Lipids having dendritic moieties

Abstract

Provided herein are dendritic lipids or pharmaceutically acceptable salts thereof. The dendritic lipids provided herein can be useful for delivery and expression of mRNA and encoded protein, e.g., as a component of liposomal delivery vehicle, and accordingly can be useful for treating various diseases, disorders and conditions, such as those associated with deficiency of one or more proteins.

Description

[0001] LIPIDS HAVING DENDRITIC MOIETIES

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to European Patent Application No. 23307434.3, filed December 29, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0004] SEQUENCE LISTING

[0005] The instant application contains a Sequence Listing which has been submitted herewith and is hereby incorporated by reference in its entirety. Said .xml copy, created on December 23, 2024, is named 758730_SA9-393PC_SL, and is 7,386 bytes in size.

[0006] BACKGROUND

[0007] Effective targeted delivery of biologically active substances such as nucleic acid molecules (e.g., mRNA) represents a continuing medical challenge. In particular, the delivery of nucleic acids to cells is made difficult by their low in vivo stability, propensity toward rapid degradation, and low cell permeability. Thus, there exists a need to develop methods and compositions to facilitate the delivery of therapeutic and / or prophylactics such as nucleic acids to cells.

[0008] Lipid-containing nanoparticle compositions have proven effective as transport vehicles into cells and / or intracellular compartments for biologically active substances such as small molecule drugs, proteins, and nucleic acids. Such compositions generally include one or more ionizable (e.g., cationic) lipids, phospholipids including polyunsaturated or saturated lipids, cholesterol-based lipids, and / or lipids containing polyethylene glycol (PEGylated lipids). Though a variety of such lipid-containing nanoparticle compositions have been demonstrated, there remains a need for lipid nanoparticle formulations that are efficacious and tolerable to patient populations.

[0009] SUMMARY

[0010] The present disclosure provides, inter alia, a dendritic lipid comprising: a lipophilic moiety comprising one or more hydrophobic tails; a generation 1 to generation 4 dendron having a core, a branching portion, and a plurality of terminal groups, each of which terminal group is an alcohol, a polyol such as a sugar moiety, an ethylene glycol chain, a polyoxazoline polymer, or a peptide such as polysarcosine; wherein said lipophilic moiety is covalently attached to the core of the dendron, optionally via a spacer; and optionally wherein each terminal group is covalently attached to the branching portion of the dendron via a linker.

[0011] The present disclosure further provides a dendritic lipid of Formula (I):

[0012] (I), or a pharmaceutically acceptable salt thereof, wherein LIP, L1, DEN1, A1, and nl are as defined herein.

[0013] The present disclosure further provides a dendritic lipid of Formula (la):

[0014] (la) or a pharmaceutically acceptable salt thereof, wherein LIP, L1, and A1are as defined herein.

[0015] The present disclosure further provides a composition comprising a nanoparticle (LNP), wherein the LNP comprises a cationic lipid; and a dendritic lipid of the present disclosure. In some embodiments, the LNP comprises a cationic lipid; and a dendritic lipid of the present disclosure, a structural lipid, and a helper lipid. In some embodiments, the composition further comprises a nucleic acid molecule encapsulated in the LNP. In some embodiments, the nucleic acid molecule is an mRNA molecule.

[0016] The present disclosure further provides a method of eliciting an immune response in a subject in need thereof, comprising administering to the subject a prophylactically effective amount of a composition described herein.

[0017] The present disclosure still further provides a method of preventing an infection or reducing one or more symptoms of an infection in a subject in need thereof, comprising administering to the subject a prophylactically effective amount of a composition described herein. The present disclosure still further provides a method of curing an infection or reducing one or more symptoms of an infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition described herein.

[0018] The present disclosure further provides a kit comprising a container comprising a singleuse or multi-use dosage of a composition described herein.

[0019] BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1A is a graph showing the integrity of dendritic lipid-containing LNP formulations over the course of six weeks as compared to a PEG-lipid control.

[0021] FIG. IB is a graph showing the colloidal stability of dendritic lipid-containing LNP formulations over the course of six weeks as compared to a PEG-lipid control.

[0022] FIG. 2A is a graph showing immune response in mice following intramuscular injection of dendritic lipid-containing LNP formulations as compared to a PEG-lipid control.

[0023] FIG. 2B is a graph showing immune response in mice following intramuscular injection of dendritic lipid-containing LNP formulations as compared to a PEG-lipid control.

[0024] FIG. 3 is a graph showing immune response in non-human primates following administration of dendritic lipid-containing LNP formulations 8, 28, 56, and 84 days after initiation of study, as compared to a PEG-lipid control.

[0025] FIG. 4 is a graph showing immune response in non-human primates following administration of dendritic lipid-containing LNP formulations, as compared to a PEG-lipid control.

[0026] FIG. 5A is a graph showing expression of erythropoietin (EPO) following repeated injections of dendritic lipid and PEG lipid LNP formulations; EPO expression decreased significantly for the PEG lipid formulation but not for the dendritic lipid formulation.

[0027] FIG. 5B is a graph showing EPO normalization following repeated injections of dendritic lipid and PEG lipid LNP formulations; EPO normalization decreased significantly for the PEG lipid formulation but not for the dendritic lipid formulation.

[0028] DETAILED DESCRIPTION

[0029] The present disclosure provides lipid nanoparticle (LNP) formulations for delivering cargo, such as a nucleic acid molecule (e.g., mRNA), to a target cell. In particular the LNPs of the present disclosure comprise a dendritic lipid, an ionizable or cationic lipid, a structural lipid, and a helper lipid. The LNPs may further comprise one or more additional lipids.

[0030] LNP formulations known in the art typically include a polyethylene glycol-conjugated (PEGylated) lipid. These lipids may provide control over particle size and stability of the nanoparticle. Furthermore, PEGylated lipids may prevent complex aggregation and provide a means for increasing circulation lifetime and increasing the delivery of a lipid-nucleic acid pharmaceutical composition to target tissues or cells. However, severe allergic reactions to PEG have been documented and could limit the utility of traditional LNP-based therapeutics. Furthermore, the increased frequency of human exposure to PEG-related products means that healthy people are likely to have endogenous anti-PEG antibodies. These anti-PEG antibodies could impact the pharmacokinetics of LNP formulations and negatively impact their therapeutic efficacy.

[0031] In recognition of this problem, Applicant has discovered that partial or complete replacement of the PEGylated lipid component of LNP formulations with the dendritic lipids of the present application results in nanoparticles having desirable size and efficacy profiles. Furthermore, while the present dendritic lipids may include short ethylene glycol chains, they do not comprise longer polyethylene glycol chains that may give rise to allergic reactions or decreased efficacy due to the presence of endogenous anti-PEG antibodies.

[0032] I. Definitions

[0033] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art.

[0034] As used in the specification and in the claims, the term “comprising” can include the embodiments “consisting of’ and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or processes as “consisting of’ and “consisting essentially of’ the enumerated ingredients / steps, which allows the presence of only the named ingredients / steps and excludes other ingredients / steps. 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 certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0035] As used herein, the term “delivery” encompasses both local and systemic delivery. For example, delivery of mRNA encompasses situations in which an mRNA is delivered to a target tissue and the encoded protein is expressed and retained within the target tissue (also referred to as “local distribution” or “local delivery”), and situations in which an mRNA is delivered to a target tissue and the encoded protein is expressed and secreted into patient's circulation system (e.g., serum) and systematically distributed and taken up by other tissues (also referred to as “systemic distribution” or “systemic delivery).

[0036] As used herein, “expression” of a nucleic acid sequence refers to translation of an mRNA into a polypeptide, assembly of multiple polypeptides (e.g., heavy chain or light chain of antibody) into an intact protein (e.g., antibody), and / or post-translational modification of a polypeptide or fully assembled protein (e.g., antibody). In this application, the terms “expression” and “production,” and grammatical equivalent, are used inter-changeably.

[0037] As used herein, the term “half-life” is the time required for a quantity such as nucleic acid or protein concentration or activity to fall to half of its value as measured at the beginning of a time period.

[0038] As used herein, the terms “improve,” “increase” or “reduce,” or grammatical equivalents, indicate values that are relative to a baseline measurement, such as a measurement in the same individual prior to initiation of the treatment described herein, or a measurement in a control subject (or multiple control subject) in the absence of the treatment described herein.

[0039] As used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism.

[0040] As used herein, the term “in vivo” refers to events that occur within a multi-cellular organism, such as a human and a non-human animal. In the context of cell-based systems, the term may be used to refer to events that occur within a living cell (as opposed to, for example, in vitro systems).

[0041] As used herein, the term "liposome" refers to any lamellar, multilamellar, or solid nanoparticle vesicle. Typically, a liposome as used herein can be formed by mixing one or more lipids or by mixing one or more lipids and polymer(s). In some embodiments, a liposome suitable for the present disclosure contains an ionizable or cationic lipid(s) and optionally noncationic lipid(s), optionally cholesterol-based lipid(s), and / or optionally PEG-modified lipid(s).

[0042] As used herein, the term “messenger RNA (mRNA)” refers to a polynucleotide that encodes at least one polypeptide. mRNA as used herein may encompass both modified and unmodified RNA. mRNA may contain one or more coding and non-coding regions. mRNA can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, etc. Where appropriate, e.g., in the case of chemically synthesized molecules, mRNA can comprise nucleoside analogs such as analogs having chemically modified bases or sugars, backbone modifications, etc. An mRNA sequence is presented in the 5' to 3' direction unless otherwise indicated. In some embodiments, an mRNA is or comprises natural nucleosides (e.g., adenosine, guanosine, cytidine, uridine); nucleoside analogs (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, O(6)-methylguanine, and 2-thiocytidine); chemically modified bases; biologically modified bases (e.g., methylated bases); intercalated bases; modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose); and / or modified phosphate groups (e.g., phosphorothi oates and 5'-N-phosphoramidite linkages).

