carbon atoms are common to two adjacent rings. The rings in a polycyclic ring system may be fused (i.e., bicyclic or tricyclic), spirocyclic, or a combination thereof. An example polycyclic ring is a steroid.

[0090] Polypeptide: The term “polypeptide”, as used herein, typically has its art-recognized meaning of a polymer of at least three amino acids or more. Those of ordinary skill in the art will appreciate that the term “polypeptide” is intended to be sufficiently general as to encompass not only polypeptides having a complete sequence recited herein, but also to encompass polypeptides that represent functional, biologically active, or characteristic fragments, portions or domains (e.g., fragments, portions, or domains retaining at least one activity) of such complete polypeptides. In some embodiments, polypeptides may contain L-amino acids, D-amino acids, or both and / or may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, e.g., terminal acetylation, amidation, methylation, etc. In some embodiments, polypeptides may comprise natural amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof (e.g., may be or comprise peptidomimetics). Prevent or prevention: As used herein, the terms “prevent” or “prevention”, when used in connection with the occurrence of a disease, disorder, and / or condition, refer to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0091] Reference: As used herein describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0092] Ribonucleotide: As used herein, the term “ribonucleotide” encompasses unmodified ribonucleotides and modified ribonucleotides. For example, unmodified ribonucleotides include the purine bases adenine (A) and guanine (G), and the pyrimidine bases cytosine (C) and uracil (U). Modified ribonucleotides may include one or more modifications including, but not limited to, for example, (a) end modifications, e.g., 5' end modifications (e.g., phosphorylation, dephosphorylation, conjugation, inverted linkages, etc.), 3' end modifications (e.g., conjugation, inverted linkages, etc.), (b) base modifications, e.g. , replacement with modified bases, stabilizing bases, destabilizing bases, or bases that base pair with an expanded repertoire of partners, or conjugated bases, (c) sugar modifications (e.g., at the 2' position or 4' position) or replacement of the sugar, and (d) internucleoside linkage modifications, including modification or replacement of the phosphodiester linkages. The term “ribonucleotide” also encompasses ribonucleotide triphosphates including modified and non-modified ribonucleotide triphosphates. Ribonucleic acid (RNA): As used herein, the term “RNA” refers to a polymer of ribonucleotides. In some embodiments, an RNA is single stranded. In some embodiments, an RNA is double stranded. In some embodiments, an RNA comprises both single and double stranded portions. In some embodiments, an RNA can comprise a backbone structure as described in the definition of “Nucleic acid / Polynucleotide" above. An RNA can be a regulatory RNA (e.g., siRNA, microRNA, etc.), or a messenger RNA (mRNA). In some embodiments where an RNA is a mRNA. In some embodiments where an RNA is a mRNA, a RNA typically comprises at its 3’ end a poly(A) region. In some embodiments where an RNA is a mRNA, an RNA typically comprises at its 5’ end an art-recognized cap structure, e.g., for recognizing and attachment of a mRNA to a ribosome to initiate translation. In some embodiments, a RNA is a synthetic RNA. Synthetic RNAs include RNAs that are synthesized in vitro (e.g., by enzymatic synthesis methods and / or by chemical synthesis methods).

[0093] Sample: As used herein, the term “sample” typically refers to an aliquot of material obtained or derived from a source of interest. In some embodiments, a source of interest is a biological or environmental source. In some embodiments, a source of interest may be or comprise a cell, tissue, or organism, such as a microbe, a plant, or an animal (e.g., a human). In some embodiments, a source of interest is or comprises biological tissue or fluid. In some embodiments, a source of interest may be or comprise a preparation generated in a production run. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and / or by adding one or more agents to) a primary sample.

[0094] Saccharide: In some embodiments, a glycolipid compound comprises one or more saccharide units. As described herein, a saccharide refers to a carbohydrate having one or more sugar residues. For example, a “monosaccharide” (one saccharide ring, example monosaccharides ring include glucose, fructose, and galactose), a “disaccharide” (two saccharide rings connected to each other either directly or a linking atom, examples of disaccharides include lactose, maltose, and sucrose), a “trisaccharide” (three saccharide rings connected to each other either directly or via a linking atom, an example of a trisaccharide is mannose), an “oligosaccharide” (a carbohydrate chain containing between 3 and 10 single sugar residues; example oligosaccharides include raffinose, stachyose, and verbascose) or a “polysaccharide” (a chain of 10 or more carhobydrate molecules). In some embodiments, a glycolipid compound can comprise a derivative of a saccharide. Examples of the derivative of saccharides include oxides such as saccharic acid; reduced products such as sugar alcohol; and modified products such as amino sugar, etherified sugar, halogenated sugar, and phosphorylated sugar. In some embodiments, saccharides or derivatives thereof, are referred to as “sugar(s)”.

[0095] As described herein, “monosaccharide” refers to a monomeric carbohydrate structural unit having a formula (CH2O)x, where conventionally x > 3. A monosaccharide can be linear or cyclic. Unless otherwise specified, as used herein, a monosaccharide unit is cyclic. Monosaccharides are the building blocks of larger sugar complexes, such as oligosaccharides or polysaccharides. In some embodiments, a monosaccharide is glucose (Glc), galactose (Gal), mannose (Man), fucose, ribose, arabinose, xylose, lixose, erythrose, furactose, psicose, N-acetyl glucosamine (GalNAc), N-acetylneuraminic acid (Neu Ac), or derivatives thereof.

[0096] As described herein, a “disaccharide” refers to a sugar complex which comprises two monosaccharide units bonded together by glycosidic linkage. Examples of disaccharides include sucrose, lactose, maltose, trehalose, lactulose, cellobiose, chitobiose, a,a’-trehalose, a-(1 →6)-mannobiose, and a-(1 →2)-mannobiose, lactose, and derivatives thereof.

[0097] As used herein, a “trisaccharide” is a sugar complex which comprises three monosaccharide units bonded together by glycosidic linkage. An example of a trisaccharide includes D-mannopyranosyl-a-(1 →3)-[(D-mannopyranosyl-a-(1 →6)]-D- mannopyranose (“Man3” or “TriMan”), cellotriose, maltotriose, a-(1 →6)-mannotriose, a- (1 →2)-mannotriose, and derivatives thereof.

[0098] As described herein, “oligosaccharide” refers to a saccharide in which 3 to 10 monosaccharides are linked together. In some embodiment, an oligosaccharide comprises a trisaccharide (i.e., three monosaccharide units linked together by glycosidic linkage). Examples of oligosaccharides include sucrose, trehalose, maltose, cellobiose, gentiobiose, isomaltose, nigerose, sophorose, kojibiose, turanose, lactose, xylobiose, maltooligosaccharide, isomaltooligosaccharide, xylooligosaccharide, cyclodextrin, or a derivative thereof.

[0099] Substituted or optionally substituted: As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., refers to at least ; and refers to at least or Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.

[0100] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)0-4R°; -(CH2)0-4OR°; -O(CH2)0-4R°, -O-(CH2)0-4C(O)OR°; -(CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2)0-4Ph, which may be substituted with R°; -(CH2)0-40(CH2)0-1Ph which may be substituted with R°; - CH=CHPh, which may be substituted with R°; -(CH2)0-4O(CH2)0-1-pyridyl which may be substituted with R°; -N02; -CN; -N3; (CH2)0-4N(Ro)2; -(CH2)0-4N(R°)C(O)R°; - N(R°)C(S)R°; -(CH2)0-4N(R°)C(O)NR°2; N(R°)C(S)NR°2; -(CH2)0-4N(R°)C(O)OR°; - N(R°)N(R°)C(O)R°; N(R°)N(R°)C(O)NR°2; N(R°)N(R°)C(O)OR°; -(CH2 4C(O)R°; C(S)R°; -(CH2)0-4C(O)OR°; -(CH2)0-4C(O)SR°; (CH2)0-4C(O)OSiRo3; -(CH2 4OC(O)R°; -OC(O)(CH2)0-4SR°; -(CH2)(4SC(O)R°; -(CH2)0-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; - SC(S)SR°, (CH2)(4OC(O)NR°2; C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; - C(NOR°)R°; (CH2)(K4SSR°; -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2OR°; -(CH2)(MOS(O)2R°; -S(O)2NR°2; (CH2)0-4S(O)R°; N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; - C(NH)NR°2; -P(O)2R°; P(O)R°2; OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C1-4straight or branched alkylene)O-N(R°)2; or -(C1-4straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6aliphatic, -CH2Ph, -O(CH2)0-1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. In some embodiments, an optional substituent is a tag, as that term is defined herein.

[0101] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, - (CH2)0-2R●, -(haloR●), -(CH2)0-2OH, -(CH2)0-2OR●, -(CH2)0-2CH(OR●)2, O(haloR’), - CN, -N3, -(CH2)0-2C(O)R●, -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR●, -(CH2)O-2SR●, - (CH2)Q-2SH, -(CH2)Q-2NH2, -(CH2)0-2NHR●, -(CH2)(P2NR●2, -NO2, -SiR●3, -OSiR●3, C(O)SR●- (C1-4straight or branched alkylene) C(O)OR●, or -SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0102] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O (“oxo”), =S, =NNR‘2, =NNHC(O)R‘, =NNHC(O)OR‘, =NNHS(O)2R‘, =NR‘, =NOR‘, -O(C(R‘2))2-3O-, or -S(C(R’2))2-3S-, wherein each independent occurrence of R‘ is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR‘2)2-3O- wherein each independent occurrence of R‘ is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0103] Suitable substituents on the aliphatic group of R* include halogen, -R●, (haloR●), OH, - OR●, -O(haloR’), -ON, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2, or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0104] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R+, -NR*2, -C(O)R+, -C(O)OR+, -C(O)C(O)R+, -C(O)CH2C(O)R+, S(O)2R+, S(O)2NR+2, -C(S)NR+2, -C(NH)NR+2, or -N(R+)S(O)2R+; wherein each R+is independently hydrogen, C1-6aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R+, taken together with their intervening atom(s) form an unsubstituted 3- to 12- membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable substituents on the aliphatic group of R+are independently halogen, -R●, (haloR●), -OH, -OR●, -O(haloR●), -ON, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2, or NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, -CH2Ph, -0(CH2)0-1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0105] Small molecule: As used herein, the term “small molecule” means a low molecular weight organic and / or inorganic compound. In general, a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, a small molecule is not a polymer.

[0106] Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain small molecule compounds described herein, including, for example, glycolipid compounds described herein, may be provided and / or utilized in any of a variety of forms such as, for example, crystal forms (e.g., polymorphs, solvates, etc), salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0107] Those of ordinary skill in the art will appreciate that certain small molecule compounds (e.g., glycolipid compounds described herein) have structures that can exist in one or more steroisomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.

[0108] Those of skill in the art will appreciate that certain small molecule compounds (e.g., glycolipid compounds described herein) have structures that can exist in one or more tautomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.

[0109] Those of skill in the art will appreciate that certain small molecule compounds (e.g., glycolipid compounds described herein) have structures that permit isotopic substitution (e.g.,2H or3H for H;11C,13C or14C for12C;13N or15N for14N;17O or18O for16O;36CI for35CI or37CI;18F for19F;1311 for127l; etc.). In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.

[0110] In some embodiments, reference to a particular small molecule compound (e.g., glycolipid compounds described herein) may relate to a specific form of that compound. In some embodiments, a particular small molecule compound may be provided and / or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0111] In some embodiments, where a small molecule compound is one that exists or is found in nature, that compound may be provided and / or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature. Those of ordinary skill in the art will appreciate that, in some embodiments, a preparation of a particular small molecule compound (e.g., an glycolipid compound described herein) that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of the preparation including, for example, another form of the compound) amount of the compound or form that is present in a reference preparation of interest (e.g., in a primary sample from a source of interest such as a biological or environmental source) is distinct from the compound as it exists in the reference preparation or source. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.

[0112] Those skilled in the art will further appreciate that, in small molecule structures, the symbol , as used herein, refers to a point of attachment between two atoms.

[0113] Subject: As used herein, the term “subject” refers an organism, typically a mammal (e.g., a human, in some embodiments including prenatal human forms). In some embodiments, a subject is suffering from a relevant disease, disorder or condition. In some embodiments, a subject is susceptible to a disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered.

[0114] Tag As used herein, the term “tag” refers to a molecule capable of detecting a target analyte. The tag can comprise, but is not limited to, a fluorescent molecule, chemiluminescent molecule, chromophore, enzyme, enzyme substrate, enzyme cofactor, enzyme inhibitor, dye, metal ion, metal sol, ligand (e.g., biotin, avidin, streptavidin or haptens), radioactive isotope, and the like. In some embodiments, the tag is a fluorescent label. A fluorescent label is also called a “fluorescent tag” or a “fluorophore”.

[0115] A fluorophore is a molecule that absorbs light (i.e., excites) at a characteristic wavelength and emits light (i.e. fluoresces and emits a signal) at a second lower-energy wavelength. The detectable agent may include, but is not limited to, one or more of the following fluorescent groups: coumarin, dansyl chloride, fluorescein, fluorescein isothiocyanate (FITC), tetrachlorofluorescein, hexachlorofluorescein, rhodamine, tetramethylrhodamine, tetramethylrhodamine isothiocyanate (TRITC), cyanine- derivative dyes, Texas Red, nitrobenz-2-oxa-1 ,3-diazol-4-yl (NBD), Bodipy, and Alexa dyes. Examples of certain fluorophores are listed at https: / / www.thermofisher.com / us / en / home / life-science / cell-analysis / fluorophores.html which is incorporated by reference herein.

[0116] In some embodiments, a fluorescent tag is . In some embodiments, a fluorescent tag is . In some embodiments, a fluorescent tag is

[0117] Therapeutic agent: As used herein, the phrase “therapeutic agent” in general refers to any agent that elicits a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, an appropriate population may be defined by various criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, etc. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. In some embodiments, a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans. In some embodiments, a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans.

[0118] Therapeutically effective amount: As used herein, is meant an amount that produces the desired effect for which it is administered. In some embodiments, the term refers to an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, and / or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence and / or severity of, and / or delays onset of, one or more symptoms of the disease, disorder, and / or condition. Those of ordinary skill in the art will appreciate that the term "therapeutically effective amount’ does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. In some embodiments, reference to a therapeutically effective amount may be a reference to an amount as measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). Those of ordinary skill in the art will appreciate that, in some embodiments, a therapeutically effective amount of a particular agent or therapy may be formulated and / or administered in a single dose. In some embodiments, a therapeutically effective agent may be formulated and / or administered in a plurality of doses, for example, as part of a dosing regimen.

[0119] Treat: As used herein, the terms “treat,” “treatment,” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0120] Glycolipid Compounds

[0121] The present disclosure provides, among other things, particles comprising particular glycolipid compounds. Said glycolipid compounds comprise carbohydrate moieties, an optional stealth moiety (e.g., a polymer-linked moiety), and a hydrophobic region, referred to as a lipid tail. The glycolipid compounds of the present disclosure can be incorporated into particle such as lipid nanoparticles (LNPs) or lipoplexes (LPXs) and used for the delivery of, among other things, nucleic acids such as RNA and DNA. In some embodiments, glycolipids of the present disclosure are useful in targeting certain C-type lectins, such as CD206 (Macrophage Mannose Receptor; MMR), CD209 (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin; DC- SIGN), CD301 (Macrophage Galactose-type C-type Lectin; MGL), and the like, which are expressed on the surface of antigen-presenting cells.

[0122] The present disclosure, provides, among other things, compositions comprising a compound that is glycolipid represented by formula I:

[0123] G1-G2-G3

[0124] I or a pharmaceutically acceptable salt thereof, wherein

[0125] G1is a glycodendron or a carbohydrate moiety;

[0126] G2is a polymer-linker moiety comprising units selected from ethylene glycol, 2-(2-(2- aminoethoxy)ethoxy)acetic acid, and sarcoosine, or is an optionally substituted C2-C175aliphatic group wherein one or more carbons are optionally and independently replaced by -Gy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, - N(RZ)C(O)N(RZ)-, -OC(O)O-, -O-, -S-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1 -3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1 -4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted Ce- C12aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20aliphatic, or C3-C12cycloaliphatic; and

[0127] G3is a lipid or phospholipid tail.

[0128] As described herein, G1is a glycodendron or a carbohydrate moiety. A glycodendron moiety, as used herein, refers to a branched moiety that comprises one or more carbohydrate rings. For example, in some embodiments, a glycodendron moiety is represented by formula I’: wherein: G4is C or N each G5is independently selected from optionally substituted C1-C6aliphatic and optionally substituted 2- to 12-membered heteroaliphatic, wherein one or more carbons of a heteroaliphatic group are optionally and independently replaced by phenyl; each G6is a monosaccharide, a disaccharide, a trisaccharide, or an oligosaccharide; and x3is 1 or 2.

[0129] In some embodiments, a glycodendron moiety is represented by formula I”: wherein:

[0130] G4is C or N each G5is independently selected from optionally substituted C1-C6aliphatic and optionally substituted 2- to 12-membered heteroaliphatic, wherein one or more carbon atoms of a heteroaliphatic group are optionally and independently replaced by phenyl; each G6is a monosaccharide, a disaccharide, a trisaccharide, or an oligosaccharide; and x3is 1 or 2.

[0131] In some embodiments, G4is C. It is understood that when G4is C, and x3is 1 , then G4further comprises a hydrogen atom (i.e., G4is CH), such that G4provides a chemically stable moiety. In some embodiments, G4is N. It is understood that when G4is N, x3is 1 (i.e., is not 2), and G5is selected from C2-C6aliphatic and optionally substituted 2- to 12-membered heteroaliphatic to thereby provide a chemically stable moiety.

[0132] As described herein, G5is, at each instance, selected from optionally substituted C1-C6aliphatic and optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, G5is optionally substituted C1-C6aliphatic. In some embodiments, G5is optionally substituted C1-C6alkylene. In some embodiments, G5is optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, G5is optionally substituted

[0133] 2- to 6- membered heteroaliphatic. In some embodiments, G5is: where * represents a point of attachment to G4. In some embodiments, G5is: where * represents a point of attachment to G4.

[0134] As described herein, G6is, at each instance, a monosaccharide, a disaccharide, a trisaccharide, or an oligosaccharide. In some embodiments, G6is a monosaccharide. In some embodiments, G6is a monosaccharide selected from N-acetylgalactosamine (GalNAc), mannose (Man), fucose (Fuc), glucose (Glc) and galactose (Gal). In some embodiments, G6is a disaccharide. In some embodiments, G6is a disaccharide wherein the disaccharide comprises monosaccharide units selected from: N-acetylgalactosamine (GalNAc), mannose (Man), fucose (Fuc), glucose (Glc), and galactose (Gal). In some embodiments, G6is a trisaccharide. In some embodiments, G6is a trisaccharide wherein the trisaccharide comprises monosaccharide units selected from: N-acetylgalactosamine (GalNAc), mannose (Man), fucose (Fuc), glucose (Glc), and galactose (Gal). In some embodiments, G6is D-mannopyranosyl-a-(1 →3)-[(D-mannopyranosyl-a-(1 →6)]-D- mannopyranose (Man3or TriMan).

[0135] In some embodiments, G1is a carbohydrate moiety. In some embodiments, a carbohydrate moiety is a monosaccharide, a disaccharide, a trisaccharide, or an oligosaccharide. In some embodiments, G1is a monosaccharide. In some embodiments, G1is a monosaccharide selected from N-acetylgalactosamine (GalNAc), mannose (Man), fucose (Fuc), glucose (Glc) and galactose (Gal). In some embodiments, G1is a disaccharide. In some embodiments, G1is a disaccharide wherein the disaccharide comprises monosaccharide units selected from: N-acetylgalactosamine (GalNAc), mannose (Man), fucose (Fuc), glucose (Glc), and galactose (Gal). In some embodiments, G1is a trisaccharide. In some embodiments, G1is a trisaccharide wherein the trisaccharide comprises monosaccharide units selected from: N-acetylgalactosamine (GalNAc), mannose (Man), fucose (Fuc), glucose (Glc), and galactose (Gal). In some embodiments, G1is D-mannopyranosyl-a-(1 →3)-[(D-mannopyranosyl-a-(1 →6)]-D- mannopyranose (Man3or TriMan).

[0136] In some embodiments, G2is a polymer-linker moiety comprising units selected from ethylene glycol, 2-(2-(2-aminoethoxy)ethoxy)acetic acid, and sarcoosine, or is an optionally substituted C2-C100aliphatic group wherein one or more carbons are optionally and independently replaced by -Gy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, - OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1 -3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1 -4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted Ce- C12aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20aliphatic, or C3-C12cycloaliphatic.

[0137] As described herein, G3is a lipid or phospholipid. In some embodiments, G3is a lipid. In some embodiments, G3is an aliphatic lipid. An aliphatic lipid, as used herein, refers to a moiety that is hydrophobic and comprises a long-chain (e.g., 12 or more carbon atoms), saturated or unsaturated, linear or branched, acyclic, cyclic, or polycyclic hydrocarbons, alcohols, aldehydes, amides, esters, or carboxylic acids. In some embodiments, G3is an aliphatic lipid comprising optionally substituted C12-C50 aliphatic. In some embodiments, G3is optionally substituted C12-C50 straight chain aliphatic. In some embodiments, G3is optionally substituted C12-C50 branched aliphatic. In some embodiments, G3is optionally substituted C12-C20alkyl. In some embodiments, G3is an aliphatic lipid comprising optionally substituted C12-C50 aliphatic, wherein one or more carbons are optionally and independently replaced by -NH-. In some embodiments, G3is optionally substituted C12-C50 branched aliphatic, wherein one or more carbons are optionally and independently replaced by -NH-. In some embodiments, G3is optionally substituted C12-C20branched aliphatic, wherein one or more carbons are optionally and independently replaced by -NH-. In some embodiments, G3is selected from:

[0138]

[0139] In some embodiments, G3is a phospholipid. In some embodiments, G3is a phospholipid comprising an aliphatic lipid moiety and a phosphate (PO3OH) group. In some embodiments, a G3is a phospholipid selected from 1 ,2-DiOleyl-sn-glycero-3- PhosphoEthanolamine (DOPE) and 1 ,2-DiStearoyl-sn-glycero-3-PhosphoEthanolamine (DSPE).

[0140] In some embodiments, the present disclosure provides a particle comprising one or more glycolipids and a nucleic acid, wherein the one or more glycolipids are represented by formula II:

[0141] R1is -A, -M1-M2-A, or -M3-N(-M1-M2-A)2;

[0142] R2is -H, -A, -M1-M2-A, or -M3-N(-M1-M2-A)2; each M1is independently an optionally substituted C2-C12aliphatic or 2- to 12-membered heteroaliphatic; each M2is independently -NHC(S)NH-, -NHS(O)2-, -NHC(O)-, -C(O)NH-, -C(O)O-, or - 00(O)-; each M3is independently an optionally substituted C2-C12aliphatic or 2- to 12-membered heteroaliphatic;

[0143] A is -A1-X-A2; each A1is, independently, at each instance, a bond, optionally substituted C2-C12aliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 12- membered heterocycle, or optionally substituted 5- to 12-membered heteroaryl; each X is independently a bond, -(CH2)I-6-, -NH-, -S-, -S(O)2-, or -O-; each A2is independently a monosaccharide, a disaccharide, an oligosaccharide, a fluorescent tag, or a moiety of formula J: wherein at least one instance of A2is a monosaccharide, a disaccharide, an oligosaccharide, or a moiety of formula J; each of R3, R4, and R5is each independently at each occurrence a monosaccharide, a disaccharide, or an oligosaccharide; each of X’ is independently, at each occurrence, a bond, -Cy’-O-, -O-Cy’-, -NH-, -S-, - S(O)2-, or -O-, wherein each Cy’ is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1 -4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted C6-C12aryl; each A3is independently, at each occurrence, a bond, optionally substituted C2-C12aliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 12- membered heterocycle, or optionally substituted 5- to 12-membered heteroaryl;

[0144] M4is optionally substituted C2-Ce aliphatic-NHC(S)NH-, or optionally substituted 2- to 12- membered heteroaliphatic-NHC(S)NH-;

[0145] L is a polymeric moiety that comprises monomers of ethylene glycol, sarcosine, 2-(2-(2- aminoethoxy)ethoxy)acetic acid, or a combination thereof, a bond, or L is an optionally substituted C20-C10o aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, - OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1 -3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1 -4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted C&- C12aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20aliphatic, or C3-C12cycloaliphatic;

[0146] M5is a bond, -OC(O)NH-, -NHC(O)O-, -NHC(O)-, -C(O)-NH-, -C1-C6aliphatic-C(O)NH-, or -NHC(O)-C1-C6aliphatic;

[0147] T is optionally substituted C10-C20aliphatic, or a moiety of formula B or B”: each R7is independently -(CH2)X2-M6-R8; each M6is independently a bond, -OC(O)-, -C(O)O-, -C(O)-, -C(S)-, -NHC(O)-, - C(O)NH-, -S-, -S-S-, and -S(O)2-; each R8is optionally substituted C10-C20aliphatic or 10- to 20-membered heteroaliphatic; n is 0 or 1 ; x1 is an integer selected from 1 to 6; and each x2 is independently selected from 0, 1 , and 2.

[0148] As described herein, in some embodiments, a compound represented by formula I is a compound represented by formula II. In some embodiments, G1in formula I corresponds to a moiety: as it is described with respect to formula II. In some embodiments, G2in formula I corresponds to a moiety L as it is described with respect to formula II. In some embodiments, G3in formula I corresponds to a moiety T as it is described with respect to formula II.

[0149] As described herein the present application provides a compound of formula II:

[0150] Said compounds of formula II represent new glycolipid compounds useful for, among other things, forming complexes for targeted delivery of therapeutic agents, such as nucleic acids, including various forms of ribonucleic acid. The presently provided compounds represent improvements over previous lipids for similar use, in that the presently claimed compound exhibit reduced inflammatory response, and further can be used to target of particular features on cells, such as antigen presenting cells, while also promoting substantially complete RNA encapsulating (i.e., almost no free RNA, that is, greater than 90% of RNA is encapsulated within a particle) with minimal to no RNA degradation. Said particles comprising lipid compounds of formula II exhibit good particle characteristics (e.g., <150 nm in size, <0.3 PDI), and further particles comprising lipid compounds described herein, such as lipid compounds of formula II are found to improve transfection efficiency into cells. Evaluation of particles comprising a lipid compound of formula II is provided in the various Examples reported herein.

[0151] The following embodiments are described with respect to compounds of formula II, and are intended to apply to subgenera of formula II that are also described herein.

[0152] As described herein, R1is -A, -M1-M2-A, -M3-N(-M1-M2-A)2. In some embodiments, R1is -A. In some embodiments, R1is -M1-M2-A. In some embodiments, R1is -M3-N(-M1-M2- A)2.

[0153] As described herein, R2is -H, -A, -M1-M2-A, -M3-N(-M1-M2-A)2. In some embodiments, R2is -A, -M1-M2-A, -M3-N(-M1-M2-A)2. In some embodiments, R2is -A. In some embodiments, R2is -M1-M2-A. In some embodiments, R2is -M3-N(-M1-M2-A)2.

[0154] In some embodiments R1is -A, -M1-M2-A, -M3-N(-M1-M2-A)2, and R2is -A, -M1-M2-A, -M3- N(-M1-M2-A)2. In some embodiments, R1is -A, -M1-M2-A, -M3-N(-M1-M2-A)2, and R2is H. In some embodiments, R1is -A, and R2is H. In some embodiments, R1is -M1-M2-A and R2is H. In some embodiments, R1is -M3-N(-M1-M2-A)2 and R2is H. In some embodiments, R1is -A and R2is -A. In some embodiments, R1is -M1-M2-A and R2is - M1-M2-A. In some embodiments, R1is -M3-N(-M1-M2-A)2 and R2is -M3-N(-M1-M2-A)2.

[0155] As described herein, each A is -A1-X-A2. As described herein, each A1is, independently, at each instance, a bond, optionally substituted C2-C12aliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 12-membered heterocycle, or optionally substituted 5- to 12-membered heteroaryl.

[0156] In some embodiments, A1is a bond.

[0157] In some embodiments, A1is optionally substituted C2-C12aliphatic. In some embodiments, A1is optionally substituted C2-Cealiphatic. In some embodiments, A1is C1- C6alkylene. In some embodiments, A1is methylene, ethylene, propylene, butylene, pentylene, or hexylene.

[0158] In some embodiments, A1is optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, A1is optionally substituted 2- to 6-membered heteroaliphatic.

[0159] In some embodiments, A1is optionally substituted C6-C12aryl. In some embodiments, A1is optionally substituted phenyl. In some embodiments, A1is:

[0160] In some embodiments, A1is optionally substituted C3-C12cycloaliphatic. In some embodiments, A1is optionally substituted C3-C6cycloaliphatic. In some embodiments, A1is optionally substituted C3-C6cycloalkylene. In some embodiments, A1is optionally substituted cycopropylene, cyclobutylene, cyclopentylene, cyclohexylene.

[0161] In some embodiments, A1is 4- to 12-membered heterocycle. In some embodiments, A1is 4- to 6-membered heterocycle. In some embodiments, A1is azetidine, pyrrolidine, or piperidine.

[0162] In some embodiments, A1is 5- to 12-membered heteroaryl. In some embodiments, A1is 5- to 6- membered heteroaryl. In some embodiments, A1is imidazole, pyrrole, pyrazole, pyridine, pyrazine, or pyrimidine.

[0163] As described herein, each X is independently a bond, -(CH2)1 -6- -NH-, -S-, or -O-. In some embodiments, X is -(CH2)1 -6-. In some embodiments, X is -CH2-. In some embodiments, X is -CH2-CH2-. In some embodiments, X is -CH2-CH2-CH2-. In some embodiments, X is -CH2-CH2-CH2-CH2-. In some embodiments, X is -CH2-CH2-CH2- CH2-CH2-. In some embodiments, X is -CH2-CH2-CH2-CH2-CH2-CH2-. In some embodiments, X is a bond. In some embodiments, X is -NH-. In some embodiments, X is -S-. In some embodiments, X is -O-.