[0043] As used herein, the term “nucleic acid,” in its broadest sense, refers to any compound and / or substance that is or can be incorporated into a polynucleotide chain. In some embodiments, a nucleic acid is a compound and / or substance that is or can be incorporated into a polynucleotide chain via a phosphodiester linkage. In some embodiments, “nucleic acid” refers to individual nucleic acid residues (e.g., nucleotides and / or nucleosides). In some embodiments, “nucleic acid” refers to a polynucleotide chain comprising individual nucleic acid residues. In some embodiments, “nucleic acid” encompasses RNA as well as single and / or double-stranded DNA and / or cDNA.

[0044] The term “pharmaceutically acceptable” as used herein, refers to substances that, within the scope of sound medical judgment, are 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.

[0045] 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 (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.

[0046] As used herein, the term “subject” refers to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine, sheep, horse or primate). A human includes pre- and post-natal forms. In many embodiments, a subject is a human being. A subject can be a patient, which refers to a human presenting to a medical provider for diagnosis or treatment of a disease. The term “subject” is used herein interchangeably with “individual” or “patient.” A subject can be afflicted with or is susceptible to a disease or disorder but may or may not display symptoms of the disease or disorder.

[0047] As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0048] As used herein, the term “target tissues” refers to any tissue that is affected by a disease to be treated. In some embodiments, target tissues include those tissues that display disease- associated pathology, symptom, or feature.

[0049] As used herein, the term “therapeutically effective amount” of a therapeutic agent means an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the symptom(s) of the disease, disorder, and / or condition. It will be appreciated by those of ordinary skill in the art that a therapeutically effective amount is typically administered via a dosing regimen comprising at least one unit dose.

[0050] As used herein, the term “treatment” or “treating,” is defined as the application or administration of a therapeutic agent to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disorder or disease as described herein, a symptom thereof; or the potential to develop such disorder or disease, where the purpose of the application or administration is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder or disease, or its symptoms. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

[0051] As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

[0052] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers. Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); and Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, Ind. 1972). The present disclosure additionally contemplates compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0053] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C1-6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl. As used herein, “lipophilic” refers to the ability of a group to dissolve in fats, oils, lipids, and lipophilic non-polar solvents such as hexane or toluene. In general, a lipophilic group refers to an unsubstituted n-alkyl or unsubstituted n-alkenyl group having 6 to 50 carbon atoms, e.g., 6 to 40, 6 to 30, 6 to 20, 8 to 20, 8 to 19, 8 to 18, 8 to 17, 8 to 16, or 8 to 15 carbon atoms.

[0054] As used herein, the term “alkyl” refers to a straight or branched saturated hydrocarbon. For example, an alkyl group can have 1 to 30 carbon atoms (i.e., (C1-C30)alkyl), 1 to 20 carbon atoms (i.e., (C1-C20)alkyl), 1 to 12 carbon atoms (i.e., (C1-C12)alkyl), 1 to 6 carbon atoms (i.e., (C1-C6)alkyl), or 1 to 3 carbon atoms (i.e., (C1-C3)alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, - CH2CH2CH3), isopropyl (z-Pr, z-propyl, -CH(CH3)2), 1 -butyl (n-bu, n-butyl, -CH2CH2CH2CH3), 2-butyl (s-bu, .s-butyl, -CH(CH3)CH2CH3), tert-butyl (t-bu, t-butyl, -CH(CH3)3), 1 -pentyl (n- pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3) CH2CH2CH3), neopentyl (CH2C(CH3)3), 1- hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), heptyl (-(CH2)6CH3), octyl (-(CH2)7CH3), 2,2,4-tnmethylpentyl (-CH2C(CH3)2CH2CH(CH3)2), nonyl (-(CH2)8CH3), decyl (-(CH2)9CH3), undecyl (-(CH2)IOCH3), and dodecyl (-(CH2)nCH3).

[0055] As used herein, “heteroalkyl” refers to an alkyl group as defined herein which further includes at least one heteroatom (e.g., 1 to 25, e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain.

[0056] As used herein, the term “alkenyl” refers to a straight or branched saturated hydrocarbon having at least one site of carbon-carbon double bond unsaturation. For example, an alkenyl group can have 2 to 30 carbon atoms (i.e., (C2-C30)alkenyl), 2 to 20 carbon atoms (i.e., (C2-C20)alkenyl), 2 to 12 carbon atoms (i.e., (C2-C12)alkenyl) or 2 to 6 carbon atoms (i.e., (C2-C6)alkenyl), and the alkenyl group can contain 1, 2, 3, or 4 carbon-carbon double bonds. The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Included within this term are the cis and trans isomers or mixtures of these isomers. Nonlimiting examples of alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2- methylprop-2-enyl, hex-2-enyl, hex- 5-enyl, 2,3-dimethylbut-2-enyl, and the like

[0057] As used herein, “heteroalkenyl” refers to an alkenyl group as defined herein which further includes at least one heteroatom (e.g., 1 to 25, e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain.

[0058] As used herein, the term “alkynyl” refers to a straight or branched saturated hydrocarbon having at least one site of carbon-carbon triple bond unsaturation occurring at any stable point along the chain. For example, an alkynyl group can have 2 to 30 carbon atoms (i.e., (C2-C30)alkynyl), 2 to 20 carbon atoms (i.e., (C2-C20)alkynyl), 2 to 12 carbon atoms (i.e., (C2-C12)alkynyl) or 2 to 6 carbon atoms (i.e., (C2-C6)alkynyl), and the alkynyl group can contain 1, 2, 3, or 4 carbon-carbon triple bonds. The one or more carbon-carbon triple bonds can be internal or terminal. Optionally, the alkynyl group may include one or more double bonds (e.g., 1, 2, 3, or 4 double bonds). For purposes of the present disclosure, a hydrocarbon group having one or more triple bonds and one or more double bonds (e.g., an “ene-yne”) is categorized as an alkynyl moiety. Nonlimiting examples of an alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, etc.

[0059] As used herein, “heteroalkynyl” refers to an alkynyl group as defined herein which further includes at least one heteroatom (e.g., 1 to 25, e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain.

[0060] As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Exemplary carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C1O), cyclodecenyl (C1O), octahydro- 1H- indenyl (C9), decahydronaphthalenyl (C1O), spiro[4.5]decanyl (C1O), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.

[0061] The term “heterocycle” or “heterocyclyl” refers to a saturated or partially unsaturated ring system that has at least one atom other than carbon in the ring system, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur. The heterocyclyl group may, for example, consist of a single ring or multiple rings (e.g., in the form of a spirocyclic or bicyclic ring system). Exemplary heterocycles include, but are not limited to oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl.

[0062] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C1O aryl”; e.g., naphthyl such as 1 -naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.

[0063] The term “heteroaryl” refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur. The term “heteroaryl” includes single aromatic rings of from 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. Exemplary heteroaryl ring systems include but are not limited to pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, imidazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, or furyl.

[0064] The term “halogen” or “halo” refers to bromo (-Br), chloro (-C1), fluoro (-F) or iodo (-1).

[0065] In order to maintain electical neutrality, the lipids of the present disclosure may be associated with a counterion, such as a counteranion or a countercation. As used herein, a “counteranion” is a negatively charged group associated with a positively charged quarternary amine in order to maintain electronic neutrality. Exemplary counteranions include halide ions (e.g., F — , Cl — , Br — , I — ), NO3-, C1O4-, OH — , H2PO4-, HSO4-, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthal ene-2-sulfonate, naphthalene- 1 -sulfonic acid- 5-sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0066] As used herein, a "countercation" is a positively charged group that is associated with a negatively charged group in order to maintain electrical neutrality. Representative countercations include inorganic cations, such as metal cations (e.g., alkali metal cations, alkaline earth metal cations, and transition metal cations, including Na+, K+, Ca2+) and organic cations, such as ammonium cations (e.g., tetramethyl ammonium, trimethylammonium chloride), sulfonium cations, phosphonium cations, and pyridinium cations.

[0067] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties) as herein defined.

[0068] As used herein, the term “saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.

[0069] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.

[0070] As used herein, the term “sugar moiety” refers to any mono or polysaccharide. For example, the sugar moiety may be an optionally substituted (e.g., optionally acetylated) monosaccharide, disaccharide, trisaccharide, or tetrasaccharide. Nonlimiting examples of sugar moieties include glucose, fructose, mannose, galactose, sucrose, lactose, maltose, trehalose, neuraminic acid, cellobiose, N-acetylglucosamine, N-acetylgalactosamine, and N- acetylneuraminic acid.

[0071] As used herein, the term “polyethylene glycol chain” or “PEG chain” refers to a poly ether moiety made up of repeating -CH2CH2O- units having a high molecular weight, e.g., greater than or equal to 1500 g / mol, more preferably greater than or equal to 2000 g / mol. In some embodiments, the polyethylene glycol has a molecular weight of about 2000-2400 g / mol. By contrast, the term “ethylene glycol chain” refers to a moiety made up of one to eight repeating -CH2CH2O- units and has a comparatively low molecular weight, e.g., less than 350 g / mol. Ethylene glycol chains of the present disclosure may have, for example, between 1 and 8 - CH2CH2O- units, between 1 and 6 -CH2CH2O- units, or between 1 and 4 -CH2CH2O- units.