[0164] In some embodiments, A1is C6-C12aryl and X is -O-. In some embodiments, A1is phenyl and X is -O-. In some embodiments, A1is C2-C6aliphatic and X is a bond.

[0165] As described herein, each A2is independently a monosaccharide, disaccharide, an oligosaccharide, a fluorescent tag, or a moiety of formula J: wherein at least one instance of A2is a monosaccharide, disaccharide, an oligosaccharide, or a moiety of formula J.

[0166] In some embodiments, A2is a monosaccharide. In some embodiments, A2is a monosaccharide selected from N-acetylgalactosamine (GalNAc), mannose (Man), fucose (Fuc), glucose (Glc) and galactose (Gal). In some embodiments, A2is a disaccharide. In some embodiments, A2is a disaccharide wherein the disaccharide comprises monosaccharide units selected from: N-acetylgalactosamine (GalNAc), mannose (Man), fucose (Fuc), glucose (Glc), and galactose (Gal). In some embodiments, A2is a trisaccharide. In some embodiments, A2is a trisaccharide wherein the trisaccharide comprises monosaccharide units selected from: N-acetylgalactosamine (GalNAc), mannose (Man), fucose (Fuc), glucose (Glc), and galactose (Gal). In some embodiments, A2is D-mannopyranosyl-a-(1 →3)-[(D-mannopyranosyl-a-(1 →6)]-D- mannopyranose (Man3or TriMan).

[0167] In some embodiments, each A2is independently selected from:

[0168]

[0169] In some embodiments, A2is a fluorescent tag. In some embodiments, A2is a dansyl moiety. In some embodiments, A2is:

[0170] In some embodiments, A1-X-A2is: In some embodiments, A2is a moiety of formula J:

[0171] In some embodiments, A1is a bond, X is -CH2-, and A2is a moiety of formula J:

[0172] As described herein, each X’ is independently, at each occurrence, a bond, -Cy’-O-, -O- Cy’-, -NH-, -S-, -S(O)2-, or -O-, wherein each Cy’ is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1 -3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1 -4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted C6-C12aryl. In some embodiments, X’ is a bond. In some embodiments, X’ is -Cy’-O-. In some embodiments, X’ is -O-Cy’-. In some embodiments, X’ is -Cy’-O-, wherein Cy’ is phenyl. In some embodiments, X’ is -O-Cy’-, wherein Cy’ is embodiments, X’ is -NH-. In some emeobidments, X’ is -S-. In some embodiments, X’ is -S(O)2-. In some embodiments, X’ is -O-.

[0173] In some embodiments, each X’ is independently, at each occurrence, a bond, -NH-, -S- , -S(O)2-, or -O-.

[0174] As described herein, each A3is independently, at each occurrence, a bond, optionally substituted C2-C12aliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 12-membered heterocycle, or optionally substituted 5- to 12-membered heteroaryl. In some embodiments, A3is optionally substituted C2-C12aliphatic. In some embodiments, A3is optionally substituted C2-C6aliphatic. In some embodiments, A3is optionally substituted C2-C6alkyl. In some embodiments, A3is optionally substituted 2- to 10 membered heteroaliphatic. In some embodiments, A3is 2- to 5-membered heteroaliphatic comprising one or more sulfur atoms. In some embodiments, A3is twhere * represents a point of attachment to R3, R4, or R5.

[0175] In some embodiments, A3is optionally substituted C6-C12aryl. In some embodiments, A3is optionally substituted C3-C12cycloaliphatic. In some embodiments, A3is optionally substituted 4- to 12-membered heterocycle. In some embodiments, A3is optionally substituted 5- to 12-membered heteroaryl.

[0176] In some embodiments, A3is optionally substituted C2-C6aliphatic or optionally substituted 2- to 6-membed heteroaliphatic. In some embodiments, A3is optionally substituted C2-C6aliphatic and X’ is -S-.

[0177] As described herein, each of R3, R4, and R5is each independently at each occurrence a monosaccharide, a disaccharide, or an oligosaccharide. In some embodiments, R3is a monosaccharide, disaccharide, or an oligosaccharide. In some embodiments, R4is a monosaccharide, disaccharide, or an oligosaccharide. In some embodiments, R5is a monosaccharide, disaccharide, or an oligosaccharide.

[0178] In some embodiments, each of R3, R4, and R5is a monosaccharide, disaccharide, or an oligosaccharide, wherein the oligosaccharide is a trisaccharide.

[0179] In some embodiments, R3, R4, and R5are each a monosaccharide. In some embodiments, R3, R4, and R5are each a disaccharide. In some embodiments, R3, R4, and R5are each an oligosaccharide, wherein the oligosaccharide is a trisaccharide. In some embodiments, R3, R4, and R5are each an oligosaccharide. In some embodiments, R3is a monosaccharide, and R4and R5are each independently a disaccharide, or an oligosaccharide. In some embodiments, R4is a monosaccharide, and R3and R5are each independently a disaccharide, or an oligosaccharide. In some embodiments, R5is a monosaccharide, and R3and R4are each independently a disaccharide, or an oligosaccharide. In some embodiments, R3is a disaccharide, and R4and R5are each independently a monosaccharide, or an oligosaccharide. In some embodiments, R4is a disaccharide, and R3and R5are each independently a monosaccharide, or an oligosaccharide. In some embodiments, R5is a disaccharide, and R3and R4are each independently a monosaccharide, or an oligosaccharide. In some embodiments, R3is an oligosaccharide, and R4and R5are each independently a monosaccharide or a disaccharide. In some embodiments, R4is an oligosaccharide, and R3and R5are each independently a monosaccharide or a disaccharide. In some embodiments, R5is an oligosaccharide, and R3and R4are each independently a monosaccharide or a disaccharide.

[0180] In some embodiments, one or more of R3, R4, and R5is a monosaccharide selected from the group consisting of mannose, galactose, fucose, glucose, N-acetylglucosamine, N- acetylneuraminic acid, and derivatives thereof.

[0181] In some embodiments, one or more of R3, R4, and R5is a disaccharide selected from the group consisting of a,a’-trehalose, sucrose, cellobiose, maltose, a-(1 →6)-mannobiose, a-(1 →2)-mannobiose, lactose and derivatives thereof.

[0182] In some embodiments, one or more of R3, R4, and R5is an oligosaccharide, wherein the oligosaccharide is a trisaccharide selected from D-mannopyranosyl-a-(1 →3)-[(D- mannopyranosyl-a-(1 →6)]-D-mannopyranose (Man3or TriMan), cellotriose, maltotriose, a-(1 →6)-mannotriose, a-(1→2)-mannotriose, and derivatives thereof.

[0183] In some embodiments, one or more of R3, R4, and R5is a branched oligosaccharide comprising from 4 to 9 mannopyranosyl units selected from the family of the High Mannose Oligosaccharide (HMOs)-type oligosaccharides, or a linear oligosaccharide comprising from 4 to 7 monosaccharide units selected form the families of the cello(n)ose-, malto(n)ose-, a-(1→6)-manno(n)ose- and a-(1 →2)-manno(n)ose-type 48ligosaccharides, and derivatives thereof.

[0184] In some embodiments, R3, R4, and R5are each independently selected from:

[0185]

[0186] In some embodiments R3, R4, and R5are each independently selected from:

[0187] In some embodiments R3, R4, and R5are each independently selected from:

[0188] In some embodiments, a moiety of formula J is a moiety of formula J-1 : wherein R3, R4, and R5are as described in classes and subclasses herein.

[0189] In some embodiments, a moiety of formula J is a moiety selected from:

[0190] and

[0191] In some embodiments, a moiety of formula J is a moiety selected from:

[0192]

[0193]

[0194] As described herein, each M1is independently an optionally substituted C2-C12aliphatic or 2- to 12-membered heteroaliphatic. In some embodiments, M1is an optionally substituted C2-C12aliphatic. In some embodiments, M1is an optionally substituted C2- Ce aliphatic. In some embodiments, M1is optionally substituted C2-C6alkyl. In some embodiments, M1is ethylene, propylene, butylene, pentylene, or hexylene.

[0195] As described herein, each M2is independently -NHC(S)NH-, -NHS(O)a-, -NHC(O)-, - C(O)NH-, -C(O)O-, or -OC(O)- In some embodiments, M2is -NHC(S)NH-. In some embodiments, M2is -NHS(O)a-. In some embodiments, M2is -NHC(O)-. In some embodiments, M2is -C(O)NH-. In some embodiments, M2is -C(O)O-. In some embodiments, M2is or -OC(O)-.

[0196] As described herein, each M3is independently an optionally substituted C2-C12aliphatic or optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, M3is optionally substituted C2-C6alkyl. In some embodiments, M3is ethylene, propylene, butylene, pentylene, or hexylene.

[0197] In some embodiments, R1is -M3-N(-M1-M2-A)2, R2is H, each A is -A1-X-A2, one instance of A2is a fluorescent tag, and one instance of A2is a moiety of formula J. In some embodiments, R1is -M3-N(-M1-M2-A)2, R2is H, M3is C1-C6aliphatic, each M1is C1-C6aliphatic, one of M2is -NHC(S)NH-, the other M2is -NHS(O)2-, each A is -A1-X-A2, each A1is a bond, each X is a bond, one instance of A2is a fluorescent tag, and one instance of A2is a moiety of formula J.

[0198] In some embodiments, R1is -M1-M2-A, R2is -M1-M2-A, each A is -A1-X-A2, and each A2is a moiety of formula J. In some embodiments, R1is -M1-M2-A, R2is -M1-M2-A, each M1is C1-C6aliphatic, each M2is -NHC(S)NH-, each A is -A1-X-A2, each A1is a bond, each X is a bond, and each A2is a moiety of formula J.

[0199] In some embodiments, R1is -A, R2is H, where A is A1-X-A2, A1is a bond, X is a bond, and A2is a formula of moiety J.

[0200] In some embodiments, R1is -A, R2is H, where A is A1-X-A2, A1is a phenyl, X is a -O-, and A2is a trisaccharide. In some embodiments, R1is -A, R2is H, where A is A1-X-A2, A1is a phenyl, X is a -O-, and A2is TriMan.

[0201] As described herein, M4is optionally substituted C2-C6aliphatic-NHC(S)NH-, or optionally substituted 2- to 10-membered heteroaliphatic-NHC(S)NH-. In some embodiments, a -NHC(S)NH- moiety of M4is attached to moiety L in formula II. In some embodiments, M4is optionally substituted C2-C6aliphatic-NHC(S)NH-*, where * indicates a point of attachment to moiety L of formula II. In some embodiments, M4is -C1-C6alkylene-NHC(S)NH-.

[0202] In some embodiments, M4is optionally substituted 2- to 10-membered heteroaliphatic- NHC(S)NH-*, where * indicates a point of attachment to moiety L of formula II. In some where * indicates a point of attachment to moiety L.

[0203] As described herein, L is a polymeric moiety that comprises monomers of ethylene glycol, sarcosine, 2-(2-(2-aminoethoxy)ethoxy)acetic acid, a bond, or a combination thereof, or is an optionally substituted C20-C100aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, - C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, -OC(O)O-, -O-, -C(O)-, - OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1 -3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1-4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted C6-C12aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20aliphatic, or C3-C12cycloaliphatic.

[0204] In some embodiments, L is a polymeric moiety that comprises monomers of ethylene glycol, sarcosine, 2-(2-(2-aminoethoxy)ethoxy)acetic acid, or a combination thereof, or is an optionally substituted C20-C100aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1 -4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted C6-C12aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20aliphatic, or C3-C12cycloaliphatic. In some embodiments, L is a polymeric moiety that comprises monomers of ethylene glycol, sarcosine, 2-(2-(2-aminoethoxy)ethoxy)acetic acid. In some embodiments, L is a polymeric moiety that comprises monomers of ethylene glycol, i.e., a monomer having a repeating unit represented by:

[0205] In some embodiments, L is a polymeric moiety that comprises between about 20 and about 100 ethylene glycol monomer units. In some embodiments, L is a polymeric moiety that comprises between about 30 and about 80 ethylene glycol monomer units. In some embodiments, L is a polymeric moiety that comprises between about 40 and about 60 ethylene glycol monomer units. In some embodiments, L is a polymeric moiety that comprises between about 40 and about 50 ethylene glycol monomer units. In some embodiments, L is a polymeric moiety that comprises about 44 ethylene glycol monomer units.

[0206] In some embodiments, L is a polymeric moiety that comprises monomers of sarcosine, i.e., a monomer having a repeating unit represented by formula:

[0207] In some embodiments, L is a polymeric moiety that comprises between about 10 and about 50 sarcosine monomer units. In some embodiments, L is a polymeric moiety that comprises between about 10 and about 40 sarcosine monomer units. In some embodiments, L is a polymeric moiety that comprises between about 15 and about 30 sarcosine monomer units. In some embodiments, L is a polymeric moiety that comprises between about 20 and about 25 sarcosine monomer units. In some embodiments, L is a polymeric moiety that comprises about 22 or 23 sarcosine monomer units.

[0208] In some embodiments, L is a polymeric moiety that comprises monomers of 2-(2-(2- aminoethoxy)ethoxy)acetic acid (“AEEA”), i.e., a monomer having a repeating unit represented by formula:

[0209] In some embodiments, L is a polymeric moiety that comprises between about 5 and about 50 AEEA monomer units. In some embodiments, L is a polymeric moiety that comprises between about 5 and about 40 AEEA monomer units. In some embodiments, L is a polymeric moiety that comprises between about 5 and about 30 AEEA monomer units. In some embodiments, L is a polymeric moiety that comprises between about 5 and about 20 AEEA monomer units. In some embodiments, L is a polymeric moiety that comprises between about 5 and about 10 AEEA monomer units.

[0210] In some embodiments, L is a polymer comprising a combination of monomers of ethylene glycol, sarcosine, and / or AEEA (i.e., is a heteropolymer).

[0211] In some embodiments, L is a bond.

[0212] In some embodiments, L is an optionally substituted C2-C100aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)- , -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, -OC(O)O-, -O-, -C(O)-, - OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1 -3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1-4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted C6-C12aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20aliphatic, or C3-C12cycloaliphatic.

[0213] In some embodiments, L is C2-C10aliphatic. In some embodiments, L is C2-C6alkylene.

[0214] In some embodiments, L is methylene, ethylene, propylene, butylene, pentylene, or hexylene.

[0215] In some embodiments, L is an optionally substituted C2-C100aliphatic group wherein one or more carbons are optionally and independently replaced by -NRZ-, and each Rzis independently H or an optionally substituted group selected from C1-C20aliphatic. In some embodiments, a C1-C20aliphatic group is optionally substituted with a tag. In some embodiments, a C1-C20aliphatic group is optionally substituted with 58 In some embodiments, a C1-C20aliphatic group is optionally substituted some embodiments, a C1-C20aliphatic group is optionally substituted with

[0216] In some embodiments, L is an optionally substituted C20-C100aliphatic group wherein one

[0217] 5 or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)- , -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, -OC(O)O-, -O-, -C(O)-, - OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1 -3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having

[0218] 10 1-4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted C6-C12aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20aliphatic, or C3-C12cycloaliphatic.

[0219] As described herein, M5is a bond, -OC(O)NH-, -NHC(O)O-, -NHC(O)-, -C(O)-NH-, -C1- Ce aliphatic-C(O)NH-, or -NHC(O)-C1-C6aliphatic. In some embodiments, M5is a bond.

[0220] 15 In some embodiments, M5is -OC(O)NH-, -NHC(O)O-, -NHC(O)-, -C(O)-NH-, -C1-C6aliphatic-C(O)NH-, or -NHC(O)-C1-C6aliphatic. In some embodiments, M5is -OC(O)NH- . In some embodiments, M5is -NHC(O)O-. In some embodiments, M5is -NHC(O)-. In some embodiments, M5is -C(O)-NH-. In some embodiments, M5is -C1-C6aliphatic- C(O)NH-. In some embodiments, M5is -NHC(O)-C1-C6aliphatic. In some embodiments,

[0221] 20 M5is -NHC(O)-CH2-CH2-*, where * indicates a point of attachment to T.

[0222] As described herein, T is optionally substituted C10-C20aliphatic, or a moiety of formula B or B”:

[0223] In some embodiments, T is optionally substituted C10-C20aliphatic, or a moiety of formula

[0224] B :

[0225] In some embodiments, T is optionally substituted C10-C20aliphatic. In some embodiments, T is optionally substituted C10-C20straight chained alkyl. In some embodiments, T is:

[0226] In some embodiments, T is a moiety of formula B:

[0227] In some embodiments, T is a moiety of formula B”:

[0228] As described herein, x1 is an integer selected from 1 to 6 (i.e., is 1 , 2, 3, 4, 5, or 6). In some embodiments, x1 is 1 . In some embodiments, x1 is 2. In some embodiments, x1 is 3. In some embodiments, x1 is 4. In some embodiments, x1 is 5. In some embodiments, x1 is 6. As described herein, each R7is -(CH2)X2-M6-R8.

[0229] As described herein, each M6is independently a bond, -OC(O)-, -C(O)O-, -C(O)-, -C(S)- , -NHC(O)-, -C(O)NH-, -S-, -S-S-, and -S(O)2-. In some embodiments, M6is a bond. In some embodiments, M6is -OC(O)-. In some embodiments, M6is -C(O)O-. In some embodiments, M6is -C(O)-. In some embodiments, M6is -C(S)-. In some embodiments, M6is -NHC(O)-. In some embodiments, M6is -C(O)NH-. In some embodiments, M6is - S-. In some embodiments, M6is -S-S-. In some embodiments, M6is -S(O)2-.

[0230] In some embodiments, ch M6is independently -OC(O)-, -C(O)O-, -C(O)-, -C(S)-, - NHC(O)-, -C(O)NH-, -S-, -S-S-, and -S(O)2-.

[0231] As described herein, each x2 is independently selected from 0, 1 , and 2. In some embodiments, x2 is 0. In some embodiments, x2 is 1 . In some embodiments, x2 is 2.

[0232] As described herein, each R8is independently optionally substituted C10-C20aliphatic or 10- to 20-membered heteroaliphatic. In some embodiments, R8is optionally substituted C10-C20aliphatic. In some embodiments, R8is C10-C20straight chain alkyl. In some embodiments, R8is C10-C20straight chain alkenyl. In some embodiments, each R8is independently selected from:

[0233] In some embodiments, each R8is independently selected from:

[0234] In some embodiments, R8is optionally substituted 10- to 20-membered heteroaliphatic. In some embodiments, R7is -CH2-M6-R8. In some embodiments, R7is -M6-R8. In some embodiments, R7is -CH2-OC(O)-R8. In some embodiments, R7is -OC(O)-R8. In some embodiments, one instance of R7is -CH2-OC(O)-R8and the other R7is -OC(O)-R8. In some embodiments, R7is -CH2-OC(O)-C10-C2O aliphatic. In some embodiments, R7is - OC(O)-C10-C20aliphatic. In some embodiments, one instance of R7is-CH2-OC(O)-C10- C20aliphatic, and the other R7is -OC(O)-C10-C20aliphatic.

[0235] In some embodiments, a moiety of formula B is:

[0236] In some embodiments, a moiety of formula B” is:

[0237] .In some embodiments, a moiety of formula B or B” is:

[0238]

[0239] In some embodiments, a compound of formula II is represented by formula 11-1 : or a pharmaceutically acceptable salt thereof, wherein R3, R4, R5, M4, L, M5, and T are as described in classes and subclasses herein.

[0240] In some embodiments, a compound of formula II is represented by formula 11-2: or a pharmaceutically acceptable salt thereof, wherein R3, R4, R5, L, M5, and T are as described in classes and subclasses herein. In some embodiments, a compound of formula II is represented by formula 11-3: or a pharmaceutically acceptable salt thereof, wherein R3, R4, R5, M4, L, M5, and T are as described in classes and subclasses herein.

[0241] In some embodiments, a compound of formula II is represented by formula 11-4: or a pharmaceutically acceptable salt thereof, wherein R3, R4, R5, M4, L, M5, and T are as described in classes and subclasses herein.

[0242] In some embodiments, a compound of formula II is represented by formula 11-5:

[0243] or a pharmaceutically acceptable salt thereof, wherein R3, R4, R5, M4, L, M5, and T are as described in classes and subclasses herein. In some embodiments, a compound of formula II is represented by formula 11-6: or a pharmaceutically acceptable salt thereof, wherein R3, R4, R5, M4, L, M5, and T are as described in classes and subclasses herein. In some embodiments, a compound of formula II is represented by formula 11-7: or a pharmaceutically acceptable salt thereof, wherein A2, L, M5, and T are as described in classes and subclasses herein. In some embodiments, a compound of formula II is represented by formula 111-1 : or a pharmaceutically acceptable salt thereof, wherein R1, R2, M4, n, L, and R7are as described in classes and subclasses herein.

[0244] In some embodiments, a compound of formula II is represented by formula III-2: or a pharmaceutically acceptable salt thereof, wherein R1, R2, M4, n, L, and R8are as described in classes and subclasses herein.

[0245] As described herein, in some embodiments, a compound of formula I is represented by formula IV: or a pharmaceutically acceptable salt thereof, wherein:

[0246] R90is -A or -CH2-A ;

[0247] R100is H, -A’ or -CH2-A”;

[0248] A” is a moiety of formula K:

[0249] K each R110is independently H or optionally substituted C1-C6aliphatic; each A is independently A4-X2-A5; each A4is independently an optionally substituted C1-C6aliphatic, optionally substituted C6-C12aryl, optionally substituted C3-C12cycloaliphatic, 4- to 12-membered heterocycle, or 5- to 12-membered heteroaryl; each X2is independently a bond, -NH-, -S-, or -O-; each A5is independently a monosaccharide, disaccharide, a trisaccharide;

[0250] T’ is optionally substituted C10-C20aliphatic, or a moiety of formula B’: each R120is independently -(CH2)X4-M9-R130; each M9is independently -0C(O)-, -C(O)O-, -C(O)-, -C(S)-, -NHC(O)-, -C(O)NH-, -S-, - S-S-, and -S(O)2-; each R130is independently optionally substituted C10-C20aliphatic or optionally substituted 10- to 20-membered heteroaliphatic; x3 is an integer selected from 1 to 6; each x4 is independently selected from 0, 1 , and 2; and n’ is an integer selected from 5 to 50.

[0251] As described herein with respect to formula IV, R90is -A or -CH2-A In some embodiments, R90is -A’. In some embodiments, R90is -CH2-A

[0252] In some embodiments, R90is -A or -M7-M8-A . In some embodiments, R90is -A’. In some embodiments, R90is -M7-M8-A .

[0253] As described herein with respect to formula IV, R100is H, -A’ or -CH2-A In some embodiments, R100is -A’ or -CH2-A In some embodiments, R100is H. In some embodiments, R100is -A’. In some embodiments -CH2-A

[0254] In some embodiments, R100is H, -A’ or -M7-M8-A . In some embodiments, R100is -A’ or -M7-M8-A . In some embodiments, R100is H. In some embodiments, R100is -A’. In some embodiments R100-M7-M8-A .

[0255] In some embodiments, R90is -A or -CH2-A and R100is H. In some embodiments, R90is -A’ and R100is H. In some embodiments, R90is -CH2-A and R100is H. In some embodiments, R90is -A’ and R100is -A’. In some embodiments, R90is -CH2-A and R100is -A’. In some embodiments, R90is -CH2-A and R100is -CH2-A

[0256] In some embodiments, R90is -A or -M7-M8-A and R100is H. In some embodiments, R90is -A’ and R100is H. In some embodiments, R90is -M7-M8-A and R100is H. In some embodiments, R90is -A’ and R100is -A’. In some embodiments, R90is -M7-M8-A and R100is -A’. In some embodiments, R90is -M7-M8-A and R100is -M7-M8-A .

[0257] As described herein with respect to formula IV, A” is a moiety of formula K:

[0258] In some embodiments, A” is

[0259] As described herein with respect to formula IV, each R110is independently H or optionally substituted C1-C6aliphatic. In some embodiments, R110is H. In some embodiments, R110is C1-C6aliphatic. In some embodiments, R110is C1-C6alkyl. In some embodiments, R110is methyl, ethyl, propyl, butyl, pentyl or hexyl. In some embodiments, R110is -CH3. As described herein with respect to formula IV, each A is independently A4-X2-A5.

[0260] As described herein with respect to formula IV, each A4is independently optionally substituted C1-C6aliphatic, optionally substituted C6-C12aryl, optionally substituted C3- C12cycloaliphatic, 4- to 12-membered heterocycle, or 5- to 12-membered heteroaryl. In some embodiments, A4is optionally substituted C1-C6aliphatic. In some embodiments, A4is optionally substituted C1-C6alkylene.

[0261] In some embodiments, A4is optionally substituted C6-C12aryl. In some embodiments, A4is optionally substituted phenyl. In some embodiments, A4is

[0262] In some embodiments, A4is optionally substituted C3-C12cycloaliphatic. In some embodiments, A4is optionally substituted 4- to 12-membered heterocycle. In some embodiments, A4is optionally substituted 5- to 12-membered heteroaryl.

[0263] In some embodiments, each A4is independently optionally substituted C1-C6aliphatic or optionally substituted C6-C12aryl. In some embodiments, each A4is independently optionally substituted C2-C3aliphatic or

[0264] As described herein with respect to formula IV, each X2is independently a bond, -NH-, -S-, or -O-. In some embodiments, X2is a bond. In some embodiments, X2is -NH-. In some embodiments, X2is -S-. In some embodiments, X2is -O-. In some embodiments, each X2is independently a bond or -O-. In some embodiments, each X2is independently

[0265] -S- or -O-.

[0266] In some embodiments, A4-X2is:

[0267] In some embodiments, A4-X2is:

[0268] As described herein with respect to formula IV, each A5is independently a monosaccharide, disaccharide, a trisaccharide.

[0269] In some embodiments, A5is a monosaccharide. In some embodiments, A5is a monosaccharide selected from N-acetylgalactosamine (GalNAc), mannose (Man), fucose (Fuc), glucose (Glc) and galactose (Gal). In some embodiments, A5is a disaccharide. In some embodiments, A2is a disaccharide wherein the disaccharide comprises monosaccharide units selected from: N-acetylgalactosamine (GalNAc), mannose (Man), fucose (Fuc), glucose (Glc), and galactose (Gal). In some embodiments, A5is a trisaccharide. In some embodiments, A5is a trisaccharide wherein the trisaccharide comprises monosaccharide units selected from: N-acetylgalactosamine (GalNAc), mannose (Man), fucose (Fuc), glucose (Glc), and galactose (Gal). In some embodiments, A5is D-mannopyranosyl-a-(1 →3)-[(D-mannopyranosyl-a-(1 →6)]-D-

[0270] 5 mannopyranose (Man3or TriMan).

[0271] In some embodiments, A5is selected from: In some embodiments, A5is selected from:

[0272] 10

[0273] As described herein with respect to formula IV, T’ is optionally substituted C10-C20aliphatic, or a moiety of formula B’:

[0274] B’ In some embodiments, T’ is optionally substituted C10-C20aliphatic. In some embodiments, T’ is optionally substituted C10-C20straight chained alkyl. In some embodiments, T’ is: ’ is a moiety of formula B’:

[0275] As described herein with respect to formula IV, x3 is an integer selected from 1 to 6 (i.e., is 1 , 2, 3, 4, 5, or 6). In some embodiments, x3 is 1 . In some embodiments, x3 is 2. In some embodiments, x3 is 3. In some embodiments, x3 is 4. In some embodiments, x3 is 5. In some embodiments, x3 is 6.

[0276] As described herein with respect to formula IV, each R120is independently -(CH2)X4-M9- R130.

[0277] As described herein with respect to formula IV, each M9is independently -OC(O)-, - C(O)O-, -C(O)-, -C(S)-, -NHC(O)-, -C(O)NH-, -S-, -S-S-, and -S(O)2-. In some embodiments, M9is -OC(O)-. In some embodiments, M9is -C(O)O-. In some embodiments, M9is -C(O)-. In some embodiments, M9is -C(S)-. In some embodiments, M9is -NHC(O)-. In some embodiments, M9is -C(O)NH-. In some embodiments, M9is - S-. In some embodiments, M9is -S-S-. In some embodiments, M9is -S(O)2-.

[0278] As described herein with respect to formula IV, each x4 is independently selected from 0, 1 , and 2. In some embodiments, x4 is 0. In some embodiments, x4 is 1. In some embodiments, x4 is 2.

[0279] As described herein with respect to formula IV, each R130is independently optionally substituted C10-C20aliphatic or 10- to 20-membered heteroaliphatic. In some embodiments, R130is optionally substituted C10-C20aliphatic. In some embodiments, R130is C10-C20straight chain alkyl. In some embodiments, R8is C10-C20straight chain alkenyl. In some embodiments, R130is:

[0280] In some embodiments, R130is optionally substituted 10- to 20-membered heteroaliphatic. In some embodiments, R120is -CH2-M9-R130. In some embodiments, R120is -M9-R120. In some embodiments, R120is -CH2-OC(O)-R130. In some embodiments, R120is -OC(O)- R130. In some embodiments, one instance of R120is -CH2-OC(O)-R130and the other R120is -OC(O)-R130. In some embodiments, R120is -CH2-OC(O)-C10-C20aliphatic. In some embodiments, R120is -OC(O)-C10-C20aliphatic. In some embodiments, one instance of R120is-CH2-OC(O)-C10-C20aliphatic, and the other R120is -OC(O)-C10-C20aliphatic.

[0281] In some embodiments, a moiety of formula B’ is:

[0282] As described herein with respect to formula IV, n’ is an integer selected from 5 to 50. In some embodiments n’ is an integer selected from 10 to 35. In some embodiments, n’ is an integer selected from 15 to 30. In some embodiments, n’ is an integer selected from 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, or 35. In some embodiments, n’ is 22.

[0283] In some embodiments, a compound of formula I is described in Table 1 . In some embodiments, a compound of formula II is described in Table 2. In some embodiments, a compound of formula IV is described in Table 3.

[0284] Table 1

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315] no

[0316] Table 3

[0317] Particles for Nucleic Acid Delivery

[0318] In some embodiments, particles of the present disclosure comprise a compound of one or more of formulae l-IV, a nucleic acid, and one or more of an cationic lipid, a helper lipid, and a steroid. In some embodiments, a particle described herein comprises a cationic lipid. Electrostatic interactions between positively charged molecules such as cationic lipids and negatively charged nucleic acid are involved in particle formation. This results in complexation and spontaneous formation of nucleic acid particles.

[0319] In some embodiments, particles described herein (e.g., nucleic acid particles, e.g., ribonucleic acid particles) comprise more than one type of nucleic acid molecules, where the molecular parameters of the nucleic acid molecules may be similar or different from each other, like with respect to molar mass or fundamental structural elements such as molecular architecture, capping, coding regions or other features.

[0320] In some embodiments, a nucleic acid particle described herein is a nanoparticle. As used in the present disclosure, “nanoparticle” refers to a particle having an average diameter suitable for parenteral administration and is less than 1000 nm in diameter. In some embodiments, a composition comprising nanoparticles can have an average nanoparticle size (e.g., mean diameter) of about 10 nm to about 500 nm, 30 nm to about 150 nm, about 40 nm to about 150 nm, about 50 nm to about 150 nm, about 60 nm to about 130 nm, about 70 nm to about 110 nm, about 70 nm to about 100 nm, about 70 to about 90 nm, or about 70 nm to about 80 nm. In some embodiments, a composition comprising nanoparticles can have an average nanoparticle size (e.g., mean diameter) of about 50 nm to about 100 nm. In some embodiments, a composition comprising nanoparticles can have an average nanoparticle size (e.g., mean diameter) of about 50 nm to about 150 nm. In some embodiments, a composition comprising nanoparticles can have an average nanoparticle size (e.g., mean diameter) of about 60 nm to about 120 nm. In some embodiments, a composition comprising nanoparticles can have an average nanoparticle size (e.g., mean diameter) of about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, or 150 nm.

[0321] A composition comprising nucleic acid particles (e.g., ribonucleic acid particles) described herein may exhibit a polydispersity index less than about 0.5, less than about 0.4, less than about 0.3, or about 0.2 or less of said nanoparticles. By way of example, a composition comprising nucleic acid particles (e.g., ribonucleic acid particles) described herein can exhibit a polydispersity index in a range of about 0.1 to about 0.3 or about 0.2 to about 0.3. In some embodiments, a composition comprising nucleic acid particles has a PDI that is from about 0.5 to about 1 .

[0322] Nucleic acid particles (e.g., ribonucleic acid particles) described herein can be characterized by an “N / P ratio,” which is the molar ratio of cationic (nitrogen) groups (the “N” in N / P) in the cationic polymer to the anionic (phosphate) groups (the “P” in N / P) in RNA. It is understood that a cationic group is one that is either in cationic form (e.g., N+), or one that is ionizable to become cationic. Use of a single number in an N / P ratio (e.g., an N / P ratio of about 5) is intended to refer to that number over 1 , e.g., an N / P ratio of about 4 is intended to mean about 4:1. In some embodiments, a nucleic acid particle (e.g., a ribonucleic acid particle) described herein has an N / P ratio greater than or equal to 4. In some embodiments, a nucleic acid particle (e.g., a ribonucleic acid particle) described herein has an N / P ratio that is about 4 to about 12. In some embodiments, a nucleic acid particle (e.g., a ribonucleic acid particle) described herein has an N / P ratio that is about 4, 5, 6, 7, 8, 9, 10, 11 , or 12. In some embodiments, an N / P ratio for a nucleic acid particle (e.g., a ribonucleic acid particle) described herein is from about 6.

[0323] Nucleic acid particles (e.g., ribonucleic acid particles) described herein can be prepared using a wide range of methods that may involve obtaining a colloid from at least one cationic or cationically ionizable lipid or lipid-like material and / or at least one cationic polymer and mixing the colloid with nucleic acid to obtain nucleic acid particles. As used herein, an “ionizable” lipid, e.g., a “cationically ionizable” lipid or “ionizable” polymer, e.g., a “cationically ionizable” polyer is a lipid or polymer that may be, in some embodiments, neutral at pH of about 7, but is capable of becoming cationic (i.e., becoming positively charged) at pH of less than about 7 .

[0324] The term “average diameter” or “mean diameter” refers to the mean hydrodynamic diameter of particles as measured by dynamic laser light scattering (DLS) with data analysis using the so-called cumulant algorithm, which provides as results the so-called Z-average with the dimension of a length, and the polydispersity index (PDI), which is dimensionless (Koppel, D., J. Chem. Phys. 57, 1972, pp 4814-4820, ISO 13321 ). Here “average diameter,” “mean diameter,” “diameter,” or “size” for particles is used synonymously with this value of the Z-average. The “polydispersity index” is preferably calculated based on dynamic light scattering measurements by the so-called cumulant analysis as mentioned in the definition of the “average diameter.” Under certain prerequisites, it can be taken as a measure of the size distribution of an ensemble of ribonucleic acid nanoparticles (e.g., ribonucleic acid nanoparticles).

[0325] Different types of nucleic acid particles have been described previously to be suitable for delivery of nucleic acid in particulate form (e.g. Kaczmarek, J. C. et al., 2017, Genome Medicine 9, 60). For non-viral nucleic acid delivery vehicles, nanoparticle encapsulation of nucleic acid physically protects nucleic acid from degradation and, depending on the specific chemistry, can aid in cellular uptake and endosomal escape.

[0326] The present disclosure describes particles comprising nucleic acid, at least one cationic or cationically ionizable lipid or lipid-like material, and / or at least one cationic polymer which associate with the nucleic acid to form nucleic acid particles (e.g., ribonucleic acid particles, e.g., ribonucleic acid nanoparticles) and compositions comprising such particles. The nucleic acid particles (e.g., ribonucleic acid particles, e.g., ribonucleic acid nanoparticles) may comprise nucleic acid which is complexed in different forms by non- covalent interactions to the particle. In some embodiments, the particles described herein are not viral particles, in particular, they are not infectious viral particles, i.e., they are not able to virally infect cells.

[0327] Some embodiments described herein relate to compositions, methods and uses involving more than one, e.g., 2, 3, 4, 5, 6 or even more nucleic acid species.

[0328] In a nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) composition, it is possible that each nucleic acid species is separately formulated as an individual nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) formulation. In that case, each individual nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) formulation will comprise one nucleic acid species. The individual nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) formulations may be present as separate entities, e.g., in separate containers. Such formulations are obtainable by providing each nucleic acid species separately (typically each in the form of a nucleic acid-containing solution) together with a particle-forming agent, thereby allowing the formation of particles. Respective particles will contain exclusively the specific nucleic acid species that is being provided when the particles are formed (individual particulate formulations).

[0329] In some embodiments, a composition such as a pharmaceutical composition comprises more than one individual nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) formulation. Respective pharmaceutical compositions are referred to as “mixed particulate formulations.” Mixed particulate formulations according to the invention are obtainable by forming, separately, individual nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) formulations, as described above, followed by a step of mixing of the individual nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) formulations. By the step of mixing, a formulation comprising a mixed population of nucleic acid-containing particles is obtainable. Individual nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) populations may be together in one container, comprising a mixed population of individual nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) formulations.

[0330] Alternatively, it is possible that different nucleic acid species are formulated together as a “combined particulate formulation.” Such formulations are obtainable by providing a combined formulation (typically combined solution) of different nucleic acid species together with a particle-forming agent, thereby allowing the formation of particles. As opposed to a “mixed particulate formulation,” a “combined particulate formulation” will typically comprise particles that comprise more than one nucleic acid species. In a combined particulate composition different nucleic acid species are typically present together in a single particle.

[0331] In certain embodiments, nucleic acids, when present in provided nucleic acid particles (e.g., ribonucleic acid particles, e.g., lipid nanoparticles, liposomes, lipoplexes, polyplexes) are resistant in aqueous solution to degradation with a nuclease.

[0332] Lipid Nanoparticles

[0333] As described herein, glycolipid compounds described herein can be incorporated into nanoparticles comprising, for example, a cationic lipid, a helper lipid, a steroid, and optionally a polymer-conjugated lipid. Incorporation of a nucleic acid agent into said nanoparticles is referred to herein as a “nucleic acid particle.”

[0334] In some embodiments, nucleic acid particles (e.g., ribonucleic acid particles) are lipid nanoparticles. In some embodiments, lipid nanoparticles are cationic lipid nanoparticles comprising one or more cationic lipids (e.g., ones described herein), a nucleic acid (e.g., RNA) and a steroid. In some embodiments, cationic lipid nanoparticles may comprise at least one cationic lipid, a steroid, and at least one helper lipid. Lipid nanoparticles (LNPs) have proven useful for the delivery of nucleic acid cargo to tissue of interest. LNPs are used, for example, in certain commercial vaccines for treatment of COVID-19. Some LNP formulations, however, cause an inflammatory response in the body, such as an increase of cytokines and interleukins. This inflammatory response is associated with pain, swelling, fever, and the like. LNPs of the present disclosure, however, do not suffer from the same deficiencies associated with previous formulations.

[0335] In some embodiments, LNPs described herein can further comprise additional additives, as described herein. LNPs of the present disclosure can be useful in a variety of contexts. For example, LNPs comprising a nucleic acid (e.g., an RNA) described herein are useful for delivery of said nucleic acid into the cell of a subject. In some embodiments, LNPs comprising a nucleic acid (e.g., an RNA) described herein are useful for causing increased expression of a protein in a subject. In some embodiments, LNPs comprising a nucleic acid (e.g., an RNA) described herein are useful for causing a pharmacological effect induced by expression of a protein in a subject. Lipid nanoparticles described herein are characterized by molar percentage (mol%) of components in the lipid nanoparticle. A mol% used in reference to a lipid component of a lipid nanoparticle is relative to the total other lipid components in the lipid nanoparticle. Cationic Lipids

[0336] As described herein, LNPs of the present disclosure comprise a cationic lipid. A cationic lipid, as described herein, is a lipid that is positively charged or is ionizable, such that the cationic lipid will become positively charged when subjected to particular physiological conditions, e.g., a pH of about 7.4 or less, and can promote lipid aggregation. In some embodiments, a cationic lipid is a lipid comprising one or more amine groups which bear or are capable of bearing (i.e., are ionizable) a positive charge. In some embodiments, a cationic lipid is selected from 1 ,2-dimyristoyl-sn-glycero-3- ethylphosphocholine (DMEPC); 2-dimyristoyl-3-trimethylammonium propane (DMTAP); dioleyl ether phosphatidylcholine (DOEPC); N,N-dioleyl-N,N-dimethylammonium chloride (DODAC); N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA); N,N-distearyl-N,N-dimethylammonium bromide (DDAB); N-(2,3- dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP); 3-(N-(N',N'- dimethylaminoethane)-carbamoyl)cholesterol (DC-Chol), N-(1 -(2,3-dioleoyloxy)propyl)- N-2-(sperminecarboxamido)ethyl)-N,N-dimethylammonium trifluoracetate (DOSPA), dioctadecylamidoglycyl carboxyspermine (DOGS), 1 ,2-dioleoyl-3-dimethylammonium propane (DODAP), N,N-dimethyl-2,3-dioleoyloxy)propylamine (DODMA), and N-(1 ,2- dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethyl ammonium bromide (DMRIE).

[0337] In some embodiments, a cationic lipid is one provided in W02012 / 016184, which is incorporated herein by reference in its entirety. For example, in some embodiments, a cationic lipid is selected from 1 ,2-dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin- DAC), 1 ,2-dilinoleyoxy-3morpholinopropane (DLin-MA), 1 ,2-dilinoleoyl-3- dimethylaminopropane (DLinDAP), 1 ,2-dilinoleylthio-3-dimethylaminopropane (DLin-S- DMA), 1 -linoleoyl-2-linoleyloxy-3dimethylaminopropane (DLin-2-DMAP), 1 ,2- dilinoleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.CI), 1 ,2-dilinoleoyl-3- trimethylaminopropane chloride salt (DLin-TAP.CI), 1 ,2-dilinoleyloxy-3-(N- methylpiperazino)propane (DLin-MPZ), 3-(N,Ndilinoleylamino)-1 ,2-propanediol (DLinAP), 3-(N,N-dioleylamino)-1 ,2-propanediol (DOAP), 1 ,2-dilinoleyloxo-3-(2-N,N- dimethylamino)ethoxypropane (DLin-EG-DMA), and 2,2-dilinoleyl-4- dimethylaminomethyl-[1 ,3]-dioxolane (DLin-K-DMA).

[0338] In some embodiments, a cationic lipid is selected from N,N-dimethyl-2,3- dioleyloxypropylamine (DODMA), 1 ,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), 3-(N-(N',N'-dimethylaminoethane)carbamoyl)cholesterol (DC-Chol), dimethyldioctadecylammonium (DDAB); 1 ,2-dioleoyl-3-trimethylammonium propane (DOTAP); 1 ,2-dioleoyl-3-dimethylammonium-propane (DODAP); 1 ,2-diacyloxy-3- dimethylammonium propanes; 1 ,2-dialkyloxy-3-dimethylammonium propane; dioctadecyldimethyl ammonium chloride (DODAC), 1 ,2-distearyloxy-N,N-dimethyl-3- aminopropane (DSDMA), 2,3-di(tetradecoxy)propyl-(2-hydroxyethyl)-dimethylazanium (DMRIE), 1 ,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (DMEPC), l,2-dimyristoyl-3- trimethylammonium propane (DMTAP), 1 ,2-dioleyloxypropyl-3-dimethyl- hydroxyethylammonium bromide (DORIE), and 2,3-dioleoyloxy-N-[2(spermine carboxamide)ethyl]-N,N-dimethyl-l-propanaminium trifluoroacetate (DOSPA), 1 ,2- dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1 ,2-dilinolenyloxy-N,N- dimethylaminopropane (DLenDMA), dioctadecylamidoglycyl spermine (DOGS), 3- dimethylamino-2-(cholest-5-en-3-beta-oxybutan-4-oxy)-1 -(cis,cis-9,12-oc- tadecadienoxy)propane (CLinDMA), 2-[5'-(cholest-5-en-3-beta-oxy)-3'-oxapentoxy)-3- dimethyl-1-(cis,cis-9',12'-octadecadienoxy)propane (CpLinDMA), N,N-dimethyl-3,4- dioleyloxybenzylamine (DMOBA), 1 ,2-N,N'-dioleylcarbamyl-3-dimethylaminopropane (DOcarbDAP), 2,3-dilinoleoyloxy-N,N-dimethylpropylamine (DLinDAP), 1 ,2-N,N'- Dilinoleylcarbamyl-3-dimethylaminopropane (DLincarbDAP), 1 ,2-dilinoleoylcarbamyl-3- dimethylaminopropane (DLinCDAP), 2,2-dilinoleyl-4-dimethylaminomethyl-[1 ,3]- dioxolane (DLin-K-DMA), 2,2-dilinoleyl-4-dimethylaminoethyl-[1 ,3]-dioxolane (DLin-K- XTC2-DMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1 ,3]-dioxolane (DLin-KC2-DMA), heptatriaconta-6,9,28,31 -tetraen-19-yl-4-(dimethylamino)butanoate (DLin-MC3-DMA), N-(2-Hydroxyethyl)-N,N-dimethyl-2,3-bis(tetradecyloxy)-1-propanaminium bromide (DMRIE), (±)-N-(3-aminopropyl)-N,N-dimethyl-2,3-bis(cis-9-tetradecenyloxy)-1 - propanaminium bromide (GAP-DMORIE), (±)-N-(3-aminopropyl)-N,N-dimethyl-2,3- bis(dodecyloxy)-1 -propanaminium bromide (GAP-DLRIE), (±)-N-(3-aminopropyl)-N,N- dimethyl-2,3-bis(tetradecyloxy)-1 -propanaminium bromide (GAP-DMRIE), N-(2- aminoethyl)-N,N-dimethyl-2,3-bis(tetradecyloxy)-1 -propanaminium bromide (PAE- DMRIE), N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1 -aminium

[0339] (DOBAQ), 2-({8-[(3P)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)- octadeca-9,12-dien-1 -yloxy]propan-1 -amine (octyl-CLinDMA), 1 ,2-dimyristoyl-3- dimethylammonium-propane (DMDAP), 1 ,2-dipalmitoyl-3-dimethylammonium-propane (DPDAP), N1 -[2-((1 S)-1 -[(3-aminopropyl)amino]-4-[di(3-amino- propyl)amino]butylcarboxamido)ethyl]-3,4-di[oleyloxy]-benzamide (MVL5), 1 ,2-dioleoyl- sn-glycero-3-ethylphosphocholine (DOEPC), 2,3-bis(dodecyloxy)-N-(2-hydroxyethyl)- N,N-dimethylpropan-1-amonium bromide (DLRIE), N-(2-aminoethyl)-N,N-dimethyl-2,3- bis(tetradecyloxy)propan-1 -aminium bromide (DMORIE), di((Z)-non-2-en-1 -yl) 8,8'- ((((2(dimethylamino)ethyl)thio)carbonyl)azanediyl)-dioctanoate (ATX), N,N-dimethyl-

[0340] 2,3-bis(dodecyloxy)propan-1 -amine (DLDMA), N,N-dimethyl-2,3- bis(tetradecyloxy)propan-1 -amine (DMDMA), Di((Z)-non-2-en-1 -yl)-9-((4-

[0341] (dimethylaminobutanoyl)-oxy)heptadecanedioate (L319), N-dodecyl-3-((2- dodecylcarbamoyl-ethyl)-{2-[(2-dodecylcarbamoyl-ethyl)-2-{(2-dodecylcarbamoyl- ethyl)-[2-(2-dodecylcarbamoyl-ethylamino)-ethyl]-amino}-ethyl-amino)propionamide (lipidoid 98Ni2-5), 1 -[2-[bis(2-hydroxydodecyl)amino]ethyl-[2-[4-[2-[bis(2 hydroxydodecyl)amino]ethyl]piperazin-1 -yl]ethyl]amino]dodecan-2-ol (lipidoid C12-200), and the following structures (XV-1) to (XV-6):

[0342] In some embodiments, a cationic lipid is one provided WO2021 / 026358,

[0343] W02020 / 219941 , WO2017 / 075531 , WO2016 / 118725, WO2016 / 118724, WO2016 / 176330, WO2017 / 049245, U.S. Pat. No. 9,670,152, each of which is incorporated herein by reference in its entirety.

[0344] In some embodiments, a cationic lipid is one provided in WO 2022 / 081750, which is incorporated herein by reference in its entirety.

[0345] In some embodiments, a cationic lipid is a compound of Formula I*: or a pharmaceutically acceptable salt thereof, wherein: one of L1*or L2*is -OC(O)-, -C(O)O-, -C(O)-, -O-, -S(O)X*-, -S-S-, -C(O)S-, SC(O)-, - NRa*C(O)-, -C(O)NRa*-, -NRa*C(O)NRa*-, -OC(O)NRa*- or -NRa*C(O)O-, and the other of L1*or L2*is -OC(O)-, -C(O)O-, -C(O)-, -O-, -S(O)X*-, -S-S-, -C(O)S-, SC(O)-, -NRa*C(O)-, -C(O)NRa*-, -NRa*C(O)NRa*-, -OC(O)NRa*-, -NRa*C(O)O-, or a direct bond; G1*and G2*are each independently unsubstituted C1-C12alkylene or C1- C12alkenylene;

[0346] G3* is C1-C24alkylene, C1-C24alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene;

[0347] Ra* is H or C1-C12alkyl; R1*and R2*are each independently C6-C24alkyl or C6-C24alkenyl; R3*is H, OR5*, GN, -C(O)OR4*, -OC(O)R4* or - R5*C(O)R4*;

[0348] R4* is C1-C12alkyl;

[0349] R5* is H or C1-C6alkyl; and x* is 0, 1 or 2.

[0350] In some embodiments, one of L1*or L2*is -OC(O)- or -C(O)O-. In some embodiments, each of L1*and L2*is -OC(O)- or -C(O)O-.

[0351] In some embodiments, G1*is C1-C12alkylene. In some embodiments, G2*is C1-C12alkylene. In some embodiments G1*and G2*are each independently C1-C12alkylene. In some embodiments G1*and G2*are each independently C5-C12alkylene.

[0352] In some embodiments, G3* is C1-C24alkylene. In some embodiments, G3* is C1-C6alkylene.

[0353] In some embodiments, R1*and R2*are each independently selected from:

[0354] In some embodiments, R3*is OH.

[0355] In some embodiments, each of L1*and L2*is -OC(O)-, G1*and G2*are each independently C5-C12alkylene, G3*is C1-C6alkylene, R3*is OH, and R1*and R2*are each independently selected from:

[0356] In some embodiments, a cationic lipid is a compound of Formula la* or lb* or a pharmaceutically acceptable salt thereof, where n is an integer from 1 to 15, Ring A* is C3-C8cycloaliphatic, each R6* is independently selected from H, OH, and C1-C24aliphatic, and wherein R1*, R2*, R3*, L1*, L2*, G1*, and G2*are as described in classes and subclasses herein with respect to formula I*, both singly and in combination.

[0357] In some embodiments, a cationic lipid that may be useful in accordance with the present disclosure is an amino lipid comprising a titratable tertiary amino head group linked via ester bonds to at least two saturated alkyl chains, which ester bonds can be hydrolyzed easily to facilitate fast degradation and / or excretion via renal pathways. In some embodiments, such an amino lipid has an apparent pKaof about 6.0-6.5 (e.g., in one embodiment with an apparent pKaof approximately 6.25), resulting in an essentially fully positively charged molecule at an acidic pH (e.g., pH 5). In some embodiments, such an amino lipid, when incorporated in LNP, can confer distinct physicochemical properties that regulate particle formation, cellular uptake, fusogenicity and / or endosomal release of RNA(s). In some embodiments, introduction of an aqueous RNA solution to a lipid mixture comprising such an amino lipid at pH 4.0 can lead to an electrostatic interaction between the negatively charged RNA backbone and the positively charged cationic lipid. Without wishing to be bound by any particular theory, such electrostatic interaction leads to particle formation coincident with efficient encapsulation of RNA drug substance. After RNA encapsulation, adjustment of the pH of the medium surrounding the resulting LNP to a more neutral pH (e.g., pH 7.4) results in neutralization of the surface charge of the LNP. When all other variables are held constant, such charge-neutral particles display longer in vivo circulation lifetimes and better delivery to hepatocytes compared to charged particles, which are rapidly cleared by the reticuloendothelial system. Upon endosomal uptake, the low pH of the endosome renders LNP comprising such an amino lipid fusogenic and allows the release of the RNA into the cytosol of the target cell.

[0358] As described herein, a LNP comprises at least one cationic lipid. In some embodiments, a cationic lipid is selected from Table 4:

[0359] Table 4

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366] or a pharmaceutically acceptable salt thereof. In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated.

[0367] In some embodiments, a cationic lipid is selected from Table 5:

[0368] or a pharmaceutically acceptable salt thereof. In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated. In some embodiments, a cationic lipid is selected from Tables 4 and / or 5.

[0369] In some embodiments, a cationic lipid is selected from DODMA, HY-501 , ALC-0315, ALC366, and SM-102. In some embodiments, a cationic lipid is selected from ALC-0315 and ALC366. In some embodiments, a cationic lipid is ALC-0315. In some embodiments, a cationic lipid is ALC366. In some embodiments, a cationic lipid is SM- 102. In some embodiments, a cationic lipid is DODMA. In some embodiments, a cationic lipid is HY-501 .

[0370] In some embodiments, LNPs of the present disclosure comprise about 30 to about 70 mol% of a cationic lipid relative to the total lipids in the LNP. In some embodiments, an LNP comprises about 35 to about 65 mol% of a cationic lipid. In some embodiments, an LNP comprises about 40 to about 60 mol% of a cationic lipid. In some embodiments, an LNP comprises about 41 to about 49 mol% of a cationic lipid. In some embodiments, an LNP comprises about 48 mol% of a cationic lipid. In some embodiments, an LNP comprises about 50 mol% of a cationic lipid.

[0371] In some embodiments, the cationically ionizable lipid has the structure of Formula (X) or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein: one of L10and L20is -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-,

[0372] -NRaC(=O)-, -C(=O)NRa-, NRaC(=O)NRa-, -OC(=O)NRa- or -NRaC(=O)O-, and the other of L10and L20is -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, NRa'C(=O)NRa'-, -OC(=O)NRa- or -NRaC(=O)O- or a direct bond;

[0373] G1’ and G2' are each independently unsubstituted C1-C12alkylene or C2-12alkenylene;

[0374] G3' is C1-24alkylene, C2-24alkenylene, C3-8cycloalkylene, or C3-8cycloalkenylene;

[0375] Ra' is H or C1-12alkyl;

[0376] R35and R36are each independently C6-24alkyl or C6-24alkenyl;

[0377] R37is H, OR50, CN, -C(=O)OR40, -OC(=O)R40or -NR50C(=O)R40;

[0378] R40is C1-12alkyl;

[0379] R50is H or C1-6alkyl; and x” is O, 1 or 2.

[0380] In some of the foregoing embodiments of Formula (X), the lipid has one of the following structures (XA) or (XB):

[0381] wherein R35’ L10, G1’, G2, L20, R36, R37, and R60are as described in classes and subclasses herein, both singly and in combination;

[0382] A is a 3 to 8-membered cycloalkyl or cycloalkylene group;

[0383] R60is, at each occurrence, independently H, OH or C1-C24alkyl; and n1’ is an integer ranging from 1 to 15.

[0384] In some of the foregoing embodiments of Formula (X), the lipid has structure (XA), and in other embodiments, the lipid has structure (XB).

[0385] In other embodiments of Formula (X), the lipid has one of the following structures (XC)

[0386] (XC) (XD) wherein R35’ L10, G1, G2, L20, R36, R37, and R60are as described in classes and subclasses herein, both singly and in combination; and y’ and z’ are each independently integers ranging from 1 to 12.

[0387] In any of the foregoing embodiments of Formula (X), one of L10and L20is -O(C=O)-. For example, in some embodiments each of L10and L20are -O(C=O)-. In some different embodiments of any of the foregoing, L10and L20are each independently -(C=O)O- or -O(C=O)-. For example, in some embodiments each of L10and L20is -(C=O)O-.

[0388] In some embodiments of Formula (X), the lipid has one of the following structures (XE) or (XF): wherein R35, R36, R37, G1, G2, and G3are as defined in classes and subclasses herein, both singly and in combination.

[0389] In some of the foregoing embodiments of Formula (X), the lipid has one of the following structures (XG), (XH), (XJ), or (XK): wherein R35, R36, R37, R60, y’, z’, n1’, and A are as defined in classes and subclasses herein, both singly and in combination.

[0390] In some of the foregoing embodiments of Formula (X), n1is an integer ranging from 2 to 12, for example from 2 to 8 or from 2 to 4. For example, in some embodiments, n1is 3, 4, 5 or 6. In some embodiments, n1is 3. In some embodiments, n1is 4. In some embodiments, n1is 5. In some embodiments, n1is 6.

[0391] In some other of the foregoing embodiments of Formula (X), y’ and z’ are each independently an integer ranging from 2 to 10. For example, in some embodiments, y’ and z’ are each independently an integer ranging from 4 to 9 or from 4 to 6.

[0392] In some of the foregoing embodiments of Formula (X), R60is H. In other of the foregoing embodiments, R60is C1-C24alkyl. In other embodiments, R60is OH. In some embodiments of Formula (X), G3is unsubstituted. In other embodiments, G3is substituted. In various different embodiments, G3is linear C1-C24alkylene or linear C2- C24alkenylene.

[0393] In some other foregoing embodiments of Formula (X), R35or R36, or both, is C6-C24alkenyl. For example, in some embodiments, R35and R36each, independently have the following structure: wherein:

[0394] R7aand R7bare, at each occurrence, independently H or C1-C12alkyl; and a is an integer from 2 to 12, wherein R7a, R7band a are each selected such that R35and R36each independently comprise from 6 to 20 carbon atoms. For example, in some embodiments a is an integer ranging from 5 to 9 or from 8 to 12.

[0395] In some of the foregoing embodiments of Formula (X), at least one occurrence of R7ais H. For example, in some embodiments, R7ais H at each occurrence. In other different embodiments of the foregoing, at least one occurrence of R7bis C1-Cs alkyl. For example, in some embodiments, C1-Cs alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.

[0396] In different embodiments of Formula (X), R35or R36, or both, has one of the following structures:

[0397] In some of the foregoing embodiments of Formula (X), R37is OH, CN, -C(=O)OR40, -OC(=O)R40or -NHC(=O)R40. In some embodiments, R40is methyl or ethyl.

[0398] In various different embodiments, a cationic lipid of Formula (X) has one of the structures set forth below.