[0072] As understood from the above, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are, in certain embodiments, optionally substituted. Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl. “substituted” or “unsubstituted” carbocyclyl. “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

[0073] Exemplary carbon atom substituents include, but are not limited to, halogen, — CN, — NO2, — N3, — SO2H, — SO3H, —OH, — ORaa, — ON(Rbb)2, — N(Rbb)2, — N(Rbb)3+X— , — N(ORcc)Rbb, — SeH, — SeRaa, — SH, — SRaa, — SSRcc, — C(=O)Raa, — CO2H, — CHO, — C(ORcc)2, — CO2Raa, — OC(=O)Raa, — OCO2Raa, — C(=O)N(Rbb)2, — OC(=O)N(Rbb)2, — NRbbC(=O)Raa, — NRbbCO2Raa, — NRbbC(=O)N(Rbb)2, — C(=NRbb)Raa, — C(=NRbb)ORaa, — OC(=NRbb)Raa, — OC(=NRbb)ORaa, — C(=NRbb)N(Rbb)2, — OC(=NRbb)N(Rbb)2, — NRbbC(=NRbb)N(Rbb)2, — C(=O)NRbbS02Raa, — NRbbS02Raa, — SO2N(Rbb)2, — S02Raa, — S02ORaa, — OSO2Raa, — S(=O)Raa, — OS(=O)Raa, — Si(Raa)3 — OSi(Raa)3 — C(=S)N(Rbb)2, — C(=O)SRaa, — C(=S)SRaa, — SC(=S)SRaa, — SC(=O)SRaa, — OC(=O)SRaa, — SC(=O)ORaa, — SC(=O)Raa, — P(=O)2Raa, — OP(=O)2Raa, — P(=O)(Raa)2, — OP(=O)(Raa)2, — OP(=O)(ORcc)2, — P(=O)2N(Rbb)2, — OP(=O)2N(Rbb)2, — P(=O)(NRbb)2, — OP(=O)(NRbb)2, — NRbbP(=O)(ORcc)2, — NRbbP(=O)(NRbb)2, — P(Rcc)2, — P(Rcc)3, — OP(Rcc)2, — OP(Rcc)3, — B(Raa)2, — B(ORcc)2, — BRaa(ORcc), C1-50 alkyl, C2- 50 alkenyl, C2- 50 alkynyl, C3-14 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raa is, independently, selected from C1-50 alkyl, C2- 50 alkenyl, C2- 50 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rbb is, independently, selected from hydrogen, — OH, — ORaa, — N(Rcc)2, — CN, — C(=O)Raa, — C(=O)N(Rcc)2, — CO2Raa, — SO2Raa, — C(=NRcc)ORaa, — C(=NRcc)N(Rcc)2, — SO2N(Rcc)2, — SO2Rcc, — SO2ORcc, — SORaa, — C(=S)N(Rcc)2, — C(=O)SRcc, — C(=S)SRcc, — P(=O)2Raa, — P(=O)(Raa)2, — P(=O)2N(Rcc)2, — P(=O)(NRcc)2, C1-50 alkyl, C2- 50 alkenyl, C2- 50 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbb groups, together with the heteroatom to which they are attached, form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rcc is, independently, selected from hydrogen, C1-50 alkyl, C2- 50 alkenyl, C2- 50 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups, together with the heteroatom to which they are attached, form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rdd is, independently, selected from halogen, — CN, — NO2, — N3, — SO2H, — SO3H, —OH, — ORee, — ON(Rff)2, — N(Rff)2, — N(Rff)3+X— , — N(ORee)Rff, — SH, — SRee, — SSRee, — C(=O)Ree, — CO2H, — CO2Ree, — OC(=O)Ree, — OCO2Ree, — C(=O)N(Rff)2, — OC(=O)N(Rff)2, — NRffC(=O)Ree, — NRffCO2Ree, — NRffC(=O)N(Rff)2, — C(=NRff)ORee, — OC(=NRff)Ree, — OC(=NRff)ORee, — C(=NRff)N(Rff)2, — OC(=NRff)N(Rff)2, — NRffC(=NRff)N(Rff)2, — NRffSO2Ree, — SO2N(Rff)2, — SO2Ree, — SO2ORee, — OSO2Ree, — S(=O)Ree, — Si(Ree)3, — OSi(Ree)3, — C(=S)N(Rff)2, — C(=O)SRee, — C(=S)SRee, — SC(=S)SRee, — P(=O)2Ree, — P(=O)(Ree)2, — OP(=O)(Ree)2, — OP(=O)(ORee)2, C1-50 alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form =O or =S; each instance of Ree is, independently, selected from C1-50 alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of Rff is, independently, selected from hydrogen, C1-50 alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, or two Rff groups, together with the heteroatom to which they are attached, form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and each instance of Rgg is, independently, halogen, — CN, — NO2, — N3, — SO2H, — SO3H, —OH, — OC1-50 alkyl, — ON(C1-50 alkyl)2, — N(C1-50 alkyl)2, — N(C1-50 alkyl)3+X— , — NH(C1-50 alkyl)2+X— , — NH2(C1-5O alkyl)+X— , — NH3+X— , — N(OC1-50 alkyl)(C1-50 alkyl), — N(OH)(C1-50 alkyl), — NH(OH), — SH, -SC1-50 alkyl, — SS(C1-5O alkyl), — C(=O)(C1-50 alkyl), — CO2H, — CO2(C1-50 alkyl), — OC(=O)(C1-50 alkyl), — OCO2(C1-50 alkyl), — C(=O)NH2, — C(=O)N(C1-50 alkyl)2, — OC(=O)NH(C1-50 alkyl), — NHC(=O)(C1-50 alkyl), — N(C1-5O alkyl)C(=O)(C1-50 alkyl), — NHCO2(C1-50 alkyl), — NHC(=O)N(C1-50 alkyl)2, — NHC(=O)NH(C1-50 alkyl), — NHC(=O)NH2, — C(=NH)O(C1- 50 alkyl), — OC(=NH)(C1-50 alkyl), — OC(=NH)OC1-50 alkyl, — C(=NH)N(C1-50 alkyl)2, — C(=NH)NH(C1-50 alkyl), — C(=NH)NH2, — OC(=NH)N(C1-50alkyl)2, — OC(NH)NH(C1-50 alkyl), — OC(NH)NH2, — NHC(NH)N(C1-50 alkyl)2, — NHC(=NH)NH2, — NHSO2 (Cl -50 alkyl), — SO2N(C1-50 alkyl)2, — SO2NH(C1-50 alkyl), — SO2NH2, — SO2C1-50 alkyl, — SO2OC1-50 alkyl, — OSO2C1-6 alkyl, — SOC1-6 alkyl, — Si(C1-50 alkyl)3, — OSi(C1-6 alkyl)3-C(=S)N(C1-50 alkyl)2, C(=S)NH(C1-50 alkyl), C(=S)NH2, — C(=O)S(C1-6 alkyl), — C(=S)SC1-6 alkyl, — SC(=S)SC1-6 alkyl, — P(=O)2(C1-50 alkyl), — P(=O)(C1-50 alkyl)2, — OP(=O)(C1-50 alkyl)2, — OP(=O)(OC1-50 alkyl)2, C1-50 alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgg substituents can be joined to form =O or =S; wherein X — is a counteranion.

[0074] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, — OH, — ORaa, — N(Rcc)2, — CN, — C(=O)Raa, — C(=O)N(Rcc)2, — CO2Raa, — SO2Raa, — C(=NRbb)Raa, — C(=NRcc)ORaa, — C(=NRcc)N(Rcc)2, — SO2N(Rcc)2, — SO2Rcc, — SO2ORcc, — SORaa, — C(=S)N(Rcc)2, — C(=O)SRcc, — C(=S)SRcc, — P(=O)2Raa, — P(=O)(Raa)2, — P(=O)2N(Rcc)2, — P(=O)(NRcc)2, C1-50 alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups, together with the N atom to which they are attached, form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined above.

[0075] Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. In case of conflict, the present specification, including definitions, will control. Generally, nomenclature used in connection with, and techniques of, cell and tissue culture, molecular biology, virology, immunology, microbiology, genetics, analytical chemistry, synthetic organic chemistry, medicinal and pharmaceutical chemistry, and protein and nucleic acid chemistry and hybridization described herein are those well-known and commonly used in the art. Enzymatic reactions and purification techniques are performed according to manufacturer’s specifications, as commonly accomplished in the art or as described herein.

[0076] Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0077] Although a number of documents are cited herein, this citation does not constitute an admission that any of these documents forms part of the common general knowledge in the art.

[0078] IL Lipids Having Dendritic Moieties

[0079] The present disclosure provides a dendritic lipid comprising: a lipophilic moiety comprising one or more hydrophobic tails; a generation 1 to generation 4 dendron having a core, a branching portion, and a plurality of terminal groups, each of which terminal group is an alcohol, a polyol (e.g., a sugar moiety), an ethylene glycol chain, a polyoxazoline polymer, or a peptide (e.g., polysarcosine); wherein said lipophilic moiety is covalently attached to the core of the dendron, optionally via a spacer; and optionally wherein each terminal group is covalently attached to the branching portion of the dendron via a linker.

[0080] In some embodiments, the lipophilic moiety comprises one, two, three, or four hydrophobic tails. In some embodiments, the lipophilic moiety comprises one, two, or three hydrophobic tails. In some embodiments, the lipophilic moiety comprises one or two hydrophobic tails. In some embodiments, the lipophilic moiety comprises two or there hydrophobic tails. In some embodiments, the lipophilic moiety comprises one hydrophobic tail.

[0081] In some embodiments, the lipophilic moiety comprises two hydrophobic tails. In some embodiments, the lipophilic moiety comprises three hydrophobic tails.

[0082] In some embodiments, the lipophilic moiety further comprises a head group, wherein the one or more hydrophobic tails are covalently attached to the head group, and the head group is covalently attached to the core of the dendron, optionally via a spacer. The head group may be any chemical moiety capable of covalent attachment of the one or more hydrophobic tails and the dendron. The head group may be, without limitation, a glycerol, a phosphatidylglycerol, a sphingosine, a phosphosphingosine, or a dialkylamide. In some embodiments, the head group is a glycerol. In some embodiments, the head group is a phosphatidylglycerol. In some embodiments, the head group is a sphingosine. In some embodiments, the head group is a phosphosphingosine. In some embodiments, the head group is a dialkylamide.

[0083] In some embodiments, the lipophilic moiety has a structure selected from: wherein R1independently for each occurrence is a hydrophobic tail, and p is an integer between

[0084] 6 and 18. In some embodiments, p is 12.

[0085] In some embodiments, the lipophilic moiety has a structure selected from:

[0086] wherein R1independently for each occurrence is a hydrophobic tail. In some embodiments, the lipophilic moiety has a structure selected from: wherein R1independently for each occurrence is a hydrophobic tail.

[0087] In some embodiments, the lipophilic moiety has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0088] In some embodiments, the lipophilic moiety has a structure selected from: , and wherein R1independently for each occurrence is a hydrophobic tail. In some embodiments, the lipophilic moiety has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0089] In some embodiments, the lipophilic moiety has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0090] In some embodiments, the lipophilic moiety has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0091] In some embodiments, the lipophilic moiety has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0092] In some embodiments, the lipophilic moiety has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0093] In some embodiments, the lipophilic moiety has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0094] In some embodiments, the lipophilic moiety has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0095] In some embodiments, the lipophilic moiety has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0096] In some embodiments, the lipophilic moiety has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0097] In some embodiments, the lipophilic moiety has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0098] In some embodiments, the lipophilic moiety has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0099] In some embodiments, the hydrophobic tails each comprise a C(6-24)alkyl, a C(6-24)alkenyl, or a C(6-24)alkynyl group. In some embodiments, the hydrophobic tails each consist of a C(6-24)alkyl, a C(6-24)alkenyl, or a C(6-24)alkynyl group. In some embodiments, the hydrophobic tails each comprise a C(6-24)alkyl group. In some embodiments, the hydrophobic tails each consist of a C(6-24)alkyl group. In some embodiments, the hydrophobic tails each comprise a C(6-24)alkenyl group. In some embodiments, the hydrophobic tails each consist of a C(6-24)alkenyl group. In some embodiments, the hydrophobic tails each comprise a C(6-24)alkynyl group. In some embodiments, the hydrophobic tails each consist of a C(6-24)alkynyl group.

[0100] In some embodiments, the hydrophobic tails each comprise a C(12-18)alkyl, a C(12-18)alkenyl, or a C(12-18)alkynyl group. In some embodiments, the hydrophobic tails each consist of a C(12-18)alkyl, a C(12-18)alkenyl, or a C(12-18)alkynyl group. In some embodiments, the hydrophobic tails each comprise a C(12-18)alkyl. In some embodiments, the hydrophobic tails each consist of a C(12-18)alkyl group. In some embodiments, the hydrophobic tails each comprise a C(12-18)alkenyl group. In some embodiments, the hydrophobic tails each consist of a C(12-i8)alkenyl group. In some embodiments, the hydrophobic tails each comprise a C(12-18)alkynyl group. In some embodiments, the hydrophobic tails each consist of a C(12-18)alkynyl group.

[0101] In some embodiments, each hydrophobic tail is selected from the group consisting of - C(6-24)alkyl, -C(6-24)alkenyl, -C(6-24)alkynyl, and ? , wherein the -C(6-24)alkyl, -C(6-24)alkenyl, and -C(6-24)alkynyl are each optionally substituted with one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl; wherein:

[0102] X1is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl;

[0103] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and X3is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl.

[0104] In some embodiments, each hydrophobic tail is selected from the group consisting of - In some embodiments, each hydrophobic tail is selected from the group consisting of -C(6-24)alkyl, -C(6-24)alkenyl, and

[0105] In some embodiments, X1is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl. In some embodiments, X1is -C(6-14)alkyl or -C(6-14)alkenyl. In some embodiments, X1is -C(6-14)alkyl. In some embodiments, X1is -C(6-14)alkenyl.

[0106] In some embodiments, X2is -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, or -OC(O)O-. In some embodiments, X2is -C(O)O-, -OC(O)-, or -OC(O)O-.

[0107] In some embodiments, X3is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl. In some embodiments, X3is -C(6-14)alkyl or -C(6-14)alkenyl. In some embodiments, X3is -C(6-14)alkyl. In some embodiments, X3is -C(6-14)alkenyl.

[0108] In some embodiments, X1is -C(6-14)alkyl or -C(6-14)alkenyl; X2is -C(O)O-, -OC(O)-, - C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and X3is -C(6-14)alkyl or -C(6-14)alkenyl.

[0109] In some embodiments, each hydrophobic tail is selected from the group consisting of - + ; X1is -C(6-14)alkyl or -C(6-14)alkenyl; X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or - NHC(O)NH-; and X3is -C(6-14)alkyl or -C(6-14)alkenyl.

[0110] In some embodiments, the lipophilic moiety has the following structure:

[0111] In some embodiments, the lipophilic moiety has the following structure: In some embodiments, the lipophilic moiety has the following structure:

[0112] In some embodiments, the lipophilic moiety has a structure selected from the group consisting of:

[0113] In some embodiments, the lipophilic moiety has a structure selected from the group consisting of:

[0114] In some embodiments, the lipophilic moiety has a structure selected from the group consisting of:

[0115] In some embodiments, the lipophilic moiety has a structure selected from the group consisting of: In some embodiments, the lipophilic moiety has a structure selected from the group consisting of:

[0116] In some embodiments, the lipophilic moiety has the following structure:

[0117] In some embodiments, the lipophilic moiety has the following structure:

[0118] In some embodiments, the lipophilic moiety has the following structure:

[0119] In some embodiments, the lipophilic moiety has the following structure:

[0120] In some embodiments, the lipophilic moiety has the following structure:

[0121] In some embodiments, the lipophilic moiety has the following structure:

[0122] In some embodiments, the lipophilic moiety has the following structure:

[0123] In some embodiments, the lipophilic moiety has the following structure: In some embodiments, the lipophilic moiety is a sterol. In some embodiments, the lipophilic moiety has the following structure:

[0124] In some embodiments, the lipophilic moiety has the following structure:

[0125] In some embodiments, the lipophilic moiety has the following structure:

[0126] In some embodiments, the lipophilic moiety has the following structure:

[0127] In some embodiments, the dendritic lipid does not comprise a spacer between the lipophilic moiety and the core of the dendron.

[0128] In some embodiments, the lipophilic moiety is covalently attached to the core of the dendron via a spacer.

[0129] In some embodiments, the spacer is -C(1-60)alkyl-, wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O-, -NH-, -S-, -S- S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH- , -NHC(O)O-, and -NHC(O)NH-. In some embodiments, the spacer is -C(1-30)alkyl-, wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O-, -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, - SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, and -NHC(O)NH-.

[0130] In some embodiments, the spacer is -O-, -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-. In some embodiments, the spacer is -S-S-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, - SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-.

[0131] In some embodiments, the spacer comprises an ethylene glycol chain. In some embodiments, the spacer comprises an ethylene glycol chain having between 1 and 8 - CH2CH2O- units. In some embodiments, the spacer comprises an ethylene glycol chain having between 2 and 6 -CH2CH2O- units. In some embodiments, the spacer comprises an ethylene glycol chain having between 2 and 4 -CH2CH2O- units.

[0132] In some embodiments, the spacer is: wherein:

[0133] X3is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0134] X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m is 1, 2, 3, 4, 5, 6, 7, or 8;

[0135] X5is absent, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, - C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl- NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-;

[0136] X6is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0137] X7is -C(1-16)alkyl-, -C(1-8)alkyl-S-S-C(1-8)alkyl-, -C(1-8)alkyl-C(O)O-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)-C(1-8)alkyl-, -C(1-8)alkyl-C(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)-C(1-8)alkyl-, - C(1-8)alkyl-C(O)S-C(1-8)alkyl-, -C(1-8)alkyl-SC(O)-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)O-C(1-8)alkyl-, - C(1-8)alkyl-OC(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)O-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)NH- C(1-8)alkyl-; and

[0138] X8is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; wherein X3forms a bond with the lipophilic moiety and X5forms a bond with the core of the dendron; or wherein X6forms a bond with the lipophilic moiety and X8forms a bond with the core of the dendron. In some embodiments, the spacer is: wherein X3forms a bond with the lipophilic moiety and X5forms a bond with the core of the dendron.

[0139] In some embodiments, X3is absent. In some embodiments, X3is -O-, -NH-, -S-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, - NHC(O)O-, or -NHC(O)NH-. In some embodiments, X3is absent or -C(O)-.

[0140] In some embodiments, X4is absent. In some embodiments, X4is -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-. In some embodiments, X4is -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl- OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-.

[0141] In some embodiments, m is 1, 2, 3, 4, 5, or 6. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8.

[0142] In some embodiments, X5is absent. In some embodiments, X5is -C(O)-, -C(O)O-, - C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, -C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl- NHC(O)NH-. In some embodiments, X5is -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, - C(O)OC(1-6)alkyl -, or -C(O)NHC(1-6)alkyl. In some embodiments, X5is -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl- NHC(O)NH-.