[0399]

[0400]

[0401] In some embodiments, the cationically ionizable lipid has the structure of Formula (XI): wherein each of R1"and R2""is independently R5"or -G1"-L1"-R6", wherein at least one of R1"and R2”is -G1"-L1"-R6"; each of R3”and R4"is independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, aryl, and C3-10cycloalkyl; each of R5"and R6"is independently a non-cyclic hydrocarbyl group having at least 10 carbon atoms; each of G1"and G2"is independently unsubstituted C1-12alkylene or C2-12alkenylene; each of L1"and L2"is independently selected from the group consisting of -O(C=O)-, - (C=O)O-,

[0402] -C(=O)-, -O-, -S(O)x"-, -S-S-, -C(=O)S-, -SC(=O)-, -NRa"C(=O)-, -C(=O)NRa"-, - NRa"C(=O)NRa’-, -OC(=O)NRa- and -NRa"C(=O)O-;

[0403] Ra"is H or C1-12alkyl; m” is 0, 1 , 2, 3, or 4; and x” is 0, 1 or 2.

[0404] In some of the foregoing embodiments of Formula (XI), G1"is independently unsubstituted C1-C12alkylene or unsubstituted C2-12alkenylene, e.g., unsubstituted, straight C1-12alkylene or unsubstituted, straight C2-12alkenylene. In some embodiments, each G1"is independently unsubstituted C6-12alkylene or unsubstituted C6-12alkenylene, e.g., unsubstituted, straight C6-12alkylene or unsubstituted, straight C6-12alkenylene. In some embodiments, each G1"is independently unsubstituted C8-12alkylene or unsubstituted C8-12alkenylene, e.g., unsubstituted, straight C8-12alkylene or unsubstituted, straight C8-12alkenylene. In some embodiments, each G1"is independently unsubstituted C6-10alkylene or unsubstituted C6-10alkenylene, e.g., unsubstituted, straight C6-10alkylene or unsubstituted, straight C6-10alkenylene. In some embodiments, each G1"is independently unsubstituted alkylene having 8, 9 or 10 carbon atoms, e.g., unsubstituted, straight alkylene having 8, 9 or 10 carbon atoms. In some embodiments, where R1"and R2”are both independently -G1"-L1"-R6", G1"for R1"may be different from G1"for R2”. In some of these embodiments, for example, G1"for R1"is unsubstituted, straight C1-12alkylene and G1"for R2”is unsubstituted, straight C2-12alkenylene; or G1"for R1"is an unsubstituted, straight C1-12alkylene group and G1"for R2”is a different unsubstituted, straight C1-12alkylene group. In some embodiments, where R1"and R2”are both independently -G1"-L1"-R6", G1"for R1"may be identical to G1"for R2”. In some of these embodiments, for example, each G1"is the same unsubstituted, straight C8-12alkylene, such as unsubstituted, straight C8-10alkylene, or each G1"is the same unsubstituted, straight C6-12alkenylene.

[0405] In some of the foregoing embodiments of Formula (XI), each L1"is independently selected from the group consisting of -O(C=O)-, -(C=O)O-, -C(=O)S-, -SC(=O)-, - NRa"C(=O)-, and -C(=O)NRa"-. In some embodiments, Ra"of L1"is H or C1-12alkyl. In some embodiments, Ra"of L1"is H or C1-6alkyl, e.g., H or C1-3alkyl. In some embodiments, Ra"of L1"is H, methyl, or ethyl. In some embodiments, each L1"is independently selected from the group consisting of -O(C=O)-, -(C=O)O-, -C(=O)S-, and -SC(=O)-. In some embodiments, each L1"is independently -O(C=O)- or -(C=O)O-. In some embodiments, where R1"and R2”are both independently -G1"-L1"-R6", L1"for R1"may be different from L1"for R2”. In some of these embodiments, for example, L1"for R1"is one moiety selected from the group consisting of -O(C=O)-,

[0406] -(C=O)O-, -C(=O)S-, -SC(=O)-, -NRa"C(=O)-, and -C(=O)NRa"- (e.g., L1"for R1"is - O(C=O)-), and L1"for R2”is a different moiety selected from the group consisting of - O(C=O)-, -(C=O)O-, -C(=O)S-, -SC(=O)-, -NRa’O(=O)-, and -C(=O)NRa"- (e.g., L1"for R2”is -(C=O)O-). In some embodiments, where R1"and R2”are both independently -G1"-L1"- R6", L1"for R1"may be identical to L1"for R2”. In some of these embodiments, for example, each L1"is the same moiety selected from the group consisting of -O(C=O), -(C=O)O-, - C(=O)S-, -SC(=O)-, -NRa"C(=O)-, and -C(=O)NRa"-, e.g., each L1"is -O(C=O)- or each L1"is -(C=O)O-.

[0407] In some of the foregoing embodiments of Formula (XI), each R6"is independently a non- cyclic hydrocarbyl group having at least 10 carbon atoms, e.g., a straight hydrocarbyl group having at least 10 carbon atoms. In some embodiments, each R6"has independently at most 30 carbon atoms, such as at most 28, at most 26, at most 24, at most 22, or at most 20 carbon atoms. In some embodiments, each R6"is independently a non-cyclic hydrocarbyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), e.g., a straight hydrocarbyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms). In some embodiments, each R6"is attached to L1"via an internal carbon atom of R6". In some embodiments, each R6"has independently at most 30 carbon atoms (such as at most 28, at most 26, at most 24, at most 22, or at most 20 carbon atoms), and each R6"is attached to L1"via an internal carbon atom of R6". In some embodiments, each R6"is independently a non-cyclic hydrocarbyl group having at least 10 carbon atoms, e.g., a straight hydrocarbyl group having at least 10 carbon atoms, and each R6"is attached to L1"via an internal carbon atom of R6". In some embodiments, each R6"is independently a non-cyclic hydrocarbyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), e.g., a straight hydrocarbyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), and each R6"is attached to L1"via an internal carbon atom of R6". In some embodiments, the hydrocarbyl group of R6"is an alkyl or alkenyl group, e.g., a C10-30alkyl or alkenyl group. Thus, in some embodiments, each R6"is independently a non-cyclic alkyl group having at least 10 carbon atoms or a non-cyclic alkenyl group having at least 10 carbon atoms, e.g., a straight alkyl group having at least 10 carbon atoms or a straight alkenyl group having at least 10 carbon atoms. In some embodiments, each R6"is independently a non-cyclic alkyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms) or a non-cyclic alkenyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), e.g., a straight alkyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms) or a straight alkenyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms). In some embodiments, each R6"is independently a non-cyclic alkyl group having 11 to 19 carbon atoms (such as 1 1 , 13, 15, 17, or 17 carbon atoms), e.g., a straight alkyl group having 1 1 to 19 carbon atoms (such as 1 1 , 13, 15, 17, or 17 carbon atoms). In some embodiments, each R6"is independently a non- cyclic alkyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms) or a non-cyclic alkenyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), e.g., a straight alkyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms) or a straight alkenyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), and each R6"is attached to L1"via an internal carbon atom of R6". In some embodiments, each R6"is independently a non-cyclic alkyl group having 1 1 to 19 carbon atoms (such as 1 1 , 13, 15, 17, or 17 carbon atoms), e.g., a straight alkyl group having 1 1 to 19 carbon atoms (such as 1 1 , 13, 15, 17, or 17 carbon atoms), and each R6"is attached to L1"via an internal carbon atom of R6". The expression "internal carbon atom" means that the carbon atom of R6"by which R6"is attached to L1"is directly bonded to at least 2 other carbon atoms of R6". For example, for the following C11alkyl group, each carbon atom at any one of positions 2, 3, 4, 5, and 7 qualifies as "internal carbon atom" according to the present disclosure, whereas the carbon atoms at positions 1 , 6, 8, 9, 10, and 1 1 do not.

[0408] Consequently, R6"being a C11alkyl group attached to L1"via an internal carbon of R6"includes the following groups: wherein represents the bond by which R6"is bound to L1". Furthermore, for a straight alkyl group, e.g., a straight C11alkyl gr,o euapch carbon atom except for the first and last carbon atoms of the straight alkyl group (i.e., except the carbon atoms at positions 1 and 1 1 of the straight C11alkyl group) qualifies as "internal carbon atom". Thus, in some embodiments, R6"being a straight alkyl group having p carbon atoms and being attached to L1"via an internal carbon atom of R6"means that R6"is attached to L1"via a carbon atom of R6"at any one of positions 2 to (p-1 ) (thereby excluding the terminal C atoms at positions 1 and p). In some embodiments, where R6"is a straight alkyl group having p’ carbon atoms (wherein p’ is an even number) and being attached to L1"via an internal carbon atom of R6", R6"is attached to L1"via a carbon at any one of positions (p’ / 2 - 1 ), (p’ / 2), and (p72 + 1 ) of R6"(e.g., if p’ is 10, R6"is attached to L1"via a carbon atom at any one of positions 4, 5, and 6 of R6"). In some embodiments, where R6"is a straight alkyl group having p” carbon atoms (wherein p” is an uneven number) and being attached to L1"via an internal carbon atom of R6", R6"is attached to L1"via a carbon atom at any one of positions (p” - 1 ) / 2 and (p” + 1 ) / 2 of R6"(e.g., if p” is 11 , R6"is attached to L1"via a carbon at any one of positions 5 and 6 of R6"). Generally, it is to be understood that if both R1"and R2”are -G1"-L1"-R6"and each R6"is attached to L1"via an internal carbon atom of R6", R6"of R1"is attached to L1"of R1"(and not to L1"of R2”) via an internal carbon atom of R6"of R1"and R6"of R2”is attached to L1"of R2”(and not to L1"of R1") via an internal carbon atom of R6"of R2”. In some embodiments, each R6"is independently selected from the group consisting of: wherein represents the bond by which R6"is bound to L1". In some embodiments, where R1"and R2”are both independently -G1"-L1"-R6", R6"for R1"is different from R6"for R2”. In some of these embodiments, for example, R6for R1"may be a non-cyclic, preferably straight, hydrocarbyl group having at least 10 carbon atoms (e.g., R6"for R1"and R6"for R2”may be a different non-cyclic, preferably straight, hydrocarbyl group having at least 10 carbon atoms (e.g., R6"for R2”is in some embodiments, where R1"and R2”are both independently -G1"- L1"-R6", R6"for R1"is identical to R6"for R2”. In some of these embodiments, for example, each R6"is the same non-cyclic, preferably straight, hydrocarbyl group having at least 10 carbon atoms (e.g., each R6"

[0409] In some of the foregoing embodiments of Formula (XI), R5"is a non-cyclic hydrocarbyl group having at least 10 carbon atoms, e.g., a straight hydrocarbyl group having at least 10 carbon atoms. In some embodiments, R5"is a non-cyclic hydrocarbyl group having at least 12 carbon atoms, such as at least 14, at least 16, or at least 18 carbon atoms, e.g., a straight hydrocarbyl group having at least 12, at least 14, at least 16, or at least 18 carbon atoms. In some embodiments, R5"has at most 30 carbon atoms, such as at most 28, at most 26, at most 24, at most 22, or at most 20 carbon atoms. In some embodiments, R5"is a non-cyclic hydrocarbyl group, e.g., a straight hydrocarbyl group, wherein each hydrocarbyl group has 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, 10 to 20 carbon atoms, or 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 22, 12 to 20 carbon atoms, or 14 to 30, 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms). In some embodiments, the hydrocarbyl group of R5"is an alkyl or alkenyl group, e.g., a C10-30alkyl or alkenyl group. Thus, in some embodiments, R5"is a non-cyclic alkyl group having at least 10 carbon atoms (such as at least 12, at least 14, at least 16, or at least 18 carbon atoms) or a non-cyclic alkenyl group having at least 10 carbon atoms (such as at least 12, at least 14, at least 16, or at least 18 carbon atoms), e.g., a straight alkyl group having at least 10 carbon atoms (such as at least 12, at least 14, at least 16, or at least 18 carbon atoms) or a straight alkenyl group having at least 10 carbon atoms (such as at least 12, at least 14, at least 16, or at least 18 carbon atoms). In some embodiments, R5"is a non-cyclic alkyl group or a non-cyclic alkenyl group, e.g., a straight alkyl group or a straight alkenyl group, wherein each of the alkyl and alkenyl groups has independently 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, 10 to 20 carbon atoms, or 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 22, 12 to 20 carbon atoms, or 14 to 30, 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms). In some embodiments, the alkenyl group has at least 2 carbon-carbon double bonds, e.g., 2 or 3 carbon-carbon double bonds, such as 2 carbon-carbon double bonds. In some embodiments, the alkenyl group has at least 1 carbon-carbon double bond in cis configuration, e.g., 1 , 2 or 3, such as 2, carbon-carbon double bonds in cis configuration. Thus, in some embodiments, R5is a non-cyclic alkyl group or a non-cyclic alkenyl group, e.g., a straight alkyl group or a straight alkenyl group, wherein each of the alkyl and alkenyl groups has independently 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, 10 to 20 carbon atoms, or 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 22, 12 to 20 carbon atoms, or 14 to 30, 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms) and the alkenyl group has at least 2 carbon-carbon double bonds, e.g., 2 or 3 carbon-carbon double bonds. In some embodiments, R5"is a non-cyclic alkyl group or a non-cyclic alkenyl group, e.g., a straight alkyl group or a straight alkenyl group, wherein each of the alkyl and alkenyl groups has independently 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, 10 to 20 carbon atoms, or 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 22, 12 to 20 carbon atoms, or 14 to 30, 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms) and the alkenyl group has at least 1 carbon-carbon double bond, such as 1 , 2, or 3 carbon-carbon double bonds, in cis configuration. In some embodiments, R5"has the following structure: wherein represents the bond by which R5"is bound to the remainder of the compound.

[0410] In some of the foregoing embodiments of Formula (XI), L2"is selected from the group consisting of -O(C=O)-, -(C=O)O-, -C(=O)-, -S-S-, -C(=O)S-, -SC(=O)-, -NRa"C(=O)-, - C(=O)NRa"-, -NRa’O(=O)NRa", -OC(=O)NRa- and -NRa’O(=O)O-. In some embodiments, L2"is selected from the group consisting of -O(C=O)-, -(C=O)O-, -C(=O)-, -C(=O)S-, - SC(=O)-, -NRa’O(=O)-, and -C(=O)NRa"-. In some embodiments, Ra"of L2"is H or C1-12alkyl. In some embodiments, Ra"of L2"is H or C1-6alkyl, e.g., H or C1-3alkyl. In some embodiments, Ra"of L2"is H, methyl, or ethyl. In some embodiments, L2"is selected from the group consisting of -O(C=O)-, -(C=O)O-, -C(=O)S-, and -SC(=O). In some embodiments, L2"is -O(C=O)- or -(C=O)O-.

[0411] In some of the foregoing embodiments of Formula (XI), G2"is unsubstituted C1-12alkylene or unsubstituted C2-12alkenylene, e.g., unsubstituted, straight C1-12alkylene or unsubstituted, straight C2-12alkenylene. In some embodiments, G2"is unsubstituted C2- 10 alkylene or unsubstituted C2-10alkenylene, e.g., unsubstituted, straight C2-10alkylene or unsubstituted, straight C2-10alkenylene. In some embodiments, G2"is unsubstituted C2-6alkylene or unsubstituted C2-6alkenylene, e.g., unsubstituted, straight C2-6alkylene or unsubstituted, straight C2-6alkenylene. In some embodiments, G2"is unsubstituted C2-4alkylene or unsubstituted C2-4alkenylene, e.g., unsubstituted, straight C2-4alkylene or unsubstituted, straight C2-4alkenylene. In some embodiments, G2"is ethylene or trimethylene.

[0412] In some of the foregoing embodiments of Formula (XI), each of R3”and R4"is independently C1-6alkyl or C2-6alkenyl. In some embodiments, each of R3”and R4"is independently C1-4alkyl or C2-4alkenyl. In some embodiments, each of R3”and R4"is independently C1-3alkyl. In some embodiments, each of R3”and R4"is independently methyl or ethyl. In some embodiments, each of R3and R4is methyl.

[0413] In some of the foregoing embodiments of Formula (XI), m” is 0, 1 , 2 or 3. In some embodiments, m” is 0 or 2. In some embodiments, m” is 0. In some embodiments, m” is 2.

[0414] In some of the foregoing embodiments of Formula (XI), the cationically ionizable lipid has the structure of Formula (XI la) or (Xllb): ), wherein each of R3”and R4"is independently C1-C6alkyl or C2-6alkenyl; R5"is a straight hydrocarbyl group having at least 14 carbon atoms (such as at least 16 carbon atoms), wherein the hydrocarbyl group preferably has at least 2 carbon-carbon double bonds; each R6"is independently a straight hydrocarbyl group (e.g., a straight alkyl group) having at least 10 carbon atoms and / or each R6"is attached to L1"via an internal carbon atom of R6", preferably each R6"is independently a straight hydrocarbyl group (e.g., a straight alkyl group) having at least 10 carbon atoms and each R6"is attached to L1"via an internal carbon atom of R6"; each G1"is independently unsubstituted, straight C4-12alkylene or C4-12alkenylene, e.g., unsubstituted, straight C6-12alkylene or C6-12alkenylene, such as unsubstituted, straight C8-12alkylene or unsubstituted, straight C8-12alkenylene; G2"is unsubstituted C2-C10alkylene or C2-10alkenylene, preferably unsubstituted C2-C6alkylene or C2-6alkenylene; each of L1"and L2"is independently -O(C=O)- or -(C=O)O-; and m” is 0, 1 , 2 or 3, preferably 0 or 2.

[0415] In some of the foregoing embodiments of Formula (Xlla), R5"has at most 30 carbon atoms, such as at most 28, at most 26, at most 24, at most 22, or at most 20 carbon atoms. In some embodiments of formulas (Xlla), R5"is a straight hydrocarbyl group having 14 to 30 carbon atoms (such as 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms). In some embodiments of formula (Xlla), R5"is a straight alkyl or alkenyl group having 14 to 30 carbon atoms (such as 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms). In some embodiments of formula (Xlla), the alkenyl group has at least 2 carbon-carbon double bonds, e.g., 2 or 3 carbon-carbon double bonds, such as 2 carbon-carbon double bonds. In some embodiments, the alkenyl group has at least 1 carbon-carbon double bond in cis configuration, e.g., 1 , 2 or 3, such as 2, carbon-carbon double bonds in cis configuration. Thus, in some embodiments of formula (Xlla), R5"is a straight alkyl group or a straight alkenyl group, wherein each of the alkyl and alkenyl groups has independently 14 to 30 carbon atoms (such as 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms) and the alkenyl group has at least 2 carbon-carbon double bonds, e.g., 2 or 3 carbon-carbon double bonds. In some embodiments of formula (Xlla), R5"is a straight alkyl group or a straight alkenyl group, wherein each of the alkyl and alkenyl groups has independently 14 to 30 carbon atoms (such as 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms) and the alkenyl group has at least 1 carbon- carbon double bond, such as 1 , 2, or 3 carbon-carbon double bonds, in cis configuration. In some embodiments of formula (Xlla), R5"is a straight alkyl group or a straight alkenyl group, wherein each of the alkyl and alkenyl groups has independently 14 to 30 carbon atoms (such as 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms) and the alkenyl group has 2 or 3 carbon-carbon double bonds, wherein at least 1 carbon-carbon double bond, such as 1 , 2, or 3 carbon-carbon double bonds, is in cis configuration. In some embodiments of formula (XI la) , R5"has the following structure: wherein represents the bond by which R5"is bound to the remainder of the compound. In some embodiments of formula (XI la), R6"has at most 30 carbon atoms, such as at most 28, at most 26, at most 24, at most 22, or at most 20 carbon atoms. In some embodiments of formula (Xlla), R6is a non-cyclic hydrocarbyl group (e.g., a non-cyclic alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), e.g., a straight hydrocarbyl group (e.g., a straight alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms). In some embodiments of formula (Xlla), R6"is a straight hydrocarbyl group (e.g., a straight alkyl group) having at least 10 carbon atoms and R6"is attached to L1"via an internal carbon atom of R6". In some embodiments of formula (Xlla), R6"is a non-cyclic hydrocarbyl group (e.g., a non-cyclic alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), e.g., a straight hydrocarbyl group (e.g., a straight alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), and R6"is attached to L1"via an internal carbon atom of R6". In some embodiments of formula (Xlla), G1"is independently unsubstituted, straight C4-12alkylene or C4-12alkenylene, e.g., unsubstituted, straight C6-12alkylene or C6-12alkenylene. In some embodiments of formula (Xlla), R5"is a straight hydrocarbyl group, e.g., a straight alkenyl group, having at least 14 carbon atoms (such as 14 to 30 carbon atoms) and 2 or 3 carbon-carbon double bonds; R6"is a straight hydrocarbyl group (e.g., a straight alkyl group) having at least 10 carbon atoms (e.g., having 10 to 30 carbon atoms) and R6"is attached to L1"via an internal carbon atom of R6"; and G1"is independently unsubstituted, straight C4-12alkylene or C4-12alkenylene, e.g., unsubstituted, straight C6-12alkylene or C6-12alkenylene.

[0416] In some of the foregoing embodiments of Formula (Xllb), each R6"has independently at most 30 carbon atoms, such as at most 28, at most 26, at most 24, at most 22, or at most 20 carbon atoms. In some embodiments of formula (Xllb), each R6"is independently a straight hydrocarbyl group (e.g., a straight alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, or 11 to 19 carbon atoms, such as 11 , 13, 15, 17, or 17 carbon atoms). In some embodiments of formula (Xllb), each R6"is independently a straight hydrocarbyl group (e.g., a straight alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, or 11 to 19 carbon atoms, such as 11 , 13, 15, 17, or 17 carbon atoms) and each R6"is attached to L1"via an internal carbon atom of R6". In some embodiments of formula (Xllb), each R6"is independently selected from the group consisting of: the bond by which R6"is bound to L1". In some embodiments of formula (Xllb), each G1"is independently unsubstituted, straight C6-12alkylene or C6-12alkenylene. In some embodiments of formula (Xllb), each G1"is independently unsubstituted, straight C8-12alkylene or C8-12alkenylene. In some embodiments of formula (Xllb), each R6"is independently a straight hydrocarbyl group (e.g., a straight alkyl group) having at least 10 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, or 11 to 19 carbon atoms, such as 11 , 13, 15, 17, or 17 carbon atoms) and is attached to L1"via an internal carbon atom of R6"; and each G1"is independently unsubstituted, straight C8-12alkylene or C8-12alkenylene.

[0417] In some of the foregoing embodiments of Formula (XI), the cationically ionizable lipid has the structure of Formula (XI I la) or (XI I lb) : wherein each of R3”and R4"is independently C1-4alkyl or C2-4alkenyl, more preferably C1-3alkyl, such as methyl or ethyl; R5"is a straight alkyl or alkenyl group having at least 16 carbon atoms, wherein the alkenyl group preferably has at least 2 carbon-carbon double bonds; each R6"is independently a straight hydrocarbyl group having at least 10 carbon atoms, wherein R6"is attached to L1"via an internal carbon atom of R6"; each G1"is independently unsubstituted, straight C6-12alkylene or unsubstituted, straight C6-12alkenylene, e.g., unsubstituted, straight C8-12alkylene or unsubstituted, straight C8-12 alkenylene, such as unsubstituted, straight C8-10alkylene or unsubstituted, straight C8-lo alkenylene, such as unsubstituted, straight Cs alkylene; G2"is unsubstituted C2-6alkylene or C2-6alkenylene, preferably unsubstituted C2-4alkylene or C2-4alkenylene, such as ethylene or trimethylene; each of L1"and L2"is independently -O(C=O)- or -(C=O)O-; and

[0418] M” is 0, 1 , 2 or 3, preferably 0 or 2.

[0419] In some of the foregoing embodiments of Formula (Xllla), R5"has at most 30 carbon atoms, such as at most 28, at most 26, at most 24, at most 22, or at most 20 carbon atoms. In some embodiments of formulas (Xllla), R5"is a straight alkyl or alkenyl group having 16 to 30 carbon atoms (such as 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms). In some embodiments of formula (Xllla), the alkenyl group has at least 2 carbon- carbon double bonds, e.g., 2 or 3 carbon-carbon double bonds, such as 2 carbon-carbon double bonds. In some embodiments, the alkenyl group has at least 1 carbon-carbon double bond in cis configuration, e.g., 1 , 2 or 3, such as 2, carbon-carbon double bonds in cis configuration. Thus, in some embodiments of formula (Xllla), R5"is a straight alkyl group or a straight alkenyl group, wherein each of the alkyl and alkenyl groups has independently 16 to 30 carbon atoms (such as 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms) and the alkenyl group has at least 2 carbon-carbon double bonds, e.g., 2 or 3 carbon-carbon double bonds. In some embodiments of formula (Xllla), R5"is a straight alkyl group or a straight alkenyl group, wherein each of the alkyl and alkenyl groups has independently 16 to 30 carbon atoms (such as 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms) and the alkenyl group has at least 1 carbon-carbon double bond, such as 1 , 2, or 3 carbon-carbon double bonds, in cis configuration. In some embodiments of formula (Xllla), R5"is a straight alkyl group or a straight alkenyl group, wherein each of the alkyl and alkenyl groups has independently 16 to 30 carbon atoms (such as 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms) and the alkenyl group has 2 or 3 carbon-carbon double bonds, wherein at least 1 carbon-carbon double bond, such as 1 , 2, or 3 carbon- carbon double bonds, is in cis configuration. In some embodiments of formula (Xllla), R5has the following structure: wherein

[0420] J'nn' represents the bond by which R5"is bound to the remainder of the compound. In some embodiments of formula (Xllla), R6"has at most 30 carbon atoms, such as at most 28, at most 26, at most 24, at most 22, or at most 20 carbon atoms. In some embodiments of formula (Xllla), R6"is a straight hydrocarbyl group (e.g., a straight alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms) and R6"is attached to L1"via an internal carbon atom of R6". In some embodiments of formula (Xllla), R6"is a straight alkyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms) and R6"is attached to L1"via an internal carbon atom of R6". In some embodiments of formula (Xllla), G1"is independently unsubstituted, straight C4-12alkylene or C4-12alkenylene, e.g., unsubstituted, straight C6-12alkylene or C6-12alkenylene. In some embodiments of formula (Xllla), R5"is a straight hydrocarbyl group, e.g., a straight alkenyl group, having at least 16 carbon atoms (such as 16 to 30 carbon atoms) and 2 or 3 carbon-carbon double bonds; R6"is a straight hydrocarbyl group (e.g., a straight alkyl group) having at least 10 carbon atoms (e.g., having 10 to 30 carbon atoms) and R6"is attached to L1"via an internal carbon atom of R6"; and G1"is independently unsubstituted, straight C4-12 alkylene or C4-12alkenylene, e.g., unsubstituted, straight C6-12alkylene or C6-12alkenylene.

[0421] In some of the foregoing embodiments of Formula (XI I lb), each R6"has independently at most 30 carbon atoms, such as at most 28, at most 26, at most 24, at most 22, or at most 20 carbon atoms. In some embodiments of formula (Xlllb), each R6"is independently a straight hydrocarbyl group (e.g., a straight alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, or 1 1 to 19 carbon atoms, such as 1 1 , 13, 15, 17, or 17 carbon atoms) and each R6"is attached to L1"via an internal carbon atom of R6". In some embodiments of formula (Xlllb), each R6"is attached to L1"via an internal carbon atom of R6"and is independently selected from the group consisting of: wherein represents the bond by which R6"is bound to L1". In some embodiments of formula (Xlllb), each G1"is independently unsubstituted, straight C8-12alkylene or C8-12alkenylene, e.g., unsubstituted, straight C8-10alkylene or C8-10alkenylene. In some embodiments of formula (Xlllb), each R6"is independently a straight hydrocarbyl group (e.g., a straight alkyl group) having at least 10 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, or 1 1 to 19 carbon atoms, such as 1 1 , 13, 15, 17, or 17 carbon atoms) and is attached to L1"via an internal carbon atom of R6"; and each G1"is independently unsubstituted, straight C8-12alkylene or C8-12alkenylene, e.g., unsubstituted, straight C8-10alkylene or C8-io alkenylene.

[0422] In some of the foregoing embodiments of Formula (XI), the cationically ionizable lipid has one of the following formulas (XIV-1 ), (XIV-2), and (XIV-3):

[0423]

[0424] In some embodiments, the cationically ionizable lipid is (6Z,16Z)-12-((Z)-dec-4-en-1- yl)docosa-6,16-dien-11-yl 5-(dimethylamino)pentanoate (3D-P-DMA). The structure of 3D-P-DMA may be represented as follows:

[0425] In various different embodiments, the cationically ionizable lipid is selected from the group consisting of N,N-dimethyl-2,3-dioleyloxypropylamine (DODMA), 1 ,2-dioleoyl-3- dimethylammonium-propane (DODAP), heptatriaconta-6,9,28,31-tetraen-19-yl-4- (dimethylamino)butanoate (DLin-MC3-DMA), and 4-((di((9Z,12Z)-octadeca-9,12-dien-1 - yl)amino)oxy)-N,N-dirnethyl-4-oxobutan-1 -amine (DPL-14).