[0143] In some embodiments, the spacer is: In some embodiments, the spacer is:

[0144] In some embodiments, the spacer is:

[0145] In some embodiments, the spacer is:

[0146] In some embodiments, the spacer is: In some embodiments, the spacer is:

[0147] In some embodiments, the spacer is:

[0148] In some embodiments, the spacer is:

[0149] In some embodiments, the spacer is: wherein X6forms a bond with the lipophilic moiety and X8forms a bond with the core of the dendron.

[0150] In some embodiments, X6is absent. In some embodiments, X6is -O-, -NH-, -S-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, - NHC(O)O-, or -NHC(O)NH-.

[0151] In some embodiments, X7is -C(1-16)alkyl- or -C(1-8)alkyl-S-S-C(1-8)alkyl-. In some embodiments, X7is -C(1-16)alkyl-. In some embodiments, X7is -C(1-8)alkyl-S-S-C(1-8)alkyl-.

[0152] In some embodiments, X8is absent. In some embodiments, X8is -O-, -NH-, -S-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, - NHC(O)O-, or -NHC(O)NH-.

[0153] The dendritic lipids of the present application comprise a dendron having a core, a branching portion, and a plurality of terminal groups. To describe the degree of branching, the notion of “generations” is used. In the present disclosure, the core refers to the branched unit (i.e., the dendritic monomeric unit) bonded directly to the lipophilic moiety, optionally via a spacer. The branched unit of the core may include 2, 3, or 4 branching valencies to which terminal groups or additional branching units may be attached. The core including terminal groups covalently attached to it are defined as the first generation. The branched units next to the core including their terminal groups is defined as the second generation. When there is another dendritic structure outside the dendritic structure of the second generation, the succeeding branched units including their terminal groups is defined as the third generation. Likewise, for the fourth and the following generations, a subsequent dendritic structure or branched units including their terminal groups is defined as the next generation.

[0154] In some embodiments, the dendron is a generation 1 to generation 4 dendron. In some embodiments, the dendron is a generation 1 to generation 3 dendron. In some embodiments, the dendron is a generation 1 to generation 2 dendron. In some embodiments, the dendron is a generation 1 dendron. In some embodiments, the dendron is a generation 1.5 dendron. In some embodiments, the dendron is a generation 2 dendron. In some embodiments, the dendron is a generation 3 dendron. In some embodiments, the dendron is a generation 4 dendron. In some embodiments, the dendron is a generation 1 dendron having a structure according to Formula D1 :

[0155] (D1), wherein DEN is a dendritic monomeric unit; L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group.

[0156] In some embodiments, the dendron is a generation 1 dendron having a structure according to Formula D2:

[0157] (D2), wherein DEN is a dendritic monomeric unit; L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group.

[0158] In some embodiments, the dendron is a generation 1.5 dendron having a structure according to Formula D3:

[0159] (D3), wherein DEN independently for each occurrence is a dendritic monomeric unit; L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group. In some embodiments, the dendron is a generation 2 dendron having a structure according to Formula D4:

[0160] (D4), wherein DEN independently for each occurrence is a dendritic monomeric unit; L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group.

[0161] In some embodiments, the dendron is a generation 2 dendron having a structure according to Formula D5:

[0162] (D5), wherein DEN independently for each occurrence is a dendritic monomeric unit; L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group.

[0163] In some embodiments, the dendron is a generation 2 dendron having a structure according to Formula D6:

[0164] (D6), wherein DEN independently for each occurrence is a dendritic monomeric unit; L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group.

[0165] In some embodiments, the dendron is a generation 3 dendron having a structure according to Formula D7:

[0166] (D7), wherein DEN independently for each occurrence is a dendritic monomeric unit; L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group. In some embodiments, the dendron is a generation 3 dendron having a structure according to Formula D8:

[0167] (D8), wherein DEN independently for each occurrence is a dendritic monomeric unit; L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group.

[0168] In some embodiments, the dendron is a generation 4 dendron having a structure according to Formula D9: (D9), wherein DEN independently for each occurrence is a dendritic monomeric unit; L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group.

[0169] In some embodiments, the dendron is a generation 4 dendron having a structure according to Formula D10:

[0170] (D10), wherein DEN independently for each occurrence is a dendritic monomeric unit; L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group.

[0171] In some embodiments, the dendron comprises dendritic monomeric units selected from 2,2-bis(hydroxymethyl) propionic acid (bis-MPA), poly(amido-amine) (PAMAM), poly(ethyleneimine) (PEI), polyester, polylysine, polypropyleneimine (PPI), diaminobutane amine polypropylenimine tetramine (DAB-Am 4), pentaerythritol, aliphatic poly ether, aromatic poly ether (e.g., poly(benzyl ether)), or combinations thereof.

[0172] In some embodiments, the dendron comprises dendritic monomeric units of 2,2- bis(hydroxymethyl) propionic acid (bis-MPA).

[0173] In some embodiments, the dendron is: wherein L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group.

[0174] In some embodiments, the dendron is: wherein L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group.

[0175] In some embodiments, the dendron is: wherein L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group.

[0176] In some embodiments, the dendron is: wherein L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group.

[0177] In some embodiments, the dendron is: wherein L2independently for each occurrence is absent or a linker, and TERM independently for each occurrence is a terminal group. In some embodiments, the dendritic lipid comprises between 2 and 24 terminal groups.

[0178] In some embodiments, the dendritic lipid comprises between 2 and 16 terminal groups. In some embodiments, the dendritic lipid comprises between 2 and 9 terminal groups. In some embodiments, the dendritic lipid comprises between 2 and 8 terminal groups. In some embodiments, the dendritic lipid comprises 2, 3, or 4 terminal groups. In some embodiments, the dendritic lipid comprises 2 terminal groups. In some embodiments, the dendritic lipid comprises 3 terminal groups. In some embodiments, the dendritic lipid comprises 4 terminal groups. In some embodiments, the dendritic lipid comprises 5 terminal groups. In some embodiments, the dendritic lipid comprises 6 terminal groups. In some embodiments, the dendritic lipid comprises 7 terminal groups. In some embodiments, the dendritic lipid comprises 8 terminal groups. In some embodiments, the dendritic lipid comprises 9 terminal groups. In some embodiments, the dendritic lipid comprises 10 terminal groups. In some embodiments, the dendritic lipid comprises 11 terminal groups. In some embodiments, the dendritic lipid comprises 12 terminal groups. In some embodiments, the dendritic lipid comprises 13 terminal groups. In some embodiments, the dendritic lipid comprises 14 terminal groups. In some embodiments, the dendritic lipid comprises 15 terminal groups. In some embodiments, the dendritic lipid comprises 16 terminal groups.

[0179] In some embodiments, the dendritic lipid does not comprise a linker between each terminal group and the branching portion of the dendron.

[0180] In some embodiments, each terminal group is covalently attached to the branching portion of the dendron via a linker.

[0181] In some embodiments, each linker is independently for each occurrence -C(1-60)alkyl-, wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O-, -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, - C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, and -NHC(O)NH-. In some embodiments, each linker is independently for each occurrence -C(1-30)alkyl-, wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O-, -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, - OC(O)O-, -OC(O)NH-, -NHC(O)O-, and -NHC(O)NH-.

[0182] In some embodiments, each linker is independently for each occurrence -O-, -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-. In some embodiments, each linker is independently for each occurrence -S-S-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, - OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-.

[0183] In some embodiments, each linker comprises an ethylene glycol chain. In some embodiments, each linker comprises an ethylene glycol chain having between 1 and 8 - CH2CH2O- units. In some embodiments, each linker comprises an ethylene glycol chain having between 2 and 6 -CH2CH2O- units. In some embodiments, each linker comprises an ethylene glycol chain having between 2 and 4 -CH2CH2O- units.

[0184] In some embodiments, each linker independently for each occurrence is: wherein:

[0185] X3’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -0C(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0186] X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m' is 1, 2, 3, 4, 5, 6, 7, or 8;

[0187] X5’ is absent, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, - C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl- NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-;

[0188] X6’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0189] X7is -C(1-16)alkyl-, -C(1-8)alkyl-S-S-C(1-8)alkyl-, -C(1-8)alkyl-C(O)O-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)-C(1-8)alkyl-, -C(1-8)alkyl-C(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)-C(1-8)alkyl-, - C(1-8)alkyl-C(O)S-C(1-8)alkyl-, -C(1-8)alkyl-SC(O)-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)O-C(1-8)alkyl-, - C(1-8)alkyl-OC(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)O-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)NH- C(1-8)alkyl-; and

[0190] X8’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; wherein X3forms a bond with the branching portion of the dendron and X5forms a bond with the terminal group; or wherein X6forms a bond with the branching portion of the dendron and X8forms a bond with the terminal group.

[0191] In some embodiments, each linker independently for each occurrence is: wherein X3forms a bond with the branching portion of the dendron and X5forms a bond with the terminal group.

[0192] In some embodiments, X3is absent. In some embodiments, X3is -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, - NHC(O)O-, or -NHC(O)NH-. In some embodiments, X3is absent or -C(O)NH-.

[0193] In some embodiments, X4is absent. In some embodiments, X4is -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-. In some embodiments, X4is -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl- OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-.

[0194] In some embodiments, m’ is 1, 2, 3, 4, 5, or 6. In some embodiments, m’ is 1, 2, 3, or 4. In some embodiments, m’ is 1. In some embodiments, m’ is 2. In some embodiments, m’ is 3. In some embodiments, m’ is 4. In some embodiments, m’ is 5. In some embodiments, m’ is 6. In some embodiments, m’ is 7. In some embodiments, m’ is 8.

[0195] In some embodiments, X5is absent. In some embodiments, X5is -C(O)-, -C(O)O-, - C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, -C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl- NHC(O)NH-. In some embodiments, X5is -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, - C(O)OC(1-6)alkyl -, or -C(O)NHC(1-6)alkyl. In some embodiments, X5is -C(1-6)alkyl-, -C(1-

[0196] 6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-

[0197] 6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl- NHC(O)NH-. In some embodiments, X5is absent or -C(1-6)alkylC(O)-.

[0198] In some embodiments, each linker is:

[0199] In some embodiments, each linker is:

[0200] In some embodiments, each linker is:

[0201] In some embodiments, each linker is:

[0202] In some embodiments, each linker is: wherein X6forms a bond with the branching portion of the dendron and X8forms a bond with the terminal group.

[0203] In some embodiments, X6is absent. In some embodiments, X6is -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, - NHC(O)O-, or -NHC(O)NH-.

[0204] In some embodiments, X7is -C(1-16)alkyl- or -C(1-8)alkyl-S-S-C(1-8)alkyl-. In some embodiments, X7is -C(1-16)alkyl-. In some embodiments, X7is -C(1-8)alkyl-S-S-C(1-8)alkyl-.

[0205] In some embodiments, X8is absent. In some embodiments, X8is -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, - NHC(O)O-, or -NHC(O)NH-.

[0206] In some embodiments, each linker is:

[0207] H

[0208] In some embodiments, each linker is:

[0209] In some embodiments, each linker is identical. In some embodiments, each linker is not identical.

[0210] In some embodiments, each terminal group is an alcohol. In some embodiments, each terminal group is a polyol (e.g., a sugar moiety). In some embodiments, each terminal group is an ethylene glycol chain. In some embodiments, each terminal group is a polyoxazoline polymer. In some embodiments, each terminal group is a peptide (e.g., polysarcosine).

[0211] In some embodiments, each terminal group is a polyol, an ethylene glycol chain, or a peptide. In some embodiments, each terminal group is a sugar moiety, an ethylene glycol chain, or polysarcosine.

[0212] In some embodiments, each terminal group is a polyol. In some embodiments, the polyol is a sugar moiety. In some embodiments, each terminal group is a sugar moiety. In some embodiments, each terminal group is a monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide. In some embodiments, each terminal group is a monosaccharide, a disaccharide, or a trisaccharide. In some embodiments, each terminal group is a monosaccharide or a disaccharide. In some embodiments, each terminal group is a monosaccharide. In some embodiments, each terminal group is a disaccharide.

[0213] In some embodiments, each terminal group is independently selected from the group consisting of glucose, galactofuranose, galactose, mannose, allose, altrose, gulose, idose, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, 6-deoxyaltrose, 6-deoxygulose, 6- deoxytalose, fucose, rhamnose, quinovose, 2-deoxyglucose, 2-deoxyribose, olivose, tyvelose, ascarylose, abequose, paratose, digitoxose, colitose, glucosamine, galactosamine, mannosamine, allosamine, altrosamine, gulosamine, idosamine, talosamine, N-acetylglucosamine, N- acetylgalactosamine, N-acetylmannosamine, N-acetylallosamine, N-acetylaltrosamine, N- acetylgulosamine, N-acetylidosamine, N-acetyltalosamine, N-acetylfucosamine, N- acetylrhamnosamine, N-acetylquinovasoamine, N-acetyl-6-deoxyaltrosamine, N-acetyl-6- deoxytalosamine, glucuronic acid, galacturonic acid, mannuronic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid, taluronic acid, sialic acid, neuraminic acid, N- acetylneuraminic acid, N-glycolylneuraminic acid, psicose, fructose, sorbose, tagatose, xlulose, sedoheptulose, apiose, bacillosamine, thevetose, acofriose, cymarose, muramic acid, N- acetylmuramic acid, N-glycolylmuramic acid, 3-deoxy-lyxo-heptulosaric acid, ketodeoxyoctonic acid, ketodeoxynononic acid, pseudaminic acid, acinetaminic acid, legionaminic acid, 4- epilegionaminic acid, sucrose, lactose, maltose, trehalose, cellobiose, chitobiose, kojibiose, nigerose, isomaltose, sophorose, laminaribiose, gentiobiose, trehalulose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melibiose, allolactose, melibiulose, lactulose, rutinose, rutinulose, and xylobiose. In some embodiments, each terminal group is independently selected from the group consisting of glucose, fructose, mannose, mannobiose, galactose, sucrose, lactose, maltose, trehalose, neuraminic acid, cellobiose, N-acetylglucosamine, N- acetylgalactosamine, N-acetylneuraminic acid, and a trisaccharide comprising three sugar molecules selected from the group consisting of glucose, fructose, and mannose. In some embodiments, each terminal group is independently selected from the group consisting of glucose, fructose, mannose, galactose, sucrose, lactose, maltose, trehalose, neuraminic acid, cellobiose, N-acetylglucosamine, N-acetylgalactosamine, and N-acetylneuraminic acid. In some embodiments, each terminal group is independently selected from the group consisting of glucose, mannose, and trehalose. In some embodiments, each terminal group is glucose. In some embodiments, each terminal group is mannose. In some embodiments, each terminal group is mannobiose. In some embodiments, each terminal group is trehalose. In some embodiments, each terminal group is a trisaccharide comprising three sugar molecules selected from the group consisting of glucose, fructose, and mannose. In some embodiments, each terminal group is a trisaccharide comprising three mannose molecules.

[0214] In some embodiments, each terminal group has a structure selected from the group consisting of:

[0215] In some embodiments, each terminal group has a structure selected from the group consisting of:

[0216] In some embodiments, each terminal group is an ethylene glycol chain, a polyoxazoline polymer, or a peptide. In some embodiments, each terminal group is an ethylene glycol chain or polysarcosine.

[0217] In some embodiments, each terminal group is an ethylene glycol chain. In some embodiments, each terminal group is an ethylene glycol chain having between 1 and 8 - CH2CH2O- units. In some embodiments, each terminal group is an ethylene glycol chain having between 2 and 8 -CH2CH2O- units. In some embodiments, each terminal group is an ethylene glycol chain having between 2 and 6 -CH2CH2O- units. In some embodiments, each terminal group is an ethylene glycol chain having between 2 and 4 -CH2CH2O- units. In some embodiments, the ethylene glycol chain terminates in -OH or alkoxy. In some embodiments, the ethylene glycol chain terminates in -OH or -OCH3. In some embodiments, the ethylene glycol chain terminates in -OH. In some embodiments, the ethylene glycol chain terminates in -OCH3. In some embodiments, each terminal group is a polyoxazoline polymer. In some embodiments, the polyoxazoline polymer has the following structure: wherein RPOZ1is alkyl (e.g., C1-3alkyl, such as methyl, ethyl, iso-propyl, or n-propyl), and nPOZis 2-200. In some embodiments, the polyoxazoline polymer terminates in -H, -OH, -SH, -NH2, - NH(alkyl), -N(alkyl)2, -CN, -N3, -COOH, halogen, alkyl, alkynyl, alkoxy, -OC(O)-alkyl, -C(O)- alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -NHC(O)-alkyl, or -N(alkyl)C(O)-alkyl. In some embodiments, the polyoxazoline polymer terminates in hydrogen or alkyl. In some embodiments, the polyoxazoline polymer terminates in -H, C1-3alkyl, -OH, -N3, C2-6alkynyl, - 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, or - OC(O)(CH2)2COOH. Further examples of polyoxazoline polymers are described in WO 2023 / 166099.

[0218] In some embodiments, each terminal group is peptide. In some embodiments, the peptide comprises naturally occurring and non-naturally occurring amino acids. In some embodiments, the peptide comprises naturally occurring amino acids. In some embodiments, the peptide comprises non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 50 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 45 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 35 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 25 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 15 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 8 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 6 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 4 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide is polysarcosine. In some embodiments, each terminal group is polysarcosine. In some embodiments, each terminal group is polysarcosine having between 2 and 45 sarcosine units. In some embodiments, each terminal group is polysarcosine having between 2 and 35 sarcosine units. In some embodiments, each terminal group is polysarcosine having between 2 and 25 sarcosine units. In some embodiments, each terminal group is polysarcosine having between 2 and 15 sarcosine units. In some embodiments, each terminal group is polysarcosine having between 2 and 8 sarcosine units. In some embodiments, each terminal group is polysarcosine having between 2 and 6 sarcosine units. In some embodiments, each terminal group is polysarcosine having between 2 and 4 sarcosine units.

[0219] In some embodiments, each terminal group is identical. In some embodiments, each terminal group is not identical.

[0220] The present disclosure further provides a dendritic lipid of Formula (I):

[0221] (I), or a pharmaceutically acceptable salt thereof, wherein:

[0222] LIP is a lipophilic moiety comprising one or more hydrophobic tails;

[0223] L1is absent or -C(1-60)alkyl- wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O-, -NH-, -S-, -S-S-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, - NHC(O)O-, and -NHC(O)NH-;

[0224] DEN1is a dendritic monomeric unit having nl branching valencies; nl is 2 or 3;

[0225] A1independently for each occurrence is:

[0226] DEN2independently for each occurrence is a dendritic monomeric unit having n2 branching valencies; n2 independently for each occurrence is 2 or 3;

[0227] A2independently for each occurrence is:

[0228] DEN3independently for each occurrence is a dendritic monomeric unit having n3 branching valencies; n3 independently for each occurrence is 2 or 3;

[0229] A3independently for each occurrence is:

[0230] DEN4independently for each occurrence is a dendritic monomeric unit having n4 branching valencies; n4 independently for each occurrence is 2 or 3;

[0231] A4independently for each occurrence is:

[0232] L2independently for each occurrence is absent or -C(1-60)alkyl- wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O- , -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, - OC(O)O-, -OC(O)NH-, -NHC(O)O-, and -NHC(O)NH-; and

[0233] TERM independently for each occurrence is an alcohol, a polyol (e.g., a sugar moiety), an ethylene glycol chain, a polyoxazoline polymer, or a peptide (e.g., polysarcosine).