[0426] Further examples of cationically ionizable lipids include, but are not limited to, 3-(N- (N',N'-dimethylaminoethane)-carbamoyl)cholesterol (DC-Chol), 1 ,2-dioleoyl-3- dimethylammonium-propane (DODAP); 1 ,2-diacyloxy-3-dimethylammonium propanes; 1 ,2-dialkyloxy-3-dimethylammonium propanes, 1 ,2-distearyloxy-N,N-dimethyl-3- aminopropane (DSDMA), 1 ,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1 ,2- dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), dioctadecylamidoglycyl spermine (DOGS), 3-dimethylamino-2-(cholest-5-en-3-beta-oxybutan-4-oxy)-1 -(cis.cis- 9,12-oc-tadecadienoxy)propane (CLinDMA), 2-[5'-(cholest-5-en-3-beta-oxy)-3'- oxapentoxy)-3-dimethyl-1 -(cis,cis-9',12'-octadecadienoxy)propane (CpLinDMA), N,N- dimethyl-3,4-dioleyloxybenzylamine (DMOBA), 1 ,2-N,N'-dioleylcarbamyl-3- dimethylaminopropane (DOcarbDAP), 2,3-Dilinoleoyloxy-N,N-dimethylpropylamine (DLinDAP), 1 ,2-N,N'-Dilinoleylcarbamyl-3-dimethylaminopropane (DLincarbDAP), 1 ,2- Dilinoleoylcarbamyl-3-dimethylaminopropane (DLinCDAP), 2,2-dilinoleyl-4- dimethylaminomethyl-[1 ,3]-dioxolane (DLin-K-DMA), 2,2-dili noleyl-4- dimethylaminoethyl-[1 ,3]-dioxolane (DLin-K-XTC2-DMA), 2,2-dilinoleyl-4-(2- dimethylaminoethyl)-[1 ,3]-dioxolane (DLin-KC2-DMA), heptatriaconta-6,9,28,31 - tetraen-19-yl-4-(dimethylamino)butanoate (DLin-MC3-DMA), 2-({8-[(3|3)-cholest-5-en-3- yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1 -yloxy]propan-1 -amine (Octyl-CLinDMA), 1 ,2-dimyristoyl-3-dimethylammonium-propane (DMDAP), 1 ,2- dipalmitoyl-3-dimethylammonium-propane (DPDAP), N1 -[2-((1 S)-1 -[(3- aminopropyl)amino]-4-[di(3-amino-propyl)amino]butylcarboxamido)ethyl]-3,4- di[oleyloxy]-benzamide (MVL5), di((Z)-non-2-en-1 -yl) 8,8'-

[0427] ((((2(dimethylamino)ethyl)thio)carbonyl)azanediyl)dioctanoate (ATX), N,N-dimethyl-2,3- bis(dodecyloxy)propan-1 -amine (DLDMA), N,N-dimethyl-2,3-bis(tetradecyloxy)propan- 1 -amine (DMDMA), di((Z)-non-2-en-1 -yl)-9-((4-

[0428] (dimethylaminobutanoyl)oxy)heptadecanedioate (L319), N-dodecyl-3-((2- dodecylcarbamoyl-ethyl)-{2-[(2-dodecylcarbamoyl-ethyl)-2-{(2-dodecylcarbamoyl- ethyl)-[2-(2-dodecylcarbamoyl-ethylamino)-ethyl]-amino}-ethylamino)propionamide (lipidoid 98N12-5), 1 -[2-[bis(2-hydroxydodecyl)amino]ethyl-[2-[4-[2-[bis(2 hydroxydodecyl)amino]ethyl]piperazin-1 -yl]ethyl]amino]dodecan-2-ol (lipidoid C1 2-200). In certain embodiments, the cationically ionizable lipid is or comprises X-3. In certain embodiments, the cationically ionizable lipid is or comprises X-45.

[0429] In some embodiments, the cationic lipid for use herein is or comprises DPL-14. As used herein, "DPL-14" is a lipid comprising the following general formula:

[0430] In some embodiments, the cationic lipid for use herein is or comprises EA-2. As used herein, "EA-2" is a lipid comprising the following general formula:

[0431] It is to be understood that any reference to a cationic or cationically ionizable lipid disclosed herein also includes the salts (in particular pharmaceutically acceptable salts), tautomers, stereoisomers, solvates (e.g., hydrates), and isotopically labeled forms thereof.

[0432] In some embodiments, wherein the nucleic acid compositions (in particular the DNA or RNA compositions) described herein comprise a cationic or cationically ionizable lipid and one or more additional lipids, the cationic or cationically ionizable lipid comprises from about 10 mol % to about 80 mol %, from about 20 mol % to about 75 mol %, from about 20 mol % to about 70 mol %, from about 20 mol % to about 60 mol %, from about 25 mol % to about 55 mol %, from about 30 mol % to about 50 mol %, from about 35 mol % to about 45 mol %, or from about 40 mol % to about 55 mol % of the total lipid present in the composition. In some embodiments of the nucleic acid (such as DNA or RNA) compositions (especially the mRNA compositions) described herein, where at least a portion of (i) the nucleic acid and (ii) the cationic or cationically ionizable lipid form particles (e.g., LNPs), the cationic or cationically ionizable lipid may comprise from about 10 mol % to about 80 mol %, from about 20 mol % to about 75 mol %, from about 20 mol % to about 70 mol %, from about 20 mol % to about 60 mol %, from about 25 mol % to about 55 mol %, from about 30 mol % to about 50 mol %, from about 35 mol % to about 45 mol %, or from about 40 mol % to about 55 mol % of the total lipid present in the particles.

[0433] Helper lipids

[0434] As described herein, LNPs of the present disclosure comprise a helper lipid. In some embodiments, a helper lipid is a phospholipid. In some embodiments, a helper lipid is or comprises 1 ,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1 ,2-dipalmitoyl-sn- glycero-3-phosphocholine (DPPC), 1 ,2-dimyristoyl-sn-glycero-3- phosphocholine (DMPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1 ,2-dioleoyl-sn- glycero-3-phosphocholine (DOPC), phophatidyl ethanol amines such as 1 ,2-dioleoyl-sn- glycero-3-phosphoethanolamine (DOPE), sphingomyelins (SM), 1 ,2-diacylglyceryl-3-O-

[0435] 4'-(N,N,N-trimethyl)-homoserine (DGTS), ceramides, cholesterol, steroids, such as sterols and their derivatives.

[0436] In some embodiments, a helper lipid is or comprises phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidic acids, phosphatidylserines or sphingomyelin. In some embodiments, a helper lipid is or comprises diacylphosphatidylcholines, such as distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine (DTPC), dilignoceroylphatidylcholine (DLPC), palmitoyloleoyl-phosphatidylcholine (POPC), 1 ,2- di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1 -oleoyl-2- cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1 -hexadecyl-sn- glycero-3-phosphocholine (C16 Lyso PC) and phosphatidylethanolamines, including, for example diacylphosphatidylethanolamines, such as dioleoylphosphatidylethanolamine (DOPE), distearoyl-phosphatidylethanolamine (DSPE), dipalmitoyl- phosphatidylethanolamine (DPPE), dimyristoyl-phosphatidylethanolamine (DMPE), dilauroyl-phosphatidylethanolamine (DLPE), diphytanoyl-phosphatidylethanolamine (DPyPE), 1 ,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine (DOPG), 1 ,2- dipalmitoyl-sn-glycero-3-phospho-(1 '-rac-glycerol) (DPPG), 1 -palmitoyl-2-oleoyl-sn- glycero-3-phosphoethanolamine (POPE), N-palmitoyl-D-erythro- sphingosylphosphorylcholine (SM). In some embodiments, a helper lipid is selected from the group consisting of DSPC, DOPC, DMPC, DPPC, POPO, DOPE, DOPG, DPPG, POPE, DPPE, DMPE, DSPE, and SM. In some embodiments, the neutral lipid is selected from the group consisting of DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM. In some embodiments, the neutral lipid is DSPC.

[0437] Helper lipids may be synthetic or naturally derived. Other helper lipids suitable for use in a lipid nanoparticle are described in WO2021 / 026358, WO 2017 / 075531 , and WO 2018 / 081480, the entire contents of each of which are incorporated herein by reference in their entirety.

[0438] In some embodiments, a lipid nanoparticle comprises about 5 to about 15 mol% of a phospholipid. In some embodiments, a lipid nanoparticle comprises about 8 to about 12 mol% of a phospholipid. In some embodiments, a lipid nanoparticle comprises about 10 mol% of a phospholipid. In some embodiments, a lipid nanoparticle comprises about 5 to about 15 mol% of DSPC. In some embodiments, a lipid nanoparticle comprises about 8 to about 12 mol% of DSPC. In some embodiments, a lipid nanoparticle comprises about 10 mol% of DSPC.

[0439] Polymer-conjugated lipids

[0440] As described herein, LNPs of the present disclosure comprise a polymer-conjugated lipid. In some embodiments, a polymer conjugated lipid is a lipid conjugated to polyethylene glycol (PEG-lipid). In some embodiments, a PEG lipid is selected from pegylated di acyl glycerol (PEG-DAG) such as l-(monomethoxy-polyethyleneglycol)- 2,3- dimyristoylglycerol (PEG-DMG) (e.g., 1 ,2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (PEG2000-DMG)), a pegylated phosphatidylethanoloamine (PEG-PE), a PEG succinate di acyl glycerol (PEG-S-DAG) such as 4-O-(2',3'-di(tetradecanoyloxy)propyl-1 -O-(ω- methoxy(polyethoxy)ethyl)butanedioate (PEG-S-DMG), 1 ,2-distearoyl-sn-glycero-3- phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000 amine), a pegylated ceramide (PEG-cer), or a PEG dialkoxypropylcarbamate such as ω-m ethoxy (polyethoxy)ethyl-N-(2,3-di(tetradecanoxy)propyl)carbamate, and 2,3- di(tetradecanoxy)propy 1 -N-(w methoxy(polyethoxy)ethyl)carbamate.

[0441] In some embodiments, a PEG-lipid is PEG2000-DMG:

[0442] In some embodiments, a PEG-lipid is DMG-PEG.

[0443] In some embodiments, a PEG-lipid is provided in WO2021 / 026358, WO 2017 / 075531 , or WO 2018 / 081480, each of which is incorporated by reference in its entirety.

[0444] In some embodiments, a PEG-lipid is 2-[(polyethylene glycol)-2000]-N,N- ditetradecylacetamide (ALC-0159). In some embodiments, a compound of Formula II is: or a pharmaceutically acceptable salt thereof, where n’ is an integer from about 45 to about 50.

[0445] In some embodiments, the PEG- lipid has the following structure: wherein n in the formula above is from 30 to 60, such as about 50. In one embodiment, the PEG-conjugated lipid (pegylated lipid) is PEG2000-C-DMA which preferably refers to 3-N-[(ω-methoxy polyethylene glycol)2000)carbamoyl]-1 ,2-dimyristyloxy-propylamine (MPEG-(2 kDa)-C-DMA) or methoxy-polyethylene glycol-2,3- bis(tetradecyloxy)propylcarbamate (2000). In some embodiments, a PEG-lipid is selected from PEG-DAG, PEG-PE, PEG-S-DAG, PEG2000-DMG, PEG-S-DMG, PEG-cer, a PEG dialkyoxypropylcarbamate (e.g., ω- methoxy(polyethoxy)ethyl-N-(2,3-di(tetradecanoxy)propyl)carbamate or 2,3- di(tetradecanoxy)propyl-N-( ω-methoxy(polyethoxy)ethyl)carbamate), ALC-0159, and combinations thereof. In some embodiments, a PEG-lipid is ALC-0159 or PEG2000- DMG. In some embodiments, a PEG-lipid is ALC-0159. In some embodiments, a PEG- lipid is PEG2000-DMG. In some embodiments, a PEG-lipid is PEG-DAG. In some embodiments, a PEG-lipid is PEG-PE. In some embodiments, a PEG-lipid is PEG-S- DAG. In some embodiments, a PEG-lipid is PEG-cer. In some embodiments, a PEG- lipid is a PEG dialkyoxypropylcarbamate.

[0446] In some embodiments, a PEG group that is part of a PEG-lipid has, on average in a composition comprising one or more PEG-lipid molecules, a number average molecular weight (Mn) of about 2000 g / mol.

[0447] In some embodiments, a polymer-conjugated lipid is a polysarcosine-conjugated lipid, also referred to herein as sarcosinylated lipid or pSar-lipid. The term "sarcosinylated lipid" refers to a molecule comprising both a lipid portion and a polysarcosine (poly(N- methylglycine) portion.

[0448] In some embodiments, a polymer-conjugated lipid is a polyoxazoline (POX)-conjugated and / or polyoxazine (POZ)-conjugated lipid, also referred to herein as a conjugate of a POX and / or POZ polymer and one or more hydrophobic chains or as oxazolinylated and / or oxazinylated lipid or POX- and / or POZ-lipid. The term "oxazolinylated lipid" or "POX-lipid" refers to a molecule comprising both a lipid portion and a polyoxazoline portion. The term "oxazinylated lipid" or "POZ-lipid" refers to a molecule comprising both a lipid portion and a polyoxazine portion. The term "oxazolinylated / oxazinylated lipid" or "POX / POZ-lipid" or "POXZ-lipid" refers to a molecule comprising both a lipid portion and a portion of a copolymer of polyoxazoline and polyoxazine.

[0449] In some embodiments, an LNP described herein may comprise a sarcosinylated lipid. In some embodiments, the nucleic acid compositions (such as DNA or RNA compositions, especially mRNA compositions) described herein comprise a sarcosinylated lipid and are substantially free of a pegylated lipid (or do not contain a pegylated lipid). In some embodiments, the nucleic acid compositions (such as DNA or RNA compositions, especially mRNA compositions) described herein comprise a cationic / cationically ionizable lipid as described herein and a sarcosinylated lipid (pSAR- conjugated lipid). In some embodiments, the nucleic acid compositions (such as DNA or RNA compositions, especially mRNA compositions) described herein may further comprise a neutral lipid (e.g., a phospholipid, cholesterol or a derivative thereof) or a combination of neutral lipids (e.g., a phospholipid, and cholesterol or a derivative thereof). In some embodiments, the nucleic acid compositions (such as DNA or RNA compositions, especially mRNA compositions) described herein comprise a cationic / cationically ionizable lipid as described herein, a sarcosinylated lipid, a neutral lipid (e.g., a phospholipid), and cholesterol or a derivative thereof. In some embodiments, the phospholipid is DSPC. In some embodiments, the cationic / cationically ionizable lipid is a cationically ionizable lipid of formula (X) (such as a cationically ionizable lipid of formula (X-3) or (X-45)). In some embodiments, the cationic / cationically ionizable lipid is a cationically ionizable lipid of formula (XI) (such as a cationically ionizable lipid of formula (XIV-1 ), (XIV-2), or (XIV-3)). In some embodiments, the cationic / cationically ionizable lipid is DPL14, EA-2, or 3D-P-DMA.

[0450] In some embodiments of the nucleic acid compositions (such as DNA or RNA compositions, especially mRNA compositions) described herein which comprise a sarcosinylated lipid, said compositions are substantially free of a pegylated lipid (or do not contain a pegylated lipid).

[0451] In some embodiments, the sarcosinylated lipid comprises between 2 and 200 sarcosine units, such as between 5 and 100 sarcosine units, between 10 and 50 sarcosine units, between 15 and 40 sarcosine units, e.g., about 23 sarcosine units.

[0452] In some embodiments, the sarcosinylated lipid comprises the structure of the following general formula (XVII): wherein s is the number of sarcosine units. In some embodiments, the sarcosinylated lipid comprises the structure of the following general formula (XVIII): wherein one of R21 and R22comprises a hydrophobic group and the other is H, a hydrophilic group or a functional group optionally comprising a targeting moiety useful for binding or associating with a target of interest; and x is the number of sarcosine units. In some embodiments of formula (XVIII), R21 is H, a hydrophilic group or a functional group optionally comprising a targeting moiety; and R22comprises one or two straight alkyl or alkenyl groups each having at least 12 carbon atoms, such as at least 14 carbon atoms. In some embodiments, each of the straight alkyl and alkenyl groups has at most 30 carbon atoms, such as at most 28, at most 26, at most 24, at most 22, at most 20, or at most 18 carbon atoms. In some embodiments, R22comprises one or two straight alkyl or alkenyl groups each having 12 to 30 carbon atoms (such as 12 to 28 carbon atoms, 12 to 26 carbon atoms, 12 to 24 carbon atoms, 12 to 22 carbon atoms, 12 to 20 carbon atoms, or 12 to 18 carbon atoms).

[0453] In some embodiments, the sarcosinylated lipid has the structure of the following general formula (IXX): wherein R is H, a hydrophilic group or a functional group optionally comprising a targeting moiety; and s is the number of sarcosine units.

[0454] In some embodiments, the sarcosinylated lipid has the structure of the following formula (IXX-1 ): wherein s1 is 23. The sarcosinylated lipid of formula (IXX-1 ) is also referred to herein as "C1 4pSar23".

[0455] In some embodiments, an LNP herein may comprise an oxazolinylated and / or / oxazinylated lipid. In some embodiments, the nucleic acid compositions (such as DNA or RNA compositions, especially mRNA compositions) described herein comprise an oxazolinylated and / or / oxazinylated lipid and are substantially free of a pegylated lipid (or do not contain a pegylated lipid).

[0456] In some embodiments, the nucleic acid compositions (such as DNA or RNA compositions, especially mRNA compositions) described herein comprise a cationic / cationically ionizable lipid as described herein and an oxazolinylated and / or oxazinylated lipid (POX and / or POZ-conjugated lipid). In some embodiments, the nucleic acid compositions (such as DNA or RNA compositions, especially mRNA compositions) described herein may further comprise a neutral lipid (e.g., a phospholipid, cholesterol or a derivative thereof) or a combination of neutral lipids (e.g., a phospholipid, and cholesterol or a derivative thereof). In some embodiments, the nucleic acid compositions (such as DNA or RNA compositions, especially mRNA compositions) described herein comprise a cationic / cationically ionizable lipid as described herein, an oxazolinylated and / or oxazinylated lipid, a neutral lipid (e.g., a phospholipid), and cholesterol or a derivative thereof. In some embodiments, the phospholipid is DSPC. In some embodiments, the cationic / cationically ionizable lipid is a cationically ionizable lipid of formula (X) (such as a cationically ionizable lipid of formula (X-3) or (X-45)). In some embodiments, the cationic / cationically ionizable lipid is a cationically ionizable lipid of formula (XI) (such as a cationically ionizable lipid of formula (XIV-1), (XIV-2), or (XIV-3)). In some embodiments, the cationic / cationically ionizable lipid is DPL14, EA-2, or 3D-P- DMA. In some embodiments of the nucleic acid compositions (such as DNA or RNA compositions, especially mRNA compositions) described herein which comprise an oxazolinylated and / or oxazinylated lipid, said compositions are substantially free of a pegylated lipid (or do not contain a pegylated lipid).

[0457] In some embodiments, in the oxazolinylated and / or oxazinylated lipid (i.e., the conjugate comprising (i) a POX and / or POZ polymer and (ii) one or more hydrophobic chains), components (i) and (ii) are linked to each other via a linker which comprises at least one functional moiety. In some embodiments, said linker comprises an alkylene moiety substituted with at least one monovalent functional moiety. In some embodiments, said linker comprises an alkylene group and a divalent functional moiety, wherein the divalent functional moiety links the alkylene group to the one or more hydrophobic chains, and the alkylene group is attached to the POX and / or POZ polymer. In some embodiments, said linker comprises an alkylene group and a divalent functional moiety, wherein the divalent functional moiety links the alkylene group to the one or more hydrophobic chains, the alkylene group is substituted with at least one monovalent functional moiety, and the alkylene group is attached to the POX and / or POZ polymer.

[0458] In some embodiments of the oxazolinylated and / or oxazinylated lipid, each monovalent functional moiety is independently selected from hydroxy, ether, halogen, cyano, azido, nitro, amino, ammonium, ester, carboxyl, thiol (sulfanyl), disulfanyl, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfinamide, sulfonamide, sulfamate, diselenide, sulfurous diamide, sulfuric diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioate, dithioate, imidate, imino, imidothioate, thionylamido, carbonate, carbonothioate, carbonodithioate, carbonotrithioate, guanidino (imidamido), carbamimidate, carbonimidate, carbamate, carbamodithioate, carbonodithioimidate, carbamimidothioate, carbamothioate, carbonimidothioate, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imide, and amide moieties.

[0459] In some embodiments of the oxazolinylated and / or oxazinylated lipid, each divalent functional moiety is independently selected from ether, amino, ester, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfinamide, sulfonamide, sulfamate, diselenide, sulfurous diamide, sulfuric diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioate, dithioate, imidate, imino, imidothioate, thionylamido, carbonate, carbonothioate, carbonodithioate, carbonotrithioate, guanidino (imidamido), carbamimidate, carbonimidate, carbamate, carbamodithioate, carbonodithioimidate, carbamimidothioate, carbamothioate, carbonimidothioate, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imine, imide, and amide moieties.

[0460] In some embodiments, the oxazolinylated and / or oxazinylated lipid comprises one of the following structures (in particular, if the one or more hydrophobic chains are attached to the N-end (i.e., the terminal N atom) of the POX and / or POZ polymer, as shown, for example in formula (XXI) herein):

[0461] (hydrophobic chain)1-2-(alkylene moiety substituted with at least one monovalent functional moiety)-(POX and / or POZ polymer)

[0462] [(hydrophobic chain)-(divalent functional moiety)]i-2-(alkylene moiety)-(POX and / or POZ polymer).

[0463] In some embodiments, the oxazolinylated and / or oxazinylated lipid has one of the following formulas (in particular, if the one or more hydrophobic chains are attached to the N-end (i.e., the terminal N atom) of the POX and / or POZ polymer, as shown, for example in formula (XXI) herein below):

[0464] (hydrophobic chain)1-2-(alkylene moiety substituted with at least one monovalent functional moiety)-(POX and / or POZ polymer)-(end group)

[0465] [(hydrophobic chain)-(divalent functional moiety)]1-2-(alkylene moiety)-(POX and / or POZ polymer)-(end group).

[0466] In some embodiments of the oxazolinylated and / or oxazinylated lipid, the alkylene moiety substituted with at least one monovalent functional moiety is substituted with one or more (such as 1 to the maximum number of hydrogen atoms bound to the alkylene moiety, e.g., 1 , 2, 3, 4, 5, or 6, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected monovalent functional moieties.

[0467] In some embodiments of the oxazolinylated and / or oxazinylated lipid, the alkylene moiety is C1-6-alkylene, such as C1-3-alkylene, e.g., methylene, ethylene, or trimethylene.

[0468] In some embodiments (in particular those, where the one or more hydrophobic chains are attached to the C-end (i.e., the terminal C atom) of the POX and / or POZ polymer, as shown, for example in formula (XXI’) herein), the linker comprises at least one difunctional moiety via which the one or more hydrophobic chains are attached to the POX and / or POZ polymer. In some embodiments, the linker may additionally comprise an alkylene moiety (such as a C1-6alkylene moiety, e.g., a C1-3alkylene moiety), a cycloalkylene moiety (preferably a C8-s-cycloalkylene, such as C3-6-cycloalkylene moiety), or a cycloalkenylene moiety (preferably a C8-s-cycloalkenylene, such as C3-6- cycloalkenylene moiety) each of which connects the difunctional moiety to the POX and / or POZ polymer (either directly to the end of the POX and / or POZ polymer or, preferably, via a further difunctional moiety). For example, one hydrophobic chain may be attached to the end of the POX and / or POZ polymer via one difunctional moiety (either directly or via an alkylene, cycloalkylene, or cycloalkenylene moiety or via an alkylene, cycloalkylene, or cycloalkenylene moiety which bears another difunctional moiety); two hydrophobic chains may be attached to the end of the POX and / or POZ polymer via two difunctional moieties (which in turn are preferably attached to an alkylene, cycloalkylene, or cycloalkenylene moiety or to an alkylene, cycloalkylene, or cycloalkenylene moiety bearing another difunctional moiety); or two hydrophobic chains may be attached to the end of the POX and / or POZ polymer via the same difunctional moiety (which is then a trifunctional moiety and which may be attached to the end of the POX and / or POZ polymer either directly or via an alkylene, cycloalkylene, or cycloalkenylene moiety or to an alkylene, cycloalkylene, or cycloalkenylene moiety bearing another difunctional moiety). In some embodiments, each divalent functional moiety is independently selected from ether, amino, ester, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfinamide, sulfonamide, sulfamate, diselenide, sulfurous diamide, sulfuric diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioate, dithioate, imidate, imino, imidothioate, thionylamido, carbonate, carbonothioate, carbonodithioate, carbonotrithioate, guanidino (imidamido), carbamimidate, carbonimidate, carbamate, carbamodithioate, carbonodithioimidate, carbamimidothioate, carbamothioate, carbonimidothioate, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imine, imide, and amide moieties.

[0469] In some embodiments of the oxazolinylated and / or oxazinylated lipid, the cycloalkylene moiety is C3-8-cycloalkylene, such as C3-6-cycloalkylene, e.g., cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, wherein the cycloalkylene moiety is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents (e.g., independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and C1-3-alkyl). In some embodiments of the oxazolinylated and / or oxazinylated lipid, the cycloalkenylene moiety is C3-8-cycloalkenylene, such as C3-6-cycloalkenylene, e.g., cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, wherein the cycloalkenylene moiety is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents (e.g., independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and C1-3-alkyl).

[0470] In some embodiments of the oxazolinylated and / or oxazinylated lipid, the alkylene moiety is C1-6-alkylene, such as C1-3-alkylene, e.g., methylene, ethylene, or trimethylene, or C2-3alkylene.

[0471] In some embodiments (in particular those, where the one or more hydrophobic chains are attached to the C-end (i.e., the terminal C atom) of the POX and / or POZ polymer, as shown, for example in formula (XXI’) herein below), the oxazolinylated and / or oxazinylated lipid comprises one of the following structures (and may have the general formula (XXI’)):

[0472] (hydrophobic chain)-(divalent functional moiety)-(POX and / or POZ polymer) [(hydrophobic chain)-(divalent functional moiety)]i-2-(alkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)

[0473] (hydrophobic chain)-(divalent functional moiety)-(cycloalkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)

[0474] (hydrophobic chain)-(divalent functional moiety)-(cycloalkenylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)

[0475] (hydrophobic chain)-(divalent functional moiety)-(alkylene moiety)-(POX and / or POZ polymer)

[0476] [(hydrophobic chain)2-(trivalent functional moiety)]-(alkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)

[0477] In some embodiments (in particular those, where the one or more hydrophobic chains are attached to the C-end (i.e., the terminal C atom) of the POX and / or POZ polymer, as shown, for example in formula (XXI’) herein below), the oxazolinylated and / or oxazinylated lipid has one of the following formulas (and may fall within general formula (XXI’)):

[0478] (hydrophobic chain)-(divalent functional moiety)-(POX and / or POZ polymer)-(end group) [(hydrophobic chain)-(divalent functional moiety)]i-2-(alkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)-(end group)

[0479] (hydrophobic chain)-(divalent functional moiety)-(cycloalkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)-(end group)

[0480] (hydrophobic chain)-(divalent functional moiety)-(cycloalkenylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)-(end group)

[0481] (hydrophobic chain)-(divalent functional moiety)-(alkylene moiety)-(POX and / or POZ polymer)-(end group)

[0482] [(hydrophobic chain)2-(trivalent functional moiety)]-(alkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)-(end group)

[0483] The POX and / or POZ polymer may comprise a neutral end group (such as H, alkyl, alkoxy, ester, or amide end group) or a functionalized end group (e.g., hydroxy, thiol, cyano, azido, or amino end group). In the case of nucleic acid-lipid particles, the POX and / or POZ polymer is conjugated to, preferably covalently bound to one or more hydrophobic chains.

[0484] In certain embodiments of the oxazolinylated and / or oxazinylated lipid, the end groups of the POX and / or POZ polymer may be functionalized with one or more molecular moieties conferring certain properties, such as positive or negative charge, or a targeting agent that will direct the particle to a particular cell type, collection of cells, or tissue.

[0485] A variety of suitable targeting agents are known in the art. Non-limiting examples of targeting agents include a peptide, a protein, an enzyme, a nucleic acid, a fatty acid, a hormone, an antibody, a carbohydrate, mono-, oligo- or polysaccharides, a peptidoglycan, a glycopeptide, or the like. In some embodiments, targeting agents include targeting pairs, such as the following pairs: antigen - antibody specific for said antigen; avidin - streptavidin; folate - folate receptor; transferrin - transferrin receptor; aptamer - molecule for which the aptamer is specific (e.g., pegaptanib- VEGF receptor); arginine-glycine-aspartic acid (RGD) peptide - αvβ3integrin; asparagine-glycine-arginine (NGR) peptide - aminopeptidase N; galactose - asialoglyco-protein receptor. For example, any of a number of different materials that bind to antigens on the surfaces of target cells can be employed. Antibodies to target cell surface antigens will generally exhibit the necessary specificity for the target. In addition to antibodies, suitable immunoreactive fragments can also be employed, such as the Fab, Fab', F(ab')2 or scFv fragments or single-domain antibodies (e.g. camelids VHH fragments). Many antibody fragments suitable for use in forming the targeting mechanism are already available in the art. Similarly, ligands for any receptors on the surface of the target cells can suitably be employed as targeting agent. These include any small molecule or biomolecule, natural or synthetic, which binds specifically to a cell surface receptor, protein or glycoprotein found at the surface of the desired target cell.

[0486] In certain embodiments of the oxazolinylated and / or oxazinylated lipid, the POX and / or POZ polymer comprises between 2 and 200, between 2 and 190, between 2 and 180, between 2 and 170, between 2 and 160, between 2 and 150, between 2 and 140, between 2 and 130, between 2 and 120, between 2 and 110, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 5 and 200, between 5 and 190, between 5 and 180, between 5 and 170, between 5 and 160, between 5 and 150, between 5 and 140, between 5 and 130, between 5 and 120, between 5 and 110, between 5 and 100, between 5 and 90, between 5 and 80, between 5 and 70, between 10 and 200, between 10 and 190, between 10 and 180, between 10 and 170, between 10 and 160, between 10 and 150, between 10 and 140, between 10 and 130, between 10 and 120, between 10 and 110, between 10 and 100, between 10 and 90, between 10 and 80, or between 10 and 70 POX and / or POZ repeating units.

[0487] In some embodiments, the POX and / or POZ polymer in the oxazolinylated and / or oxazinylated lipid comprises the following general formula (XX): wherein a is an integer between 1 and 2; Rir is alkyl, in particular C1-3alkyl, such as methyl, ethyl, iso-propyl, or n-propyl, and is independently selected for each repeating unit; and m refers to the number of POX and / or POZ repeating units.