[0234] In some embodiments of the dendritic lipid of Formula (I),

[0235] LIP is a lipophilic moiety comprising one, two, or three hydrophobic tails and a head group, wherein the one or more hydrophobic tails are covalently attached to the head group, and wherein the head group is covalently attached to L1; each hydrophobic tail is selected from the group consisting of -C(6-24)alkyl, -C(6-24)alkenyl,

[0236] -C(6-24)alkynyl, and wherein the -C(6-24)alkyl, -C(6-24)alkenyl, and -C(6-24)alkynyl are each optionally substituted with one to six groups independently selected from halo, -OC(1-

[0237] 6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl;

[0238] X1is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl; X2is -C(O)O-, -0C(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0239] X3is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl; the head group is a glycerol, a phosphatidylglycerol, a sphingosine, a phosphosphingosine, or a dialkylamide;

[0240] L1is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, - SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, -NHC(O)NH-,

[0241] X3is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0242] X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0243] X5is absent, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, - C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl- NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-;

[0244] X6is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0245] X7is -C(1-16)alkyl-, -C(1-8)alkyl-S-S-C(1-8)alkyl-, -C(1-8)alkyl-C(O)O-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)-C(1-8)alkyl-, -C(1-8)alkyl-C(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)-C(1-8)alkyl-, - C(1-8)alkyl-C(O)S-C(1-8)alkyl-, -C(1-8)alkyl-SC(O)-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)O-C(1-8)alkyl-, - C(1-8)alkyl-OC(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)O-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)NH- C(1-8)alkyl-; X8is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -0C(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0246] DEN1is a dendritic monomeric unit having nl branching valencies; nl is 2 or 3;

[0247] A1independently for each occurrence is:

[0248] DEN2independently for each occurrence is a dendritic monomeric unit having n2 branching valencies; n2 independently for each occurrence is 2 or 3;

[0249] A2independently for each occurrence is:

[0250] DEN3independently for each occurrence is a dendritic monomeric unit having n3 branching valencies; n3 independently for each occurrence is 2 or 3;

[0251] A3independently for each occurrence is:

[0252] DEN4independently for each occurrence is a dendritic monomeric unit having n4 branching valencies; n4 independently for each occurrence is 2 or 3;

[0253] A4independently for each occurrence is:

[0254] L2independently for each occurrence is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, - OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, - NHC(O)NH-, X3’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -0C(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0255] X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0256] X5’ is absent, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, - C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl- NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-;

[0257] X6’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0258] X7is -C(1-16)alkyl-, -C(1-8)alkyl-S-S-C(1-8)alkyl-, -C(1-8)alkyl-C(O)O-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)-C(1-8)alkyl-, -C(1-8)alkyl-C(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)-C(1-8)alkyl-, - C(1-8)alkyl-C(O)S-C(1-8)alkyl-, -C(1-8)alkyl-SC(O)-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)O-C(1-8)alkyl-, - C(1-8)alkyl-OC(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)O-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)NH- C(1-8)alkyl-;

[0259] X8’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and

[0260] TERM independently for each occurrence is a monosaccharide, a disaccharide, an ethylene glycol chain, or a peptide (e.g., polysarcosine).

[0261] In some embodiments, the dendritic lipid has a structure according to Formula (la): or a pharmaceutically acceptable salt thereof, wherein:

[0262] LIP is

[0263]

[0264] R1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, or « ;

[0265] X1is -C(6-14)alkyl or -C(6-14)alkenyl;

[0266] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -

[0267] OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0268] X3is -C(6-14)alkyl or -C(6-14)alkenyl L1is absent,

[0269] X3is absent, -C(O)-, -C(O)O-, or -C(O)NH-;

[0270] X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m is 1, 2, 3, 4, 5, 6, 7, or 8;

[0271] X5is absent, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, -C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, - C(1-6)alkylO-, -C(1-6)alkylNH-, or -C(1-6)alkylS-;

[0272] X6is absent, -C(O)-, -C(O)O-, or -C(O)NH-;

[0273] X7is -C(1-16)alkyl- or -C(1-8)alkyl-S-S-C(1-8)alkyl-; X8is absent, -O-, -NH-, or -S-;

[0274] A1independently for each occurrence is:

[0275] A2independently for each occurrence is:

[0276] A3independently for each occurrence is:

[0277] A4independently for each occurrence is:

[0278] L2independently for each occurrence is absent, -C(O)-, -C(O)O-, -C(O)NH-,

[0279] X3’ is absent, -C(O)-, -C(O)O-, or -C(O)NH-;

[0280] X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m' is 1, 2, 3, 4, 5, 6, 7, or 8;

[0281] X5’ is absent, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, - C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl- NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; X6is absent, -C(O)-, -C(O)O-, or -C(O)NH-;

[0282] X7is -C(1-16)alkyl- or -C(1-8)alkyl-S-S-C(1-8)alkyl-;

[0283] X8’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and

[0284] TERM independently for each occurrence is selected from the group consisting of sucrose, lactose, maltose, trehalose, cellobiose, glucose, fructose, mannose, mannobiose, galactose, an ethylene glycol chain, polysarcosine, or a trisaccharide comprising three sugar molecules selected from the group consisting of glucose, frutose, and mannose.

[0285] In some embodiments, the dendritic lipid has a structure according to Formula (la): or a pharmaceutically acceptable salt thereof, wherein:

[0286] LIP is

[0287] R1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, or ? ;

[0288] X1is -C(6-14)alkyl or -C(6-14)alkenyl;

[0289] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0290] X3is -C(6-14)alkyl or -C(6-14)alkenyl

[0291] L1is absent,

[0292] X3is absent, -C(O)-, -C(O)O-, or -C(O)NH-;

[0293] X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m is 1, 2, 3, 4, 5, 6, 7, or 8;

[0294] X5is absent, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, -C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -

[0295] C(1-6)alkylO-, -C(1-6)alkylNH-, or -C(1-6)alkylS-;

[0296] X6is absent, -C(O)-, -C(O)O-, or -C(O)NH-;

[0297] X7is -C(1-16)alkyl- or -C(1-8)alkyl-S-S-C(1-8)alkyl-;

[0298] X8is absent, -O-, -NH-, or -S-;

[0299] A1independently for each occurrence is:

[0300] A2independently for each occurrence is:

[0301] A3independently for each occurrence is:

[0302] A4independently for each occurrence is:

[0303] L2independently for each occurrence is absent, -C(O)-, -C(O)O-, -C(O)NH-,

[0304] X3’ is absent, -C(O)-, -C(O)O-, or -C(O)NH-;

[0305] X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-

[0306] 6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m' is 1, 2, 3, 4, 5, 6, 7, or 8;

[0307] X5’ is absent, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, - C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl- NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-;

[0308] X6’ is absent, -C(O)-, -C(O)O-, or -C(O)NH-;

[0309] X7is -C(1-16)alkyl- or -C(1-8)alkyl-S-S-C(1-8)alkyl-;

[0310] X8’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and

[0311] TERM independently for each occurrence is selected from the group consisting of sucrose, lactose, maltose, trehalose, cellobiose, glucose, fructose, mannose, galactose, an ethylene glycol chain, or polysarcosine.

[0312] In some embodiments of the dendritic lipid of Formula (I) or (la), the lipophilic moiety comprises one, two, three, or four hydrophobic tails. In some embodiments of the dendritic lipid of Formula (I) or (la), the lipophilic moiety comprises one, two, or three hydrophobic tails. In some embodiments of the dendritic lipid of Formula (I) or (la), the lipophilic moiety comprises one hydrophobic tail. In some embodiments of the dendritic lipid of Formula (I) or (la), the lipophilic moiety comprises two hydrophobic tails. In some embodiments of the dendritic lipid of Formula (I) or (la), the lipophilic moiety comprises three hydrophobic tails.

[0313] In some embodiments of the dendritic lipid of Formula (I) or (la), the lipophilic moiety further comprises a head group, wherein the one or more hydrophobic tails are covalently attached to the head group, and the head group is covalently attached to the core of the dendron, optionally via a spacer. The head group may be any chemical moiety capable of covalent attachment of the one or more hydrophobic tails and the dendron. The head group may be, without limitation, a glycerol, a phosphatidylglycerol, a sphingosine, a phosphosphingosine, or a dialkylamide. In some embodiments of the dendritic lipid of Formula (I) or (la), the head group is a glycerol. In some embodiments of the dendritic lipid of Formula (I) or (la), the head group is a phosphatidylglycerol. In some embodiments of the dendritic lipid of Formula (I) or (la), the head group is a sphingosine. In some embodiments of the dendritic lipid of Formula (I) or (la), the head group is a phosphosphingosine. In some embodiments of the dendritic lipid of Formula

[0314] (I) or (la), the head group is a dialkylamide.

[0315] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has a structure selected from: wherein R1independently for each occurrence is a hydrophobic tail, and p is an integer between

[0316] 6 and 18. In some embodiments, p is 12.

[0317] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has a structure selected from:

[0318] wherein R1independently for each occurrence is a hydrophobic tail. In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has a structure selected from: wherein R1independently for each occurrence is a hydrophobic tail.