[0488] In some embodiments of the oxazolinylated and / or oxazinylated lipid, the POX and / or POZ polymer is a polymer of POX and comprises repeating units of the following general formula (XXa):

[0489] In some embodiments of the oxazolinylated and / or oxazinylated lipid, the POX and / or POZ polymer is a polymer of POZ and comprises repeating units of the following general formula (XXb):

[0490] In any of the above embodiments of formulas (XX), (XXa), and (XXb), m ( / .e., the number of repeating units of formula (XXa) or formula (XXb) in the polymer) preferably is between 2 and 190, such as between 2 and 180, between 2 and 170, between 2 and 160, between 2 and 150, between 2 and 140, between 2 and 130, between 2 and 120, between 2 and 110, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 5 and 200, between 5 and 190, between 5 and 180, between 5 and 170, between 5 and 160, between 5 and 150, between 5 and 140, between 5 and 130, between 5 and 120, between 5 and 110, between 5 and 100, between 5 and 90, between 5 and 80, between 5 and 70, between 10 and 200, between 10 and 190, between 10 and 180, between 10 and 170, between 10 and 160, between 10 and 150, between 10 and 140, between 10 and 130, between 10 and 120, between 10 and 110, between 10 and 100, between 10 and 90, between 10 and 80, or between 10 and 70. In certain embodiments of any of the above embodiments of formulas (XX), (XXa), and (XXb), m is 2 to 180, such as 4 to 160, 6 to 140, 8 to 120 or 10 to 100, e.g., 20 to 80, 30 to 70, or 40 to 50.

[0491] In some embodiments of the oxazolinylated and / or oxazinylated lipid, the POX and / or POZ polymer is a copolymer comprising repeating units of the following general formulas (XXa) and (XXb): wherein the number of repeating units of formula (XXa) in the copolymer is 1 to 199; the number of repeating units of formula (XXb) in the copolymer is 1 to 199; and the sum of the number of repeating units of formula (XXa) and the number of repeating units of formula (XXb) in the copolymer is 2 to 200.

[0492] In some embodiments of the oxazolinylated and / or oxazinylated lipid, the number of repeating units of formula (XXa) in the copolymer is 1 to 179, such as 1 to 159, 1 to 139, 1 to 119 or 1 to 99; the number of repeating units of formula (XXb) in the copolymer is 1 to 179, such as 1 to 159, 1 to 139, 1 to 119 or 1 to 99; and the sum of the number of repeating units of formula (XXa) and the number of repeating units of formula (XXb) in the copolymer is 2 to 180, such as 4 to 160, 6 to 140, 8 to 120 or 10 to 100, e.g., 20 to 80, 30 to 70, or 40 to 50.

[0493] In some of the above embodiments of formulas (XX), (XXa), and (XXb), R11at each occurrence (i.e., in each repeating unit) may be the same alkyl group (e.g., R11may be methyl in each repeating unit). In some alternative embodiments of formulas (XX), (XXa), and (XXb), R11in at least one repeating unit differs from R11in another repeating unit (e.g., for at least one repeating unit R11is one specific alkyl (such as ethyl), and for at least one different repeating unit R11is a different specific alkyl (such as methyl)). For example, each R11may be selected from two different alkyl groups (such as methyl and ethyl) and not all R11are the same alkyl.

[0494] In any of the above embodiments of formulas (XX), (XXa), and (XXb), R11preferably is methyl or ethyl, more preferably methyl. Thus, in some embodiments of formulas (XX), (XXa), and (XXb), each R11is methyl or each R11is ethyl. In some alternative embodiments of formulas (XX), (XXa), and (XXb), R11is independently selected from methyl and ethyl for each repeating unit, wherein in at least one repeating unit R11is methyl, and in at least one repeating unit R11is ethyl.

[0495] In some embodiments, the oxazolinylated and / or oxazinylated lipid has the following general formula (XXI) or (XXI’): wherein: a is an integer between 1 and 2;

[0496] R11is alkyl, in particular C1-3alkyl, such as methyl, ethyl, iso-propyl, or n-propyl, and is independently selected for each repeating unit; m is 2 to 200;

[0497] R12is R14or -L11(R14)p, wherein each R14is independently a hydrocarbyl group; L11is a linker; and p is 1 or 2; and

[0498] R13 is selected from the group consisting of H, C1-6alkyl, C2-6alkynyl, -OR20, -SR20, halogen,

[0499] -CN, -N3, -OC(O)R21, -C(O)R21, -NR22R23, -COOH, -C(O)NR22R23, -NR22C(O)R21, a sugar, an amino acid, a peptide, and a member of a targeting pair, wherein the C1-6alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of -OH, SH, halogen, -CN, -N3, C2-6alkynyl, -COOH, -NR22R23, - C(O)NR22R23, -NR22C(O)R21, a sugar, an amino acid, a peptide, and a member of a targeting pair; R20is selected from the group consisting of H, C1-3alkyl and 3- to 6- membered heterocyclyl, wherein each of the C1-3alkyl and 3- to 6-membered heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of -OH, SH, halogen, -CN, -N3, C2-6alkynyl, -COOH, -NR22R23, a sugar, an amino acid, a peptide, and a member of a targeting pair; R21 is selected from the group consisting of C1-6alkyl and 3- to 6-membered heterocyclyl, wherein each of the C1-6alkyl and 3- to 6-membered heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of -OH, SH, halogen, -CN, -N3, C2-6alkynyl, -COOH, -NR22R23, a sugar, an amino acid, a peptide, and a member of a targeting pair; and each of R22and R23is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R22and R23may join together with the nitrogen atom to which they are attached to form a heterocyclyl group, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of -OH, SH, halogen, -CN, -N3, C26 alkynyl, -COOH, -NH2, -NH(C1-3alkyl), - N(C1-3alkyl)2, a sugar, an amino acid, a peptide, and a member of a targeting pair. In formula (XXI) R12 is attached to the N-end (i.e., the terminal N atom) of the POX and / or POZ polymer and RI3is attached to the C-end (i.e., the terminal C atom) of the POX and / or POZ polymer, whereas in formula (XXI’) R12 is attached to the C-end (i.e., the terminal C atom) of the POX and / or POZ polymer and RI3is attached to the N-end (i.e., the terminal N atom) of the POX and / or POZ polymer.

[0500] In some embodiments (in particular of the oxazolinylated and / or oxazinylated lipid of formulas (XXI) and (XXI’)), the targeting pair is selected from the following pairs: antigen - antibody specific for said antigen; avidin - streptavidin; folate - folate receptor; transferrin - transferrin receptor; aptamer - molecule for which the aptamer is specific; arginine-glycine-aspartic acid (RGD) peptide - αvβ3integrin; asparagine-glycine-arginine (NGR) peptide - aminopeptidase N; galactose - asialoglyco-protein receptor. Thus, in some embodiments, a member of a targeting pair includes one of the following: an antigen, an antibody, avidin, streptavidin, folate, transferrin, an aptamer; an RGD peptide; an NGR peptide; and galactose.

[0501] In some embodiments of formula (XXI), a is 1 , i.e., the oxazolinylated and / or oxazinylated lipid has the following general formula (XXIa) or (XXIa’):

[0502] In some embodiments of formula (XXI), a is 2, i.e., the oxazolinylated and / or oxazinylated lipid has the following general formula (XXIb) or (XXIb’): In any of the above embodiments of formulas (XXIa), (XXIa’), (XXIb), and (XXIb’), R11, R12, R13, and m are as defined for formula (XXI) / (XXI’).

[0503] In some of the above embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), and (XXIb’), Ri 1 at each occurrence (i.e., in each repeating unit) may be the same alkyl group (e.g., R11may be methyl in each repeating unit). In some alternative embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), and (XXIb’), R11in at least one repeating unit differs from R11in another repeating unit (e.g., for at least one repeating unit R11is one specific alkyl (such as ethyl), and for at least one different repeating unit R11is a different specific alkyl (such as methyl)). For example, each R11may be selected from two different alkyl groups (such as methyl and ethyl) and not all R11are the same alkyl. In any of the above embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), and (XXIb’), R11preferably is methyl or ethyl, more preferably methyl. Thus, in some embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), and (XXIb’), each R11is methyl or each R11is ethyl. In some alternative embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), and (XXIb’), R11is independently selected from methyl and ethyl for each repeating unit, wherein in at least one repeating unit R11is methyl, and in at least one repeating unit R11is ethyl.

[0504] In any of the above embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), and (XXIb’), m preferably is between 2 and 190, such as between 2 and 180, between 2 and 170, between 2 and 160, between 2 and 150, between 2 and 140, between 2 and 130, between 2 and 120, between 2 and 110, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 5 and 200, between 5 and 190, between 5 and 180, between 5 and 170, between 5 and 160, between 5 and 150, between 5 and 140, between 5 and 130, between 5 and 120, between 5 and 110, between 5 and 100, between 5 and 90, between 5 and 80, between 5 and 70, between 10 and 200, between

[0505] 10 and 190, between 10 and 180, between 10 and 170, between 10 and 160, between

[0506] 10 and 150, between 10 and 140, between 10 and 130, between 10 and 120, between

[0507] 10 and 110, between 10 and 100, between 10 and 90, between 10 and 80, or between

[0508] 10 and 70. In certain embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), and (XXIb’), m is 2 to 180, such as 4 to 160, 6 to 140, 8 to 120 or 10 to 100, e.g., 20 to 80, 30 to 70, or 40 to 50. In some embodiments of formulas (XXI), (XXI’), (XXIIa), (XXIa’), (XXIb), and (XXIb’), L11comprises at least one functional moiety, such as an alkylene moiety substituted with at least one monovalent functional moiety and / or linked, at the end by which the alkylene group is attached to R14, to a divalent functional moiety, wherein preferably each monovalent functional moiety is independently selected from hydroxy, ether, halogen, cyano, azido, nitro, amino, ammonium, ester, carboxyl, thiol (sulfanyl), disulfanyl, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfinamide, sulfonamide, sulfamate, diselenide, sulfurous diamide, sulfuric diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioate, dithioate, imidate, imino, imidothioate, thionylamido, carbonate, carbonothioate, carbonodithioate, carbonotrithioate, guanidino (imidamido), carbamimidate, carbonimidate, carbamate, carbamodithioate, carbonodithioimidate, carbamimidothioate, carbamothioate, carbonimidothioate, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imide, and amide; and / or each divalent functional moiety is independently selected from ether, amino, ester, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfinamide, sulfonamide, sulfamate, diselenide, sulfurous diamide, sulfuric diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioate, dithioate, imidate, imino, imidothioate, thionylamido, carbonate, carbonothioate, carbonodithioate, carbonotrithioate, guanidino (imidamido), carbamimidate, carbonimidate, carbamate, carbamodithioate, carbonodithioimidate, carbamimidothioate, carbamothioate, carbonimidothioate, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imine, imide, and amide.

[0509] In some embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), and (XXIb’), L11comprises an alkylene moiety substituted with at least one monovalent functional moiety as specified above. Thus, in some embodiments, the oxazolinylated and / or oxazinylated lipid may comprise the following structure (in particular, if the one or more hydrophobic chains are attached to the N-end (i.e., the terminal N atom) of the POX and / or POZ polymer, as shown, for example in formula (XXI)):

[0510] (hydrophobic chain)1-2-(alkylene moiety substituted with at least one monovalent functional moiety)-(POX and / or POZ polymer), wherein "hydrophobic chain" represents R14; "alkylene moiety substituted with at least one monovalent functional moiety" represents L11; and "POX and / or POZ polymer" represents the polymer specified in formula (XX).

[0511] In some embodiments, the oxazolinylated and / or oxazinylated lipid has the following formula (XXIc) (in particular, if the one or more hydrophobic chains are attached to the N-end (i.e., the terminal N atom) of the POX and / or POZ polymer, as shown, for example in formula (XXI)):

[0512] (hydrophobic chain)i-2-(alkylene moiety substituted with at least one monovalent functional moiety)-(POX and / or POZ polymer)-R13

[0513] In some embodiments (in particular of the oxazolinylated and / or oxazinylated lipid of formula (XXIc)), the at least one monovalent functional moiety may be any one of the monovalent functional moieties specified herein, e.g., selected from the groups consisting of hydroxy, ether, halogen, cyano, azido, nitro, amino, ammonium, ester, carboxyl, thiol (sulfanyl), disulfanyl, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfinamide, sulfonamide, sulfamate, diselenide, sulfurous diamide, sulfuric diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioate, dithioate, imidate, imino, imidothioate, thionylamido, carbonate, carbonothioate, carbonodithioate, carbonotrithioate, guanidino (imidamido), carbamimidate, carbonimidate, carbamate, carbamodithioate, carbonodithioimidate, carbamimidothioate, carbamothioate, carbonimidothioate, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imide, and amide.

[0514] In some embodiments (in particular of the oxazolinylated and / or oxazinylated lipid of formula (XXIc)), the alkylene moiety substituted with at least one monovalent functional moiety is C1-6-alkylene, such as C1-3-alkylene, e.g., methylene, ethylene, or trimethylene. In some embodiments (in particular of the oxazolinylated and / or oxazinylated lipid of formula (XXIc)), the alkylene moiety substituted with at least one monovalent functional moiety is substituted with one or more (such as 1 to the maximum number of hydrogen atoms bound to the alkylene moiety, e.g., 1 , 2, 3, 4, 5, or 6, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected monovalent functional moieties.

[0515] In some embodiments (in particular of the oxazolinylated and / or oxazinylated lipid of formula (XXIc)), the alkylene moiety substituted with at least one monovalent functional moiety is C1-6-alkylene, such as C1-3-alkylene, e.g., methylene, ethylene, or trimethylene, and is substituted with one or more (such as 1 to the maximum number of hydrogen atoms bound to the alkylene moiety, e.g., 1 , 2, 3, 4, 5, or 6, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected monovalent functional moieties.

[0516] In some embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), and (XXIb’), L11comprises an alkylene moiety linked, at the end by which the alkylene group is attached to R14, to a divalent functional moiety as specified above. Thus, in some embodiments, the oxazolinylated and / or oxazinylated lipid may comprise the following structure (in particular, if the one or more hydrophobic chains are attached to the N-end (i.e., the terminal N atom) of the POX and / or POZ polymer, as shown, for example in formula (XXI)):

[0517] [(hydrophobic chain)-(divalent functional moiety)]i-2-(alkylene moiety)-(POX and / or POZ polymer), wherein "hydrophobic chain" represents R14; "-(divalent functional moiety)]i-2-(alkylene moiety)" represents L11; and "POX and / or POZ polymer" represents the polymer specified in formula (XX).

[0518] In some embodiments, the oxazolinylated and / or oxazinylated lipid has the following formula (XXId) (in particular, if the one or more hydrophobic chains are attached to the N-end (i.e., the terminal N atom) of the POX and / or POZ polymer, as shown, for example in formula (XXI)):

[0519] [(hydrophobic chain)-(divalent functional moiety)]i-2-(alkylene moiety)-(POX and / or POZ polymer)-Ri3

[0520] In some embodiments (in particular of the oxazolinylated and / or oxazinylated lipid of formula (XXId)), the divalent functional moiety may be any one of the divalent functional moieties specified herein, e.g., selected from the groups consisting of ether, amino, ester, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfinamide, sulfonamide, sulfamate, diselenide, sulfurous diamide, sulfuric diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioate, dithioate, imidate, imino, imidothioate, thionylamido, carbonate, carbonothioate, carbonodithioate, carbonotrithioate, guanidino (imidamido), carbamimidate, carbonimidate, carbamate, carbamodithioate, carbonodithioimidate, carbamimidothioate, carbamothioate, carbonimidothioate, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imine, imide, and amide. In some embodiments, the linker comprises at least one divalent functional moiety selected from the group consisting of ester, sulfide, disulfide, sulfone, orthoester, acylhydrazone, hydrazine, oxime, acetal, ketal, amino, and amide moieties. In some preferred embodiments, the linker comprises at least one divalent functional moiety selected from the group consisting of ester, sulfide, sulfone, amino, and amide moieties. In some embodiments (in particular of the oxazolinylated and / or oxazinylated lipid of formula (XXId)), the alkylene moiety is C1-6-alkylene, such as C1-3-alkylene, e.g., methylene, ethylene, or trimethylene.

[0521] In some embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), (XXIb’), (XXIc), and (XXId) (in particular those, where the one or more hydrophobic chains are attached to the N-end (i.e., the terminal N atom) of the POX and / or POZ polymer, as shown, for example in formula (XXI)), L11comprises at least one ester, sulfide, disulfide, sulfone, orthoester, acylhydrazone, hydrazine, oxime, acetal, ketal, or amide moiety. In certain embodiments, L11is selected from the group consisting of [*-NHC(O)]p(C1-6-alkylene), [*- C(O)NH]p(C1-6-alkylene)-, [*-C(O)O]p(C1-6-alkylene)-, [*-OC(O)]p-(C1-6-alkylene)-, [*- S]p(C1-6-alkylene)-, [*-SS]p(C1-6-alkylene)-, [*-S(O)2]p(C1-6-alkylene)-, [(*-O)rC(OR25)3- r](C1-6-alkylene)-, [*-C(OR25)2O]P(C1-6-alkylene)-, [*-C(R25)(=N-N(R26)C(O)-)]P(C1-6- alkylene)-, [*-C(O)(N(R26)-N=)C(R25)-]p(C1-6-alkylene)-, [*=C(=N-N(R26)C(O)(R25))]p(C1-6- alkylene)-, [*N(R26)N(R26)]P(C1-6-alkylene)-, [*=C(=N(OH))]p(C1-6-alkylene)-, and [*- OC(R25)(R26)O]p(C1-6-alkylene)-, wherein * represents the attachment point to R14; p is 1 or 2; C1-6-alkylene is either bivalent (if p is 1 ) or trivalent (if p is 2); R25is selected from the group consisting of C1-6alkyl, aryl, and aryl-(C1-6alkyl); R26is selected from the group consisting of H, C1-6alkyl, aryl, and aryl(C1-6alkyl); and r is an integer between 1 and 2. For example, L11may be selected from the group consisting of [*-NHC(O)]p(C1-3- alkylene)-, [*-C(O)NH]p(C1-3-alkylene)-, [*-C(O)O]p(C1-3-alkylene)-, [*-OC(O)]p(C1-3- alkylene)-, [*-S]p(C1-3-alkylene)-, [*-SS]p(C1-3-alkylene)-, [*-S(O)2]p(C1-3-alkylene)-, [(*-O)rC(OR25)3-r](C1-3-alkylene)-, [*-C(OR25)2O]p(C1-3-alkylene)-, [*-C(R25)(=N- N(R26)C(O)-)]p(C1-3-alkylene)-, [*-C(O)(N(R26)-N=)C(R25)-]P(C1-3-alkylene)-, [*=C(=N- N(R26)C(O)(R25))]p(C1-3-alkylene)-, [*N(R26)N(R26)]P(C1-3-alkylene)-, [*=C(=N(OH))]p(C1-3- alkylene)-, and [*-OC(R25)(R26)O]p(C1-3-alkylene)-, wherein * represents the attachment point to R14; p is 1 or 2; C1-3-alkylene is either bivalent (if p is 1 ) or trivalent (if p is 2); R25is selected from the group consisting of C1-6alkyl, aryl, and aryl(C1-6alkyl); R26is selected from the group consisting of H, C1-6alkyl, aryl, and aryl(C1-6alkyl); and r is an integer between 1 and 2.

[0522] In some embodiments, R25is selected from the group consisting of C1-3alkyl, phenyl, and phenyl(C1-3alkyl), such as from the group consisting of methyl, ethyl, phenyl, benzyl, and phenylethyl.

[0523] In some embodiments, R26is selected from the group consisting of H, C1-3alkyl, phenyl, and phenyl(C13alkyl), such as from the group consisting of H, methyl, ethyl, phenyl, benzyl, and phenylethyl.

[0524] In some embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), (XXIb’), (XXIc), and (XXId) (in particular those, where the one or more hydrophobic chains are attached to the N-end (i.e., the terminal N atom) of the POX and / or POZ polymer, as shown, for example in formula (XXI)), L11is selected from the group consisting of [*-NHC(O)]P(C1-6- alkylene)-, [*-C(O)NH]p(C1-6-alkylene)-, [*-C(O)O]p(C1-6-alkylene)-, [*-OC(O)]p(C1-6- alkylene)-, [*-S]p(C1-6-alkylene)-, and [*-S(O)2]p(C1-6-alkylene)-, preferably from the group consisting of [*-NHC(O)]p(C1-6-alkylene)-, [*-C(O)O]p(C1-6-alkylene)-, [*-OC(O)]p(C1-6- alkylene)-, [*-S]p(C1-6-alkylene)-, and [*-S(O)2]p(C1-6-alkylene)-, more preferably from the group consisting of [*-NHC(O)]p(C1-6-alkylene)- and [*-C(O)O]p(C1-6-alkylene)-, wherein * represents the attachment point to R14; p is 1 or 2; and C1-6-alkylene is either bivalent (if p is 1 ) or trivalent (if p is 2).

[0525] In some embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), (XXIb’), (XXIc), and (XXId) (in particular those, where the one or more hydrophobic chains are attached to the N-end (i.e., the terminal N atom) of the POX and / or POZ polymer, as shown, for example in formula (XXI)), L11is selected from the group consisting of [*-NHC(O)]P(CI-3- alkylene)-, [*-C(O)NH]p(C1-3-alkylene)-, [*-C(O)O]p(C1-3-alkylene)-, [*-OC(O)]p-( C1-3- alkylene)-, [*-S]p(C1-3-alkylene)-, and [*-S(O)2]p(C1-3-alkylene)-, preferably from the group consisting of [*-NHC(O)]p(C1-3-alkylene)-, [*-C(O)O]p(C1-3-alkylene)-, [*-OC(O)]p(C1-3- alkylene)-, [*-S]p(C1-3-alkylene)-, and [*-S(O)2]p(C1-3-alkylene)-, more preferably from the group consisting of [*-NHC(O)]p(C1-3-alkylene)- and [*-C(O)O]p(C1-3-alkylene)-, wherein * represents the attachment point to R14; p is 1 or 2; and C1-3-alkylene is either bivalent (if p is 1 ) or trivalent (if p is 2).

[0526] In some embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), (XXIb’), (XXIc), and (XXId) (in particular those, where the one or more hydrophobic chains are attached to the N-end (i.e., the terminal N atom) of the POX and / or POZ polymer, as shown, for example in formula (XXI)), L11is selected from the group consisting of *-NHC(O)-(CH2)- , *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)-, *-C(O)NH-(CH2)2-, -(CH2)-CH(OC(O)-*)- (CH2OC(O)-*), -(CH2)-CH(S-*)2, -(CH2)-CH(S-*)-CH2(S-*), *-S-(CH2)3-, *-S(O)2-(CH2)3-, and *-OC(O)-(CH2)-, wherein * represents the attachment point to R14. Thus, RI2may be selected from the group consisting of R14, -L11R14, -(CH2)-CH(OC(O)R14)(CH2OC(O)R14), -(CH2)-CH(SR14)2, and -(CH2)-CH(SR14)-CH2(SR14); and L11is selected from the group consisting of *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)-, *-C(O)NH-(CH2)2-, *-S-(CH2)3-, *-S(O)2-(CH2)3-, and *-OC(O)-(CH2)-, preferably L11is *-NHC(O)-(CH2)- or *- NHC(O)-(CH2)2-, wherein * represents the attachment point to R14.

[0527] In some embodiments of formulas (XXI), (XXIa), and (XXIb), RI2is -L11(R14)p, i.e., the POX and / or POZ polymer is conjugated to the one or more hydrophobic chains (i.e., R14) via the linker L11.

[0528] In some embodiments of formulas (XXI’), (XXIa’), and (XXIb’), the linker comprises at least one difunctional moiety via which the one or more hydrophobic chains (R14) are attached to the C-end of the POX and / or POZ polymer. In some embodiments, the linker may additionally comprise an alkylene moiety (such as a One alkylene moiety, e.g., a C1-3alkylene moiety), a cycloalkylene moiety (preferably a C3-8-cycloalkylene, such as C3-6- cycloalkylene moiety), or a cycloalkenylene moiety (preferably a C3-8-cycloalkenylene, such as C3-6-cycloalkenylene moiety) each of which connects the difunctional moiety to the C-end POX and / or POZ polymer (either directly to the C-end or, preferably, via a further difunctional moiety). For example, one hydrophobic chain (R14) may be attached to the C-end of the POX and / or POZ polymer via one difunctional moiety (either directly or via an alkylene, cycloalkylene, or cycloalkenylene moiety or via an alkylene, cycloalkylene, or cycloalkenylene moiety which bears another difunctional moiety); two hydrophobic chains (R14) may be attached to the C-end of the POX and / or POZ polymer via two difunctional moieties (which in turn are preferably attached to an alkylene, cycloalkylene, or cycloalkenylene moiety or to an alkylene, cycloalkylene, or cycloalkenylene moiety bearing another difunctional moiety); or two hydrophobic chains (R14) may be attached to the C-end of the POX and / or POZ polymer via the same difunctional moiety (which is then a trifunctional moiety and which may be attached to the C-end of the POX and / or POZ polymer either directly or via an alkylene, cycloalkylene, or cycloalkenylene moiety or to an alkylene, cycloalkylene, or cycloalkenylene moiety bearing another difunctional moiety). In some embodiments, each divalent functional moiety is independently selected from ether, amino, ester, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfinamide, sulfonamide, sulfamate, diselenide, sulfurous diamide, sulfuric diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioate, dithioate, imidate, imino, imidothioate, thionylamido, carbonate, carbonothioate, carbonodithioate, carbonotrithioate, guanidino (imidamido), carbamimidate, carbonimidate, carbamate, carbamodithioate, carbonodithioimidate, carbamimidothioate, carbamothioate, carbonimidothioate, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imine, imide, and amide moieties. In some preferred embodiments of formulas (XXI’), (XXIa’), and (XXIb’), the linker comprises at least one divalent functional moiety selected from the group consisting of amide, sulfide, sulfone, and amino moieties.

[0529] In some embodiments of formulas (XXI’), (XXIa’), and (XXIb’), the cycloalkylene moiety is C3-8-cycloalkylene, such as C3-6-cycloalkylene, e.g., cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, wherein the cycloalkylene moiety is optionally substituted, such as optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and C1-3-alkyl.

[0530] In some embodiments of formulas (XXI’), (XXIa’), and (XXIb’), the cycloalkenylene moiety is C3-8-cycloalkenylene, such as C3-6-cycloalkenylene, e.g., cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, wherein the cycloalkenylene moiety is optionally substituted, such as optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents (e.g., independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and C1-3-alkyl). In some embodiments of formulas (XXI’), (XXIa’), and (XXIb’), the alkylene moiety is C16-alkylene, such as C1-3-alkylene, e.g., methylene, ethylene, or trimethylene, or C2-3alkylene.

[0531] In some embodiments of formulas (XXI’), (XXIa’), and (XXIb’), the oxazolinylated and / or oxazinylated lipid comprises one of the following structures:

[0532] (hydrophobic chain)-(divalent functional moiety)-(POX and / or POZ polymer) [(hydrophobic chain)-(divalent functional moiety)]i-2-(alkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)

[0533] (hydrophobic chain)-(divalent functional moiety)-(cycloalkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)

[0534] (hydrophobic chain)-(divalent functional moiety)-(cycloalkenylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)

[0535] (hydrophobic chain)-(divalent functional moiety)-(alkylene moiety)-(POX and / or POZ polymer)

[0536] [(hydrophobic chain)2-(trivalent functional moiety)]-(alkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)

[0537] In some embodiments of formulas (XXI’), (XXIa’), and (XXIb’), the oxazolinylated and / or oxazinylated lipid has one of the following formulas (XXIe’) to (XXIj’) :

[0538] (hydrophobic chain)-(divalent functional moiety)-(POX and / or POZ polymer)-R13(XXIe’) [(hydrophobic chain)-(divalent functional moiety)]i-2-(alkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)-R13(XXIf ’)

[0539] (hydrophobic chain)-(divalent functional moiety)-(cycloalkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)-Ri3 (XXIg’)

[0540] (hydrophobic chain)-(divalent functional moiety)-(cycloalkenylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)-R13(XXIh’)

[0541] (hydrophobic chain)-(divalent functional moiety)-(alkylene moiety)-(POX and / or POZ polymer)-Ri3 (XXIi’)

[0542] [(hydrophobic chain)2-(trivalent functional moiety)]-(alkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)-R13(XXIj’)

[0543] In some embodiments of formulas (XXI’), (XXIa’), (XXIb’), (XXIe’), (XXIf’), (XXIg’), (XXIh’), (XXIi’), and (XXIj’), L11is selected from the group consisting of [*-Z]p(C1-6- alkylene)-Z-, *-Z-(C3 8-cycloalkylene)-Z-, *-Z-(C3-8-cycloalkenylene)-Z-, (*=N)(C1-6- alkylene)-Z-, *-Z-(C1-6-alkylene)-, and *-Z-, wherein * represents the attachment point to R14; p is 1 or 2; C1-3-alkylene is either bivalent (if p is 1 ) or trivalent (if p is 2); each of the C3-8-cycloalkylene and C3-8-cycloalkenylene groups is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and C1-3-alkyl ; and each Z is independently selected from the group consisting of -OP(O)2O(C1-3-alkylene)NH-, -NH(C1-3-alkylene)OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NR22-, wherein R22is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl. For example, the linker can be selected from the group consisting of [*-C(O)O]p(C1-6-alkylene)-Z-, (*-NH)(C1-6-alkylene)-Z-, (*=N)(C1-6-alkylene)-Z-, (*-NH)C(O)(C1-6-alkylene)-Z-, (*-C(O)NH(C1-6-alkylene)-Z-, (*- NH)C(O)(C1-6-alkylene)-, (*-C(O)NH(C1-6-alkylene)-, (*-NH)C(O)-, *-C(O)NH-, *-Z-(C3.8- cycloalkenylene)-Z-, -S-, and -S(O)2-, wherein * represents the attachment point to R14; p is 1 or 2; C1-6-alkylene is either bivalent (if p is 1 ) or trivalent (if p is 2); the C3-8- cycloalkenylene group is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and C1-3-alkyl; and Z is selected from the group consisting of -OP(O)2O(C1-3- alkylene)NH-, -NH(C1-3-alkylene)OP(O)2O-, -OC(O)NH-, -NHC(O)O-, -O-, -S-, and -NH-

[0544] In some embodiments of formulas (XXI’), (XXIa’), (XXIb’), (XXIe’), (XXIf), (XXIg’), (XXIh’), (XXIi’), and (XXIj’), L11is selected from the group consisting of [*-Z]p(C1-3- alkylene)-Z-, *-Z-(C3 6-cycloalkylene)-Z-, *-Z-(C3 6-cycloalkenylene)-Z-, (*=N)(CI-3- alkylene)-Z-, *-Z(C1-3-alkylene)-, and *-Z-, wherein * represents the attachment point to R14; p is 1 or 2; C1-3-alkylene is either bivalent (if p is 1 ) or trivalent (if p is 2); each of the C3 6-cycloalkylene and C3 6-cycloalkenylene groups is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and C1-3-alkyl ; and each Z is independently selected from the group consisting of -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, - NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, -N(C1-3-alkyl)-, and -NH-. For example, the linker can be selected from the group consisting of [*- C(O)O]p(C1-3-alkylene)-Z-, (*-NH)(C1-3-alkylene)-Z-, (*=N)(C1-3-alkylene)-Z-, (*- NH)C(O)(C1-3-alkylene)-Z-, (*-C(O)NH(C1-3-alkylene)-Z-, (*-NH)C(O)(C1-3-alkylene)-, (*- C(O)NH(C1-3-alkylene)-, (*-NH)C(O)-, *-C(O)NH-, *-Z-(C3-6-cycloalkenylene)-Z-, -S-, and -S(O)2-, wherein * represents the attachment point to R14; p is 1 or 2; C1-3-alkylene is either bivalent (if p is 1) or trivalent (if p is 2); the C3-6-cycloalkenylene group is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and Ci3-alkyl ; and Z is selected from the group consisting of -OP(O)2O(C1-2-alkylene)NH-, -NH(C1-2-alkylene)OP(O)2O-, -OC(O)NH-, -NHC(O)O-,

[0545] -O-, -S-, and -NH-.

[0546] In some embodiments of formulas (XXI’), (XXIa’), (XXIb’), (XXIe’), (XXIf’), (XXIg’), (XXIh’), (XXIi’), and (XXIj’), L11is selected from the group consisting of [*-Z]p(C1-3- alkylene)-Z-, *-Z-(C3 6-cycloalkylene)-Z-, *-Z-(C3 6-cycloalkenylene)-Z-, (*=N)(C1-3- alkylene)-Z-, *-Z(C1-3-alkylene)-, and *-Z-, wherein * represents the attachment to R14; p is 1 or 2; C1-3-alkylene is either bivalent (if p is 1) or trivalent (if p is 2); each of the C3-6- cycloalkylene and C3-6-cycloalkenylene groups is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and Ci3-alkyl; and each Z is independently selected from the group consisting of -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, -N(C1-3-alkyl)-, and -NH-. For example, the linker can be selected from the group consisting of [*-C(O)O]p(C1-3- alkylene)-Z-, (*-NH)(C1-3-alkylene)-Z-, (*=N)(C1-3-alkylene)-Z-, (*-NH)C(O)(C1-3- alkylene)-Z-, (*-C(O)NH(C1-3-alkylene)-Z-, (*-NH)C(O)(C1-3-alkylene)-, (*-C(O)NH(C1-3- alkylene)-, (*-NH)C(O)-, *-C(O)NH-, *-Z-(C3-6-cycloalkenylene)-Z-, -S-, and -S(O)2-, wherein * represents the attachment point to R14; p is 1 or 2; C1-3-alkylene is either bivalent (if p is 1 ) or trivalent (if p is 2); the C3-6-cycloalkenylene group is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and Ci3-alkyl; and Z is selected from the group consisting of -OP(O)2O(CH2)2NH-, - NH(CH2)2OP(O)2O-, -OC(O)NH-, -NHC(O)O-, -O-, -S-, and -NH-. In some embodiments of formulas (XXI’), (XXIa’), (XXIb’), (XXIe’), (XXIf’), (XXIg’), (XXIh’), (XXIi’), and (XXIj’), L11is selected from the group consisting of (*- C(O)O)(CH(OC(O)-*))(CH2)-Z-, (*=N)(C1-3-alkylene)-NHC(O)-, (*-Z)(C1-3-alkylene)-Z-, *- Z-(C3 6-cycloalkenylene)-Z-, and *-Z-, wherein * represents the attachment point to R14; the C3 6-cycloalkenylene group is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and C1-3-alkyl; and each Z is independently selected from the group consisting of -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, - OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NH-. For example, the linker can be selected from the group consisting of (*-C(O)O)(CH(OC(O)-*))(CH2)-Z-, (*=N)(C1-3-alkylene)-NHC(O)-, (*-NH)(C1-3-alkylene)-NHC(O)-, *-C(O)NH-, (*-NH)C(O)-, *-Z-(C3 6-cycloalkenylene)-Z-, -S-, and -S(O)2-, wherein * represents the attachment point to R14; the C3 6-cycloalkenylene group is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, - SH, halogen, -CN, -N3, and C1-3-alkyl; and Z is selected from the group consisting of - OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -OC(O)NH-, -NHC(O)O-, -O-, -S-, and -NH.

[0547] In some embodiments of formulas (XXI’), (XXIa’), (XXIb’), (XXIe’), (XXIf), (XXIg’), (XXIh’), (XXIi’), and (XXIj’), RI2is selected from the group consisting of (R14C(O)O)(CH(OC(O)R14))(CH2)-Z-, (R14)2N(C1-3-alkylene)-NHC(O)-, R14Z(C1-3- alkylene)-Z-, R14Z-(C3 6-cycloalkenylene)-Z-, and R14Z-, wherein the C3-6- cycloalkenylene group is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and C1-3-alkyl ; and each Z is independently selected from the group consisting of -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, - NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NH-. For example, the linker can be selected from the group consisting of (R14C(O)O)(CH(OC(O)R14))(CH2)-Z-, (R14)2N(C1-3-alkylene)-NHC(O)-, R14NH(C1-3-alkylene)-NHC(O)-, R14C(O)NH-, (R14NH)C(O)-, R14Z-(C3 6-cycloalkenylene)-Z-, R14S-, and R14S(O)2-, wherein the C3-6- cycloalkenylene group is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and C1-3-alkyl; and Z is selected from the group consisting of - OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -OC(O)NH, -NHC(O)O-, -O-, -S-, -S(O)2-, and -NH-.

[0548] In some embodiments of formulas (XXI’), (XXIa’), (XXIb’), (XXIe’), (XXIf’), (XXIg’), (XXIh’), (XXII’), and (XXIj’), RI2is -LH(R14)P, i.e., the POX and / or POZ polymer is conjugated to the one or more hydrophobic chains (i.e., R14) via the linker L11.

[0549] In any of the above embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), (XXIb’), (XXIc), (XXId), (XXIe’), (XXIf’), (XXIg’), (XXIh’), (XXIi’), and (XXIj’), each R14preferably is independently a non-cyclic, more preferably straight hydrocarbyl group. For example, each R14is independently a hydrocarbyl group having at least 8 carbon atoms, such as at least 10 carbon atoms, preferably up to 30 carbon atoms, such as up to 28, 26, 24, 22, or 20 carbon atoms, or up to 16 carbon atoms, such as up to 15, 14, 13, 12, 1 1 , or 10 carbon atoms. In some embodiments, each R14is a hydrocarbyl group having 10 to 16 carbon atoms, such as 10 to 15 or 10 to 14 carbon atoms. In some embodiments, each R14is a straight hydrocarbyl group having 10 to 16 carbon atoms, such as 10 to 15 or 10 to 14 carbon atoms.

[0550] In any of the above embodiments of formulas (XXI’), (XXIa’), (XXIb’), (XXIe’), (XXIF), (XXIg’), (XXIh’), (XXIi’), and (XXIj’), each R14may preferably be a hydrocarbyl group having 10 to 18 carbon atoms, such as a straight alkyl group havingl O to 18 carbon atoms or a straight alkenyl group having 10 to 18 carbon atoms. For example, a straight alkyl group may have 10, 1 1 , 12, 13, 14, 15, 16, 17, or 18 carbon atoms; and / or a straight alkenyl group may have 10, 1 1 , 12, 13, 14, 15, 16, 17, or 18 carbon atoms and 1 , 2, or 3 carbon-carbon double bonds.

[0551] In any of the above embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), (XXIb’), (XXIc), (XXId), (XXIe’), (XXIf’), (XXIg’), (XXIh’), (XXIi’), and (XXIj’), RI3is preferably selected from the group consisting of H, C1-3alkyl, -OR20, -N3, C2-6alkynyl, - OC(O)R21, -C(O)R21, -NR22R23, -COOH, -C(O)NR22R23, -NR22C(O)R21, and a member of a targeting pair, wherein the C1-3alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of -OH, SH, halogen, - CN, -N3, C2-6alkynyl, -COOH, -NR22R23, -C(O)NR22R23, -NR22C(O)R21, and a member of a targeting pair; R20is selected from the group consisting of H, C1-3alkyl and 3- to 6- membered heterocyclyl, wherein each of the Ci3alkyl and 3- to 6-membered heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of -OH, SH, halogen, -CN, -N3, C2-6alkynyl, -COOH, -NR22R23, and a member of a targeting pair; R21 is selected from the group consisting of C1-3alkyl and 3- to 6-membered heterocyclyl, wherein each of the C1-6alkyl and 3- to 6- membered heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of -OH, SH, halogen, -CN, -N3, C2-6alkynyl, -COOH, -NR22R23, and a member of a targeting pair; and each of R22and R23is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, or R22and R23may join together with the nitrogen atom to which they are attached to form a heterocyclyl group, wherein each of the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl groups is optionally substituted with one or more substituents independently selected from the group consisting of -OH, SH, halogen, -CN, -N3, C2-6alkynyl, -COOH, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, and a member of a targeting pair.

[0552] In any of the above embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), (XXIb’), (XXIc), (XXId), (XXIe’), (XXIf), (XXIg’), (XXIh’), (XXIi’), and (XXIj’), R13 is preferably selected from the group consisting of H, C1-3alkyl, -OR20, -N3, C2-6alkynyl, - OC(O)R21, -C(O)R21, -NR22R23, -COOH, -C(O)NR22R23, -NR22C(O)R21, and a member of a targeting pair, wherein the C1-3alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of -OH, -N3, C2-6alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NR22R23, -NR22C(O)R21, and a member of a targeting pair; R20is selected from the group consisting of H and C1-3alkyl; R21 is C1-3alkyl optionally substituted with one or more substituents independently selected from the group consisting of -OH, SH, halogen, -CN, -N3, C2-6alkynyl, -COOH, -NR22R23, and a member of a targeting pair; and each of R22and R23is independently selected from the group consisting of H, C1-3alkyl, C2-3alkenyl, and C2-3alkynyl, wherein each of the C1-3alkyl, C2-3alkenyl, and C2-3alkynyl groups is optionally substituted with one or more (such as 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, SH, halogen, -CN, -N3, C2-6alkynyl, -COOH, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, and a member of a targeting pair, or R22and R23may join together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclyl group. In any of the above embodiments of formulas (XXI), (XXI’), (XXIa), (XXIa’), (XXIb), (XXIb’), (XXIc), (XXId), (XXIe’), (XXIf’), (XXIg’), (XXIh’), (XXII’), and (XXIj’), RI3is preferably selected from the group consisting of H, C1-3alkyl, -OH, -N3, C26 alkynyl, - COOH, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -NHC(O)(CH2)2COOH, - N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -C(O)NH2, -C(O)NHCH3, - OC(O)(CH2)2COOH, and a member of a targeting pair, wherein the C1-3alkyl group is optionally substituted with one or more (such as 1 or 2) substituents independently selected from the group consisting of -OH, -N3, C2-6alkynyl, -COOH, -NH2, -NHCH3, - N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and a member of a targeting pair. In some embodiments of formulas (XXI), (XXIa), (XXIb), (XXIc), and (XXId), RI3is selected from the group consisting of H, -OH, -N3, C2 6alkynyl, -COOH, -NH2, -NHCH3, - N(CH3)2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, - NH(CH2CH3), -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and a member of a targeting pair. In some embodiments of formulas (XXI), (XXIa), (XXIb), (XXIc), and (XXId), RI3is selected from the group consisting of -OH, -N3, C2 6alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, - N(CH2CH3)C(O)CH3, -NH(CH2CH3), -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and a member of a targeting pair. In some embodiments of formulas (XXI), (XXIa), (XXIb), (XXIc), and (XXId), RI3is selected from the group consisting of -OH, -N3, C2 6alkynyl, - COOH, -NH2, -NHCH3, -N(CH3)2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), -OC(O)(CH2)2COOH, and a member of a targeting pair. In some embodiments of formulas (XXI), (XXIa), (XXIb), (XXIc), and (XXId), RI3is selected from the group consisting of -OH, -N3, -NH2, -NHC(O)(CH2)2COOH, - N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), and OC(O)(CH2)2COOH.

[0553] In some embodiments of formulas (XXI’), (XXIa’), (XXIb’), (XXIe’), (XXIf’), (XXIg’), (XXIh’), (XXIi’), and (XXIj’), RI3is C1-3alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, -N3, C2 6alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and a member of a targeting pair. In some embodiments of formulas (XXI’), (XXIa’), (XXIb’), (XXIe’), (XXIf’), (XXIg’), (XXIh’), (XXIi’), and (XXIj’), RI3is C1-3alkyl optionally substituted with one substituent selected from the group consisting of -COOH and - C(O)NH(CH2)2NH2.

[0554] In certain embodiments, the oxazolinylated and / or oxazinylated lipid has the following general formula (XXII) or (XXII’): wherein: a is an integer between 1 and 2;

[0555] Ri 1 is methyl or ethyl, and is independently selected for each repeating unit; m is 10 to 100 (preferably 20 to 80, 30 to 70, or 40 to 50);

[0556] RI2, for formula (XXII), is selected from the group consisting of -L11R14, -(CH2)- CH(OC(O)R14)(CH2OC(O)R14), -(CH2)-CH(SR14)2, and -(CH2)-CH(SR14)-CH2(SR14), wherein each R14is independently a straight hydrocarbyl group having at least 10 carbon atoms (preferably having 10 to 16 carbon atoms); and L11is selected from the group consisting of *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)-, *-C(O)NH-(CH2)2-, *-S-(CH2)3-, *-S(O)2-(CH2)3-, and *-OC(O)-(CH2)- (preferably L11is selected from the group consisting of *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)-, and *- C(O)NH-(CH2)2-, such as *-NHC(O)-(CH2)- or *-NHC(O)-(CH2)2-), wherein * represents the attachment point to R14; or RI2, for formula (XXII’), is selected from the group consisting of (R14C(O)O)(CH(OC(O)R14))(CH2)-Z-, (R14)2N(C1-3-alkylene)-Z-, R14Z(C1-3- alkylene)-Z-, R14Z-(C3-6-cycloalkenylene)-Z-, and R14Z-, wherein the C3-6- cycloalkenylene group is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and C1-3-alkyl; and each Z is independently selected from the group consisting of -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, - NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NH-; and

[0557] RI3is selected from the group consisting of H, C1-3alkyl, -OH, -N3, C26alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -NHC(O)(CH2)2COOH, N(CH2CH3)C(O)(CH2)2COOH,

[0558] -N(CH2CH3)C(O)CH3, -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and a member of a targeting pair, wherein the C1-3alkyl group is optionally substituted with one or more (such as one or two) substituents independently selected from the group consisting of - OH, -N3, C-6alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, - C(O)NH(CH2)2NH2, and a member of a targeting pair.

[0559] In some embodiments of formula (XXII) or (XXII’), a is 1 , i.e., the oxazolinylated and / or oxazinylated lipid has the following general formula (XXIIa) or (XXIIa’):

[0560] In some embodiments of formula (XXII) or (XXII’), a is 2, i.e., the oxazolinylated and / or oxazinylated lipid has the following general formula (XXIIb) or (XXIIb’):

[0561] In any of the above embodiments of formulas (XXIIa), (XXIIa’), (XXI lb), and (XXI lb’), R11, R12, R13, and m are as defined for formula (XXI l) / (XXI I’) .

[0562] In some embodiments of formulas (XXII), (XXII’), (XXIIa), (XXIIa’), (XXI lb), and (XXI lb’), each R11 is methyl or each R11is ethyl. In some alternative embodiments of formulas (XXII), (XXII’), (XXIIa), (XXIIa’), (XXIIb), and (XXIIb’), R11is independently selected from methyl and ethyl for each repeating unit, wherein in at least one repeating unit R11is methyl, and in at least one repeating unit R11is ethyl.

[0563] In some embodiments of formulas (XXII), (XXIIa), and (XXIIb), RI2is selected from the group consisting of R14-NHC(O)-(CH2)-, R14-NHC(O)-(CH2)2-, -(CH2)-

[0564] CH(OC(O)R14)(CH2OC(O)R14), -(CH2)-CH(SR14)-CH2(SR14), R14S-(CH2)3-, R14S(O)2- (CH2)3-, and R14-OC(O)-(CH2)-; and / or RI3is selected from the group consisting of -OH, -N3, C2-6alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NHC(O)(CH2)2COOH, - N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), OC(O)(CH2)2COOH, and a member of a targeting pair (e.g., RI3is selected from the group consisting of -OH, -N3, -NH2, -NHC(O)(CH2)2COOH,

[0565] N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), and OC(O)(CH2)2COOH).

[0566] In some embodiments of formulas (XXII’), (XXIIa’), and (XXI lb’), RI2is selected from the group consisting of R14C(O)NH-, R14S-, R14S(O)2-, and R14NH-(3,4-dioxocyclobut-1 -en- 1 ,2-diyl)-N H- ; and / or RI3is C1-3alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, -N3, C2 6alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and a member of a targeting pair (e.g., RI3is C1-3alkyl optionally substituted with one substituent selected from the group consisting of -COOH and -C(O)NH(CH2)2NH2).

[0567] In some embodiments, the oxazolinylated and / or oxazinylated lipid has the following general formula (XXIII):

[0568] R15-POXZ-R16wherein:

[0569] R15 is R17or -L12(R17)q, wherein each R17is independently a hydrocarbyl group; L12is a linker; and q is 1 or 2;

[0570] POXZ is a copolymer containing repeating units of the following general formulas (XXa) and (XXb): wherein each of R11is independently alkyl, in particular C1-3alkyl, such as methyl, ethyl, iso-propyl, or n-propyl, and is independently selected for each repeating unit; the number of repeating units of formula (XXa) in the copolymer is 1 to 199; the number of repeating units of formula (XXb) in the copolymer is 1 to 199; the sum of the number of repeating units of formula (XXa) and the number of repeating units of formula (XXb) in the copolymer is 2 to 200; and the repeating units of formulas (XXa) and (XXb) are arranged in a random, periodic, alternating or block wise manner; and

[0571] Ri6 is selected from the group consisting of H, C1-6alkyl, alkynyl, -OR20, -SR20, halogen, -CN, -N3, -OC(O)R21, -C(O)R21, -NR22R23, -COOH, -C(O)NR22R23, NR22C(O)R21, a sugar, an amino acid, a peptide, and a member of a targeting pair, wherein the C1-6alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of -OH, SH, halogen, -CN, -N3, C2-6alkynyl, -COOH, -NR22R23, -C(O)NR22R23, -NR22C(O)R21, a sugar, an amino acid, a peptide, and a member of a targeting pair; R20is selected from the group consisting of H, C1-3alkyl and 3- to 6-membered heterocyclyl, wherein each of the C1-3alkyl and 3- to 6-membered heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of -OH, SH, halogen, -CN, -N3, C2-6alkynyl, -COOH, -NR22R23, a sugar, an amino acid, a peptide, and a member of a targeting pair; R21 is selected from the group consisting of C1-6alkyl and 3- to 6- membered heterocyclyl, wherein each of the C1-6alkyl and 3- to 6-membered heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of -OH, SH, halogen, -CN, -N3, C2-6alkynyl, -COOH, -NR22R23, a sugar, an amino acid, a peptide, and a member of a targeting pair; and each of R22and R23is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R22and R23may join together with the nitrogen atom to which they are attached to form a heterocyclyl group, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of -OH, SH, halogen, -CN, -N3, C2-6alkynyl, -COOH, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, a sugar, an amino acid, a peptide, and a member of a targeting pair.

[0572] In some embodiments of formula (XXIII), the targeting pair is selected from the following pairs: antigen - antibody specific for said antigen; avidin - streptavidin; folate - folate receptor; transferrin - transferrin receptor; aptamer - molecule for which the aptamer is specific; arginine-glycine-aspartic acid (RGD) peptide - avPs integrin; asparagine- glycine-arginine (NGR) peptide - aminopeptidase N; galactose - asialoglyco-protein receptor. Thus, in some embodiments of formula (XXIII), a member of a targeting pair includes one of the following: an antigen, an antibody, avidin, streptavidin, folate, transferrin, an aptamer; an RGD peptide; an NGR peptide; and galactose.

[0573] In some of the above embodiments of formula (XXIII), R11at each occurrence (i.e., in each repeating unit) may be the same alkyl group (e.g., R11may be methyl in each repeating unit). In some alternative embodiments of formula (XXIII), R11in at least one repeating unit differs from R11in another repeating unit (e.g., for at least one repeating unit R11is one specific alkyl (such as ethyl), and for at least one different repeating unit Ri 1 is a different specific alkyl (such as methyl)). For example, each R11may be selected from two different alkyl groups (such as methyl and ethyl) and not all R1are the same alkyl.

[0574] In some embodiments of formula (XXIII), each of R11is independently methyl or ethyl, preferably methyl. Thus, in some embodiments of formula (XXIII), each R11is methyl or each R11is ethyl. In some alternative embodiments of formula (XXIII), R11is independently selected from methyl and ethyl for each repeating unit, wherein in at least one repeating unit R11is methyl, and in at least one repeating unit R11is ethyl.

[0575] In some embodiments of formula (XXIII), the sum of the number of repeating units of formula (XXa) and the number of repeating units of formula (XXb) in the copolymer preferably is between 2 and 190, such as between 2 and 180, between 2 and 170, between 2 and 160, between 2 and 150, between 2 and 140, between 2 and 130, between 2 and 120, between 2 and 110, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 4 and 200, between 4 and 190, between 4 and 180, between 4 and 170, between 4 and 160, between 4 and 150, between 4 and 140, between 4 and 130, between 4 and 120, between 4 and 110, between 4 and 100, between 4 and 90, between 4 and 80, between 4 and 70, between 10 and 200, between

[0576] 10 and 190, between 10 and 180, between 10 and 170, between 10 and 160, between

[0577] 10 and 150, between 10 and 140, between 10 and 130, between 10 and 120, between

[0578] 10 and 110, between 10 and 100, between 10 and 90, between 10 and 80, or between

[0579] 10 and 70. In certain embodiments of formula (XXIII), the sum of the number of repeating units of formula (XXa) and the number of repeating units of formula (XXb) in the copolymer is 2 to 180, such as 4 to 160, 6 to 140, 8 to 120 or 10 to 100, e.g., 20 to 80, 30 to 70, or 40 to 50.

[0580] Accordingly, in some embodiments of formula (XXIII), the number of repeating units of formula (XXa) in the copolymer is 1 to 179, such as 1 to 159, 1 to 139, 1 to 119 or 1 to 99; the number of repeating units of formula (XXb) in the copolymer is 1 to 179, such as 1 to 159, 1 to 139, 1 to 119 or 1 to 99; and the sum of the number of repeating units of formula (XXa) and the number of repeating units of formula (XXb) in the copolymer is 2 to 180, such as 4 to 160, 6 to 140, 8 to 120 or 10 to 100.

[0581] In some embodiments of formula (XXIII), L12 comprises at least one functional moiety, such as an alkylene moiety substituted with at least one monovalent functional moiety and / or linked, at the end by which the alkylene group is attached to R17, to a divalent functional moiety, wherein preferably each monovalent functional moiety is independently selected from hydroxy, ether, halogen, cyano, azido, nitro, amino, ammonium, ester, carboxyl, thiol (sulfanyl), disulfanyl, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfinamide, sulfonamide, sulfamate, diselenide, sulfurous diamide, sulfuric diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioate, dithioate, imidate, imino, imidothioate, thionylamido, carbonate, carbonothioate, carbonodithioate, carbonotrithioate, guanidino (imidamido), carbamimidate, carbonimidate, carbamate, carbamodithioate, carbonodithioimidate, carbamimidothioate, carbamothioate, carbonimidothioate, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imide, and amide; and / or each divalent functional moiety is independently selected from ether, amino, ester, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfinamide, sulfonamide, sulfamate, diselenide, sulfurous diamide, sulfuric diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioate, dithioate, imidate, imino, imidothioate, thionylamido, carbonate, carbonothioate, carbonodithioate, carbonotrithioate, guanidino (imidamido), carbamimidate, carbonimidate, carbamate, carbamodithioate, carbonodithioimidate, carbamimidothioate, carbamothioate, carbonimidothioate, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imide, and amide.

[0582] In some embodiments of formula (XXIII), R15 is attached to the N-end (i.e., the terminal N atom) of the POXZ copolymer and R16is attached to the C-end (i.e., the terminal C atom) of the POXZ copolymer. In some alternative embodiments of formula (XXIII), R15 is attached to the C-end (i.e., the terminal C atom) of the POXZ copolymer and Ri6 is attached to the N-end (i.e., the terminal N atom) of the POXZ copolymer. The latter alternative embodiments of formula (XXIII) (i.e., where R15 is attached to the C-end (i.e., the terminal C atom) of the POXZ copolymer and Ri6 is attached to the N-end (i.e., the terminal N atom) of the POXZ copolymer) are designated as formula (XXIII’) herein.

[0583] In some embodiments of formula (XXIII), L12 comprises an alkylene moiety substituted with at least one monovalent functional moiety as specified above. Thus, in some embodiments, the oxazolinylated and / or oxazinylated lipid may comprise the following structure (optionally R16is attached to the terminal C atom of the POXZ copolymer): (hydrophobic chain)1-2-(alkylene moiety substituted with at least one monovalent functional moiety)-(POXZ copolymer), wherein "hydrophobic chain" represents R17; "alkylene moiety substituted with at least one monovalent functional moiety" represents L12; and "POXZ copolymer" represents the copolymer specified in formula (XXIII).

[0584] In some embodiments, the oxazolinylated and / or oxazinylated lipid has the following formula (XXIIIa) (optionally R16is attached to the terminal C atom of the POXZ copolymer):

[0585] (hydrophobic chain)1-2-(alkylene moiety substituted with at least one monovalent functional moiety)-(POXZ copolymer)-R16

[0586] In some embodiments of formulas (XXIII) and (XXIIIa), the at least one monovalent functional moiety may be any one of the monovalent functional moieties specified herein, e.g., selected from the groups consisting of hydroxy, ether, halogen, cyano, azido, nitro, amino, ammonium, ester, carboxyl, thiol (sulfanyl), disulfanyl, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfinamide, sulfonamide, sulfamate, diselenide, sulfurous diamide, sulfuric diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioate, dithioate, imidate, imino, imidothioate, thionylamido, carbonate, carbonothioate, carbonodithioate, carbonotrithioate, guanidino (imidamido), carbamimidate, carbonimidate, carbamate, carbamodithioate, carbonodithioimidate, carbamimidothioate, carbamothioate, carbonimidothioate, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imide, and amide. In some embodiments of formulas (XXIII) and (XXIIIa), the alkylene moiety substituted with at least one monovalent functional moiety is C1-6-alkylene, such as C1-3-alkylene, e.g., methylene, ethylene, or trimethylene.

[0587] In some embodiments of formulas (XXIII) and (XXIIIa), the alkylene moiety substituted with at least one monovalent functional moiety is substituted with one or more (such as 1 to the maximum number of hydrogen atoms bound to the alkylene moiety, e.g., 1 , 2, 3, 4, 5, or 6, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected monovalent functional moieties.

[0588] In some embodiments, the alkylene moiety substituted with at least one monovalent functional moiety is C1-6-alkylene, such as C1-3-alkylene, e.g., methylene, ethylene, or trimethylene, and is substituted with one or more (such as 1 to the maximum number of hydrogen atoms bound to the alkylene moiety, e.g., 1 , 2, 3, 4, 5, or 6, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected monovalent functional moieties. In some embodiments of formula (XXIII) (in particular those, where Rie is attached to the terminal C atom of the POXZ copolymer), L12 comprises an alkylene moiety linked, at the end by which the alkylene group is attached to RI7, to a divalent functional moiety as specified above. Thus, in some embodiments (in particular those, where Rie is attached to the terminal C atom of the POXZ copolymer), the oxazolinylated and / or oxazinylated lipid may comprise the following structure:

[0589] [(hydrophobic chain)-(divalent functional moiety)]i-2-(alkylene moiety)-(POXZ copolymer), wherein "hydrophobic chain" represents RI7; "-(divalent functional moiety)]i-2-(alkylene moiety)" represents L12; and "POXZ copolymer" represents the copolymer specified in formula (XXIII).

[0590] In some embodiments (in particular those, where R16is attached to the terminal C atom of the POXZ copolymer), the oxazolinylated and / or oxazinylated lipid has the following formula (XXIIIb):

[0591] [(hydrophobic chain)-(divalent functional moiety)]i-2-(alkylene moiety)-(POXZ copolymer)-Ri6

[0592] In some embodiments of formulas (XXIII) and (XXIIIb), the divalent functional moiety may be any one of the divalent functional moieties specified herein, e.g., selected from the groups consisting of ether, amino, ester, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfinamide, sulfonamide, sulfamate, diselenide, sulfurous diamide, sulfuric diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioate, dithioate, imidate, imino, imidothioate, thionylamido, carbonate, carbonothioate, carbonodithioate, carbonotrithioate, guanidino (imidamido), carbamimidate, carbonimidate, carbamate, carbamodithioate, carbonodithioimidate, carbamimidothioate, carbamothioate, carbonimidothioate, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imine, imide, and amide.

[0593] In some embodiments of formulas (XXIII) and (XXIIIb), the alkylene moiety is Ci 6- alkylene, such as C1-3-alkylene, e.g., methylene, ethylene, or trimethylene.

[0594] In some embodiments of formula (XXIII), where Rie is attached to the terminal N atom of the POXZ copolymer (i.e., in the embodiments of formula (XXIII’)), L12 comprises at least one difunctional moiety via which the one or more hydrophobic chains (R17) are attached to the POXZ copolymer. In some embodiments, L12 may additionally comprise an alkylene moiety (such as a C1-6alkylene moiety, e.g., a C1-3alkylene moiety), a cycloalkylene moiety (preferably a C3-8-cycloalkylene, such as C3 -6-cycloalkylene moiety), or a cycloalkenylene moiety (preferably a C3-8-cycloalkenylene, such as C3-6- cycloalkenylene moiety) each of which connects the difunctional moiety to the POXZ copolymer (either directly to the end of the POXZ copolymer or, preferably, via a further difunctional moiety). For example, one hydrophobic chain may be attached to the end of the POXZ copolymer via one difunctional moiety (either directly or via an alkylene, cycloalkylene, or cycloalkenylene moiety or via an alkylene, cycloalkylene, or cycloalkenylene moiety which bears another difunctional moiety); two hydrophobic chains may be attached to the end of the POXZ copolymer via two difunctional moieties (which in turn are preferably attached to an alkylene, cycloalkylene, or cycloalkenylene moiety or to an alkylene, cycloalkylene, or cycloalkenylene moiety bearing another difunctional moiety); or two hydrophobic chains may be attached to the end of the POXZ copolymer via the same difunctional moiety (which is then a trifunctional moiety and which may be attached to the end of the POXZ copolymer either directly or via an alkylene, cycloalkylene, or cycloalkenylene moiety or to an alkylene, cycloalkylene, or cycloalkenylene moiety bearing another difunctional moiety). In some embodiments, each divalent functional moiety is independently selected from ether, amino, ester, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfinamide, sulfonamide, sulfamate, diselenide, sulfurous diamide, sulfuric diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioate, dithioate, imidate, imino, imidothioate, thionylamido, carbonate, carbonothioate, carbonodithioate, carbonotrithioate, guanidino (imidamido), carbamimidate, carbonimidate, carbamate, carbamodithioate, carbonodithioimidate, carbamimidothioate, carbamothioate, carbonimidothioate, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imine, imide, and amide moieties.

[0595] In some embodiments of formula (XXIII’), the cycloalkylene moiety is C3-8-cycloalkylene, such as C3 6-cycloalkylene, e.g., cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, wherein the cycloalkylene moiety is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents (e.g., independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and Ci3-alkyl) .

[0596] In some embodiments of formula (XXIII’), the cycloalkenylene moiety is C33- cycloalkenylene, such as C3-6-cycloalkenylene, e.g., cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, wherein the cycloalkenylene moiety is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents (e.g., independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and Ci3-alkyl) .

[0597] In some embodiments of formula (XXIII’), the alkylene moiety is C1-6-alkylene, such as C1-3-alkylene, e.g., methylene, ethylene, or trimethylene, or C23alkylene.

[0598] In some embodiments of formula (XXIII’), the oxazolinylated and / or oxazinylated lipid comprises one of the following structures:

[0599] (hydrophobic chain)-(divalent functional moiety)-(POX and / or POZ polymer)

[0600] [(hydrophobic chain)-(divalent functional moiety)]i-2-(alkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)

[0601] (hydrophobic chain)-(divalent functional moiety)-(cycloalkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)

[0602] (hydrophobic chain)-(divalent functional moiety)-(cycloalkenylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)

[0603] (hydrophobic chain)-(divalent functional moiety)-(alkylene moiety)-(POX and / or POZ polymer) [(hydrophobic chain)2-(trivalent functional moiety)]-(alkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)

[0604] In some embodiments formula (XXIII’), the oxazolinylated and / or oxazinylated lipid has one of the following formulas (XXIIIc’) to (XXIIIh’):

[0605] (hydrophobic chain)-(divalent functional moiety)-(POXZ copolymer)-R16(XXIIIc’) [(hydrophobic chain)-(divalent functional moiety)]i-2-(alkylene moiety)-(divalent functional moiety)-(POXZ copolymer)-R16(XXI I Id’)

[0606] (hydrophobic chain)-(divalent functional moiety)-(cycloalkylene moiety)-(divalent functional moiety)-(POXZ copolymer)-R16(XXIIIe’)

[0607] (hydrophobic chain)-(divalent functional moiety)-(cycloalkenylene moiety)-(divalent functional moiety)-(POXZ copolymer)-R16(XXI I If’)

[0608] (hydrophobic chain)-(divalent functional moiety)-(alkylene moiety)-(POXZ copolymer)- RI6(XXIIIg’)

[0609] [(hydrophobic chain)2-(trivalent functional moiety)]-(alkylene moiety)-(divalent functional moiety)-(POXZ copolymer)-R16(XXIIIh’)

[0610] In some embodiments of formulas (XXIII), (XXIIIa), and (XXIIIb), L12 comprises at least one ester, sulfide, disulfide, sulfone, orthoester, acylhydrazone, hydrazine, oxime, acetal, ketal, or amide moiety. In some embodiments, L12 is selected from the group consisting of [*-NHC(O)]q(C1-6-alkylene)-, [*-C(O)NH]q(C1-6-alkylene)-, [*-C(O)O]q(C1-6- alkylene)-, [*-OC(O)]q(C1-6-alkylene)-, [*-S]q(C1-6-alkylene)-, [*-SS]q(C1-6-alkylene)-, [*- S(O)2]p(C1-6-alkylene)-, [(*-O)sC(OR25)3 s](C1-6-alkylene)-, [*-C(OR25)2O]q(C1-6-alkylene)-, [*-C(R25)(=N-N(R26)C(O)-)]q(C1-3-alkylene)-, [*-C(O)(N(R26)-N=)C(R25)-]q(C1-3-alkylene)-, [*=C(=N-N(R26)C(O)(R25))]q(C1-3-alkylene)-, [*N(R26)N(R26)]q-(C1-6-alkylene)-,

[0611] [*=C(=N(OH))]q(C1-6-alkylene)-, and [*-OC(R25)(R26)O]q(C1-6-alkylene)-, wherein * represents the attachment point to R17; q is 1 or 2; C1-6-alkylene is either bivalent (if q is 1 ) or trivalent (if q is 2); R25is selected from the group consisting of C1-6alkyl, aryl, and aryl(C1-6alkyl); R26is selected from the group consisting of H, C1-6alkyl, aryl, and aryl(C1- 6 alkyl); and s is an integer between 1 and 2. For example, L12 may be selected from the group consisting of [*-NHC(O)]q(C1-3-alkylene)-, [*-C(O)NH]q(C1-3-alkylene)-, [*- C(O)O]q(C1-3-alkylene)-, [*-OC(O)]q(C1-3-alkylene)-, [*-S]q(C1-3-alkylene)-, [*-SS]q(C1-3- alkylene)-, [*-S(O)2]p(C1-3-alkylene)-, [(*-O)sC(OR25)3 s](C1-3-alkylene)-, [*- C(OR25)2O]q(C1-3-alkylene)-, [*-C(R25)(=N-N(R26)C(O)-)]q(C1-3-alkylene)-, [*-C(O)(N(R26)- N=)C(R25)-]q(C1-3-alkylene)-, [*=C(=N-N(R26)C(O)(R25))]q(C1-3-alkylene)-,

[0612] [*N(R26)N(R26)]q(C1-3-alkylene)-, [*=C(=N(OH))]q(C1-3-alkylene)-, and [*-

[0613] OC(R25)(R26)O]q(C1-3-alkylene)-, wherein * represents the attachment point to R17; q is 1 or 2; C1-3-alkylene is either bivalent (if q is 1 ) or trivalent (if q is 2); R25is selected from the group consisting of C1-6alkyl, aryl, and aryl(C1-6alkyl); R26is selected from the group consisting of H, C1-6alkyl, aryl, and aryl(C1-6alkyl); and s is an integer between 1 and 2. In some embodiments of formulas (XXIII), (XXII la), and (XXIIIb), R25is selected from the group consisting of C1-3alkyl, phenyl, and phenyl(C1-3alkyl), such as from the group consisting of methyl, ethyl, phenyl, benzyl, and phenylethyl.

[0614] In some embodiments of formulas (XXIII), (XXII la), and (XXIIIb), R26is selected from the group consisting of H, C1-3alkyl, phenyl, and phenyl(Ci3 alkyl), such as from the group consisting of H, methyl, ethyl, phenyl, benzyl, and phenylethyl.

[0615] In some embodiments of formulas (XXIII), (XXI I la), and (XXIIIb), L12 is selected from the group consisting of [*-NHC(O)]q(C1-6-alkylene)-, [*-C(O)NH]q(C1-6-alkylene)-, [*- C(O)O]q(C1-6-alkylene)-, [*-OC(O)]q(C1-6-alkylene)-, [*-S]q(C1-6-alkylene)-, and [*- S(O)2]p(C1-6-alkylene)-, preferably from the group consisting of [*-NHC(O)]qC1-6- alkylene)-, [*-C(O)O]q(C1-6-alkylene)-, [*-OC(O)]q(C1-6-alkylene)-, [*-S]q(C1-6-alkylene)-, and [*-S(O)2]p(C1-6-alkylene)-, more preferably from the group consisting of [*- NHC(O)]q(C1-6-alkylene)- and [*-C(O)O]q(C1-6-alkylene)-, wherein * represents the attachment point to R17; q is 1 or 2; and C1-6-alkylene is either bivalent (if q is 1 ) or trivalent (if q is 2).

[0616] In some embodiments of formulas (XXIII), (XXIII a), and (XXIII b), L12 is selected from the group consisting of [*-NHC(O)]q(C1-3-alkylene)-, [*-C(O)NH]q(C1-3-alkylene)-, [*- C(O)O]q(C1-3-alkylene)-, [*-OC(O)]q(C1-3-alkylene)-, [*-S]q(C1-3-alkylene)-, and [*- S(O)2]p(C1-3-alkylene)-, preferably from the group consisting of [*-NHC(O)]q(C1-3- alkylene)-, [*-C(O)O]qC1-3-alkylene)-, [*-OC(O)]q(C1-3-alkylene)-, [*-S]q(C1-3-alkylene)-, and [*-S(O)2]p(C1-3-alkylene)-, more preferably from the group consisting of [*- NHC(O)]q(C1-3-alkylene)- and [*-C(O)O]q(C1-3-alkylene)-, wherein * represents the attachment point to R17; q is 1 or 2; and C1-3-alkylene is either bivalent (if q is 1 ) or trivalent (if q is 2). In some embodiments of formulas (XXIII), (XXI I la), and (XXI I lb), L12is selected from the group consisting of *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)-, *-C(O)NH- (CH2)2-, -(CH2)-CH(OC(O)-*), (CH2OC(O)-*), -(CH2)-CH(S-*)2, -(CH2)-CH(S-*)-CH2(S-*), *-S-(CH2)3-, *-S(O)2-(CH2)3-, and *-OC(O)-(CH2)-, wherein * represents the attachment point to R17. Thus, R15 may be selected from the group consisting of R17, -L12R17, -(CH2)- CH(OC(O)R17)(CH2OC(O)R17), -(CH2)-CH(SR17)2, and -(CH2)-CH(S R17)-CH2(S R17); and L12 is selected from the group consisting of *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *- C(O)NH-(CH2)-, *-C(O)NH-(CH2)2-, *-S-(CH2)3-, *-S(O)2-(CH2)3-, and *-OC(O)-(CH2)-, preferably L12is selected from the group consisting of *-NHC(O)-(CH2)-, *-NHC(O)- (CH2)2-, *-C(O)NH-(CH2)-, and *-C(O)NH-(CH2)2-, such as *-NHC(O)-(CH2)- or *- NHC(O)-(CH2)2-, wherein * represents the attachment point to R17.

[0617] In some embodiments of formulas (XXIII), (XXI 11 a) , and (XXI I lb), R15 is -L12( R15)q, / .e., the POXZ copolymer is conjugated to the one or more hydrophobic chains (i.e., R17) via the linker L12.

[0618] In some embodiments of formulas (XXIII’), (XXII lc’), (XXIIId’), (XXIIIe’), (XXII If’), (XXIIIg’) and (XXI I I h’), L12is selected from the group consisting of [*-Z1]q(C1-6-alkylene)-Z1-, *-Z1- (C3-8-cycloalkylene)-Z1-, *-Z1-(C38-cycloalkenylene)-Z1-, (*=N)(C1-6-alkylene)-Z1-, *-Z1(C1- 6-alkylene)-, and *-Z1-, wherein * represents the attachment point to R17; q is 1 or 2; C1- 6-alkylene is either bivalent (if q is 1 ) or trivalent (if q is 2); each of the C3-s-cycloalkylene and C3-8-cycloalkenylene groups is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and Ci3-alkyl ; and each Z1 is independently selected from the group consisting of -OP(O)2O(C1-3-alkylene)NH-, -NH(C1-3-alkylene)OP(O)2O-, -C(O)NH-, - NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NR22. For example, L12can be selected from the group consisting of [*-C(O)O]q(C1-6-alkylene)-Z1-, (*-NH)(C1-6-alkylene)-Z1-, (*=N)(C1-6-alkylene)-Z1-, (*-NH)C(O)(C1-6-alkylene)-Z1-, (*- C(O)NH(C1-6-alkylene)-Z1-, (*-NH)C(O)(C1-6-alkylene)-, (*-C(O)NH(C1-6-alkylene)-, *-Z1- (C3-8-cycloalkenylene)-Z1-, *-S-, *-S(O)2-, (*-NH)C(O)-, and *-C(O)NH-, wherein * represents the attachment point to R17; q is 1 or 2; C1-6-alkylene is either bivalent (if q is 1 ) or trivalent (if q is 2); and Z1 is selected from the group consisting of -OP(O)2O(C1-3- alkylene)NH-, -NH(C1-3-alkylene)OP(O)2O-, -OC(O)NH-, -NHC(O)O-, -O-, -S-, and -NH-

[0619] In some embodiments of formulas (XXIII’), (XXII lc’), (XXIIId’), (XXIIIe’), (XXII If’), (XXIIIg’) and (XXI 11 h’), L12is selected from the group consisting of [*-Z1]q(C1-3-alkylene)-Z1-, *-Z1- (C3-6-cycloalkylene)-Z1-, *-Z1-(C3-6-cycloalkenylene)-Z1-, (*=N)(C1-3-alkylene)-Z1-, *-Z1(C1-3-alkylene)-, and *-Z1-, wherein * represents the attachment point to RI7; q is 1 or 2; Ci- s-alkylene is either bivalent (if q is 1 ) or trivalent (if q is 2); each of the C3-6-cycloalkylene and C3-6-cycloalkenylene groups is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and Ci3-alkyl ; and each Z1is independently selected from the group consisting of -OP(O)2O(C1-2-alkylene)NH-, -NH(C1-2-alkylene)OP(O)2O-, -C(O)NH-, - NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NR22. For example, L12can be selected from the group consisting of [*-C(O)O]q(C1-3-alkylene)-Z1-, (*-NH)(C1-3-alkylene)-Z1-, (*=N)(C1-3-alkylene)-Z1-, (*-NH)C(O)(C1-3-alkylene)-Z1-, (*- C(O)NH(C1-3-alkylene)-Z1-, (*-NH)C(O)(C1-3-alkylene)-, (*-C(O)NH(C1-3-alkylene)-, *-Z1- (C3-6-cycloalkenylene)-Z1-, *-S-, *-S(O)2-, (*-NH)C(O)-, and *-C(O)NH-, wherein * represents the attachment point to RI7; q is 1 or 2; C1-3-alkylene is either bivalent (if q is 1) or trivalent (if q is 2); and Z1is selected from the group consisting of -OP(O)2O(C1-2- alkylene)NH-, -NH(C1-2-alkylene)OP(O)2O-, -OC(O)NH-, -NHC(O)O-, -O-, -S-, and -NH-

[0620] In some embodiments of formulas (XXIII’), (XXII lc’), (XXIIId’), (XXIIIe’), (XXII If’), (XXIIIg’) and (XXI 11 h’), L12is selected from the group consisting of [*-Z1]q(C1-3-alkylene)-Z1-, *-Z1- (C3-6-cycloalkylene)-Z1-, *-Z1-(C3-6-cycloalkenylene)-Z1-, (*=N)(C1-3-alkylene)-Z1-, *-Z1(C1-3-alkylene)-, and *-Z1-, wherein * represents the attachment point to RI7; p is 1 or 2; Ci- s-alkylene is either bivalent (if q is 1 ) or trivalent (if q is 2); each of the C3-6-cycloalkylene and C3-6-cycloalkenylene groups is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and Ci3-alkyl ; and each Z1is independently selected from the group consisting of -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, - OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, -N(C1-3-alkyl)-, and -NH-. For example, L12can be selected from the group consisting of [*-C(O)O]q(C1-3-alkylene)- Z1-, (*-NH)(C1-3-alkylene)-Z1-, (*=N)(C1-3-alkylene)-Z1-, (*-NH)C(O)(C1-3-alkylene)-Z1-, (*- C(O)NH(C1-3-alkylene)-Z1-, (*-NH)C(O)(C1-3-alkylene)-, (*-C(O)NH(C1-3-alkylene)-, *-Z1- (C3-6-cycloalkenylene)-Z1-, *-S-, *-S(O)2-, (*-NH)C(O)-, and *-C(O)NH-, wherein * represents the attachment point to RI7; p is 1 or 2; C1-3-alkylene is either bivalent (if q is 1) or trivalent (if q is 2); and Z1is selected from the group consisting of - OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -OC(O)NH-, -NHC(O)O-, -O-, -S-, and -NH-. In some embodiments of formulas (XXIII’), (XXII lc’), (XXIIId’), (XXIIIe’), (XXII If’), (XXIIIg’) and (XXII lh’), L12is selected from the group consisting of (*-C(O)O)(CH(OC(O)-*))(CH2)- Z1-, (*=N)(C1-3-alkylene)-NHC(O)-, (*-Z1(C1-3-alkylene)-Z1-, *-Z1-(C3-6-cycloalkenylene)- Z1-, and *-Z1-, wherein * represents the attachment point to RI7; the C3-6-cycloalkenylene groups is optionally substituted with one or more (e.g., 1 , 2, 3, or 4) substituents independently selected from the group consisting of -OH, =O, -SH, halogen, -CN, -N3, and Ci3-alkyl; and each Z1is independently selected from the group consisting of - OP(O)2O(CH2)2-NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, - NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NH-. For example, L12can be selected from the group consisting of (*-C(O)O)(CH(OC(O)-*))(CH2)-ZI-, (*=N)(C1-3- alk...

Claims

CLAIMS1 . A glycolipid compound represented by formula II:IIR1is -A, -M1-M2-A, or -M3-N(-M1-M2-A)2;R2is -H, -A, -M1-M2-A, or -M3-N(-M1-M2-A)2; each M1is independently an optionally substituted C2-C12aliphatic or 2- to 1 -membered heteroaliphatic; each M2is independently -NHC(S)NH-, -NHS(O)2-, -NHC(O)-, -C(O)NH-, -C(O)O-, or - OC(O)-; each M3is independently an optionally substituted C2-C12aliphatic or optionally substituted 2- to 12-membered heteroaliphatic;A is -A1-X-A2; each A1is independently, at each instance, a bond, optionally substituted C2-C12aliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 12- membered heterocycle, or optionally substituted 5- to 12-membered heteroaryl; each X is independently a bond, -(CH2)I.6-, -NH-, -S-, -S(O)2-, or -O-; each A2is independently a monosaccharide, a disaccharide, an oligosaccharide, a fluorescent tag, or a moiety of formula J:wherein at least one instance of A2is a monosaccharide, a disaccharide, an oligosaccharide, or a moiety of formula J; each of R3, R4, and R5is each independently at each occurrence a monosaccharide, a disaccharide, or an oligosaccharide; each X’ is independently a bond, -Cy’-O-, -O-Cy’-, -NH-, -S-, -S(O)2-, or -O-, wherein each Cy’ is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1 -3 heteroatoms selected from N, O, and S, an optionally substituted 3-8membered bivalent heteroaryl ring having 1 -4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted C6-C12aryl; each A3is independently, at each occurrence, a bond, optionally substituted C2-C12aliphatic, optionally substituted 2- to 1 -membered heteroaliphatic, optionally substituted C6-Ci2 aryl, optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 12- membered heterocycle, or optionally substituted 5- to 12-membered heteroaryl;M4is optionally substituted C2-C6aliphatic-NHC(S)NH-, or optionally substituted 2- to 12- membered heteroaliphatic-NHC(S)NH-;L is a polymeric moiety that comprises monomers of ethylene glycol, sarcosine, 2-(2-(2- aminoethoxy)ethoxy)acetic acid, or a combination thereof, a bond, or L is an optionally substituted C20-C100aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, - OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered bivalent heterocyclyl ring having 1 -3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1 -4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted Ce- C12aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20aliphatic, or C3-C12cycloaliphatic;M5is a bond, -OC(O)NH-, -NHC(O)O-, -NHC(O)-, -C(O)-NH-, -C1-C6aliphatic-C(O)NH-, or -NHC(O)-C1-C6aliphatic;T is optionally substituted C10-C20aliphatic, or a moiety of formula B or B”:each R7is independently -(CH2)x2-M6-R8; each M6is independently a bond, -OC(O)-, -C(O)O-, -C(O)-, -C(S)-, -NHC(O)-, - C(O)NH-, -S-, -S-S-, and -S(O)2-; each R® is optionally substituted C10-C20aliphatic or 10- to 20-membered heteroaliphatic; n is 0 or 1 ;x1 is an integer selected from 1 to 6; and each x2 is independently selected from 0, 1 , and 2.

2. The compound of claim 1 , wherein R1is -M1-M2-A and R2is -M1-M2-A.

3. The compound of claim 1 , wherein R1is -A, and R2is H.

4. The compound of any one of claims 1-3, wherein A1is optionally substituted phenyl.

5. The compound of claim 1 , wherein A1is:

6. The compound of any one of claims 1-5, wherein X is -CH2- or -O-.

7. The compound of any one of claims 1-6, wherein A2is a monosaccharide.

8. The compound of claim 7, wherein the monosaccharide is selected from N- acetylgalactosamine (GalNAc), mannose (Man), fucose (Fuc), glucose (Glc) and galactose (Gal).

9. The compound of any one of claims 1-6, wherein A2is an oligosaccharide, wherein the oligosaccharide is a trisaccharide of formula:

10. The compound of claim 1 , wherein each A2is independently selected from11. The compound of claim 1 , wherein A1-X-A2is:

12. The compound of claim 1 , wherein A2is a moiety of formula J:

13. The compound of claim 12, wherein A2is a moiety of formula J-1 :

14. The compound of claim 13, wherein each of R3, R4, and R5is each independently a monosaccharide.

15. The compound of claim 14 wherein each of R3, R4, and R5is each independently selected from16. The compound of claim 1 , wherein the moiety of formula J is a moiety selected from:

17. The compound of claim 1 , wherein R1is -M3-N(-M1-M2-A)2, R2is H, M3is C1-C6aliphatic, each M1is C1-C6aliphatic, one of M2is -NHC(S)NH-, the other M2is -NHS(O)2- , each A is -A1-X-A2, each A1is a bond, one instance of X is a bond and one instance ofX is -CH2-, one instance of A2is a fluorescent tag, and one instance of A2is a moiety of formula J.

18. The compound of claim 1 , wherein R1is -M1-M2-A, R2is -M1-M2-A, each A is -A1- X-A2, and each A2is a moiety of formula J.

19. The compound of claim 1 , wherein R1is -M1-M2-A, R2is -M1-M2-A, each M1is C C6aliphatic, each M2is -NHC(S)NH-, each A is -A1-X-A2, each A1is a bond, each X is - CH2-, and each A2is a moiety of formula J.

20. The compound of claim 1 , R1is -A, R2is H, where A is A1-X-A2, A1is a bond, X is a -CH2-, and A2is a formula of moiety J.21 . The compound of claim 1 , wherein R1is -A, R2is H, where A is A1-X-A2, A1is a phenyl, X is a -O-, and A2is a trisaccharide.

22. The compound of claim 1 , wherein R1is -A, R2is H, where A is A1-X-A2, A1is a phenyl, X is a -O-, and A2is TriMan.

23. The compound of any one of claims 1 -22, wherein M4is optionally substituted 2- to 1 O-membered heteroaliphatic-NHC(S)NH-*, where * indicates a point of attachment to moiety L of formula II.

24. The compound of any one of claims 1 -23, wherein L is a polymeric moiety that comprises monomers of ethylene glycol, sarcosine, 2-(2-(2-aminoethoxy)ethoxy)acetic acid.

25. The compound of any one of claims 1 -23, wherein L is C2-C10aliphatic.

26. The compound of any one of claims 1 -25, wherein M5is a bond, -OC(O)NH-, - NHC(O)O-, -NHC(O)-, -C(O)-NH-, -C1-C6aliphatic-C(O)NH-, or -NHC(O)-CI-C6aliphatic.

27. The compound of any one of claims 1 -26, wherein T is optionally substituted C10- C20aliphatic.

28. The compound of claim 27, wherein T is:

29. The compound of any one of claims 1-26, wherein T is a moiety of formula B or30. The compound of claim 29, wherein x1 is 2.

31. The compound of any one of claims 1-30, wherein each R8is independently selected from:

32. The compound of claim 1 , wherein one instance of R7is -CH2-OC(O)-R8and the other R7is -OC(O)-R8.

33. The compound of claim 1 , wherein a moiety of formula B or B” is represented by:

34. The compound of claim 1 , wherein the compound of formula II is represented by formula 11-1 :or a pharmaceutically acceptable salt thereof.

35. The compound of claim 1 , wherein the compound of formula II is represented by formula II-2:or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1 , wherein the compound of formula II is represented by formula II-3:or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1 , wherein the compound of formula II is represented by formula II-4:or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1 , wherein the compound of formula II is represented by formula 11-5:or a pharmaceutically acceptable salt thereof.

39. The compound of claim 1 , wherein the compound of formula II is represented by formula II-6:or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1 , wherein the compound of formula II is represented by formula II-7:or a pharmaceutically acceptable salt thereof.41 . The compound of claim 1 , wherein the compound of formula II is represented by formula 111-1 :or a pharmaceutically acceptable salt thereof.

42. The compound of claim 1 , wherein the compound of formula II is represented by formula III-2:or a pharmaceutically acceptable salt thereof.

43. A glycolipid compound of any one of Tables 1 -3.

44. A particle comprising one or more glycolipid compounds of any one of claims 1- 43 and a nucleic acid.

45. The particle of claim 44, wherein the particle comprises about 0.5 mol% to about 20 mol% of the one or more glycolipids.

46. The particle of claims 44 or 45, wherein the particle comprises two or more glycolipids.

47. The particle of any one of claims 44-46, wherein the particle further comprises one or more of a cationic lipid, a helper lipid, and a steroid.

48. The particle of claim 47, wherein the cationic lipid is selected from SM-102, ALC- 0315, ALC0366, or HY-501.

49. The particle of claims 47 or 48, wherein the steroid is cholesterol.

50. The particle of any one of claims 47-49, wherein the particle further comprises a polymer-conjugated lipid.51 . The particle of any one of claims 44-50, wherein the nucleic acid is RNA.

52. The particle of claim 51 , wherein the RNA is mRNA.

53. The particle of claim 52, wherein the RNA is modRNA, saRNA, taRNA, or uRNA.

54. The particle of any one of claims 1-50, wherein the nucleic acid is DNA.

55. A composition comprising one or more particles of claims 44-54.

56. The composition of claim 55, wherein an average diameter of the one or more particles is from about 10 nm to about 500 nm.

57. The composition of claims 55 or 56, wherein a PDI of the particles in the composition is from about 0.5 to about 1 .

58. A method of treating a disease, disorder, or condition comprising administering to a subject a particle of any one of claims 1-54, or a composition of any one of claims 55-57.

59. The method of claim 58, wherein the disease, disorder, or condition is an infectious disease, cancer, a genetic disorder, an autoimmune disease, or a rare disease.

60. A method of increasing or causing increased expression of RNA in a target in a subject comprising administering to the subject a particle of any one of claims 1-54, or a composition of any one of claims 55-57.

61. The method of claim 60, wherein the target is selected from the lungs, liver, spleen, heart, brain, lymph nodes, bladder, kidneys, and pancreas.

62. The method of any one of claims 58-61 , wherein the composition is administered intramuscularly, intranasally, intravenously, subcutaneously, or intratumoraly.

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