[0319] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0320] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has a structure selected from: wherein R1independently for each occurrence is a hydrophobic tail.

[0321] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0322] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0323] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0324] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0325] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0326] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0327] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0328] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0329] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure: wherein R1independently for each occurrence is a hydrophobic tail. In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0330] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure: wherein R1independently for each occurrence is a hydrophobic tail.

[0331] In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each comprise a C(6-24)alkyl, a C(6-24)alkenyl, or a C(6-24)alkynyl group. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each consist of a C(6-24)alkyl, a C(6-24)alkenyl, or a C(6-24)alkynyl group. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each comprise a C(6-24)alkyl group. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each consist of a C(6-24)alkyl group. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each comprise a C(6-24)alkenyl group. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each consist of a C(6-24)alkenyl group. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each comprise a C(6-24)alkynyl group. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each consist of a C(6-24)alkynyl group.

[0332] In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each comprise a C(12-18)alkyl, a C(12-18)alkenyl, or a C(12-18)alkynyl group. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each consist of a C(12-18)alkyl, a C(12-18)alkenyl, or a C(12-18)alkynyl group. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each comprise a C(12-18)alkyl. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each consist of a C(12-18)alkyl group. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each comprise a C(12-18)alkenyl group. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each consist of a C(12-18)alkenyl group. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each comprise a C(12-18)alkynyl group. In some embodiments of the dendritic lipid of Formula (I) or (la), the hydrophobic tails each consist of a C(12-18)alkynyl group.

[0333] In some embodiments of the dendritic lipid of Formula (I) or (la), each hydrophobic tail is selected from the group consisting of -C(6-24)alkyl, -C(6-24)alkenyl, -C(6-24)alkynyl, and , wherein the -C(6-24)alkyl, -C(6-24)alkenyl, and -C(6-24)alkynyl are each optionally substituted with one to six groups independently selected from halo, -OC(1-6)alkyl, -OC( 2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl; wherein:

[0334] X1is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl;

[0335] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and

[0336] X3is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl.

[0337] In some embodiments of the dendritic lipid of Formula (I) or (la), each hydrophobic tail is selected from the group consisting of -C(6-24)alkyl, -C(6-24)alkenyl, -C(6-24)alkynyl, and . In some embodiments of the dendritic lipid of Formula (I) or (la), each hydrophobic tail is selected from the group consisting of -C(6-24)alkyl, -C(6-24)alkenyl, and

[0338] In some embodiments of the dendritic lipid of Formula (I) or (la), X1is -C(6-14)alkyl, - C(6-14)alkenyl, or -C(6-14)alkynyl. In some embodiments of the dendritic lipid of Formula (I) or (la), X1is -C(6-14)alkyl or -C(6-14)alkenyl. In some embodiments of the dendritic lipid of Formula (I) or (la), X1is -C(6-14)alkyl. In some embodiments of the dendritic lipid of Formula (I) or (la), X1is -C(6-14)alkenyl. In some embodiments of the dendritic lipid of Formula (I) or (la), X2is -C(O)O-, - OC(O)-, -C(O)S-, -SC(O)-, or -OC(O)O-. In some embodiments of the dendritic lipid of Formula (I) or (la), X2is -C(O)O-, -OC(O)-, or -OC(O)O-.

[0339] In some embodiments of the dendritic lipid of Formula (I) or (la), X3is -C(6-14)alkyl, - C(6-14)alkenyl, or -C(6-14)alkynyl. In some embodiments of the dendritic lipid of Formula (I) or (la), X3is -C(6-14)alkyl or -C(6-14)alkenyl. In some embodiments of the dendritic lipid of Formula (I) or (la), X3is -C(6-14)alkyl. In some embodiments of the dendritic lipid of Formula (I) or (la), X3is -C(6-14)alkenyl.

[0340] In some embodiments of the dendritic lipid of Formula (I) or (la), X1is -C(6-14)alkyl or - C(6-14)alkenyl; X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and X3is -C(6-14)alkyl or -C(6-14)alkenyl.

[0341] In some embodiments of the dendritic lipid of Formula (I) or (la), each hydrophobic tail is selected from the group consisting of -C(6-24)alkyl, -C(6-24)alkenyl, and X1is -C(6-

[0342] 14)alkyl or -C(6-14)alkenyl; X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, - OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and X3is -C(6-14)alkyl or -C(6-14)alkenyl.

[0343] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0344] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0345] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0346] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has a structure selected from the group consisting of:

[0347] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has a structure selected from the group consisting of: In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has a structure selected from the group consisting of:

[0348] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0349] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0350] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0351] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0352] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure: In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0353] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0354] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0355] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP is a sterol. In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0356] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0357] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0358] In some embodiments of the dendritic lipid of Formula (I) or (la), LIP has the following structure:

[0359] In some embodiments of the dendritic lipid of Formula (I) or (la), L1is absent. In some embodiments of the dendritic lipid of Formula (I) or (la), L1is not absent.

[0360] In some embodiments of the dendritic lipid of Formula (I) or (la), L1is -C(1-60)alkyl-, wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O-, -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, - C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, and -NHC(O)NH-. In some embodiments of the dendritic lipid of Formula (I) or (la), L1is -C(1-30)alkyl-, wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O- , -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, - OC(O)O-, -OC(O)NH-, -NHC(O)O-, and -NHC(O)NH-.

[0361] In some embodiments of the dendritic lipid of Formula (I) or (la), L1is -O-, -NH-, -S-, - S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-. In some embodiments of the dendritic lipid of Formula (I) or (la), L1is -S-S-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, - OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-.

[0362] In some embodiments of the dendritic lipid of Formula (I) or (la), L1comprises an ethylene glycol chain. In some embodiments of the dendritic lipid of Formula (I) or (la), L1comprises an ethylene glycol chain having between 1 and 8 -CH2CH2O- units. In some embodiments of the dendritic lipid of Formula (I) or (la), L1comprises an ethylene glycol chain having between 2 and 6 -CH2CH2O- units. In some embodiments of the dendritic lipid of Formula (I) or (la), L1comprises an ethylene glycol chain having between 2 and 4 -CH2CH2O- units.

[0363] In some embodiments of the dendritic lipid of Formula (I) or (la), L1is: wherein:

[0364] X3is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0365] X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m is 1, 2, 3, 4, 5, 6, 7, or 8;

[0366] X5is absent, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, - C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl- NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-;

[0367] X6is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0368] X7is -C(1-16)alkyl-, -C(1-8)alkyl-S-S-C(1-8)alkyl-, -C(1-8)alkyl-C(O)O-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)-C(1-8)alkyl-, -C(1-8)alkyl-C(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)-C(1-8)alkyl-, - C(1-8)alkyl-C(O)S-C(1-8)alkyl-, -C(1-8)alkyl-SC(O)-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)O-C(1-8)alkyl-, - C(1-8)alkyl-OC(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)O-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)NH- C(1-8)alkyl-; and

[0369] X8is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-.

[0370] In some embodiments of the dendritic lipid of Formula (I) or (la), L1is:

[0371] In some embodiments of the dendritic lipid of Formula (I) or (la), X3is absent. In some embodiments of the dendritic lipid of Formula (I) or (la), X3is -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or - NHC(O)NH-. In some embodiments of the dendritic lipid of Formula (I) or (la), X3is absent or - C(O)-.

[0372] In some embodiments of the dendritic lipid of Formula (I) or (la), X4is absent. In some embodiments of the dendritic lipid of Formula (I) or (la), X4is -C(1-6)alkylO-, -C(1-6)alkylNH-, - C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl- OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-. In some embodiments of the dendritic lipid of Formula (I) or (la), X4is -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-.

[0373] In some embodiments of the dendritic lipid of Formula (I) or (la), m is 1, 2, 3, 4, 5, or 6. In some embodiments of the dendritic lipid of Formula (I) or (la), m is 1, 2, 3, or 4. In some embodiments of the dendritic lipid of Formula (I) or (la), m is 1. In some embodiments of the dendritic lipid of Formula (I) or (la), m is 2. In some embodiments of the dendritic lipid of Formula (I) or (la), m is 3. In some embodiments of the dendritic lipid of Formula (I) or (la), m is 4. In some embodiments of the dendritic lipid of Formula (I) or (la), m is 5. In some embodiments of the dendritic lipid of Formula (I) or (la), m is 6. In some embodiments of the dendritic lipid of Formula (I) or (la), m is 7. In some embodiments of the dendritic lipid of Formula (I) or (la), m is 8.

[0374] In some embodiments of the dendritic lipid of Formula (I) or (la), X5is absent. In some embodiments of the dendritic lipid of Formula (I) or (la), X5is -C(O)-, -C(O)O-, -C(O)NH-, - C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, -C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-. In some embodiments of the dendritic lipid of Formula (I) or (la), X5is -C(O)-, -C(O)O-, -C(O)NH- , -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, or -C(O)NHC(1-6)alkyl. In some embodiments of the dendritic lipid of Formula (I) or (la), X5is -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl- OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-. In some embodiments of the dendritic lipid of Formula (I) or (la), L1is:

[0375] In some embodiments of the dendritic lipid of Formula (I) or (la), L1is: In some embodiments of the dendritic lipid of Formula (I) or (la), L1is:

[0376] In some embodiments of the dendritic lipid of Formula (I) or (la), L1is:

[0377] In some embodiments of the dendritic lipid of Formula (I) or (la), L1is:

[0378] In some embodiments of the dendritic lipid of Formula (I) or (la), L1is:

[0379] In some embodiments of the dendritic lipid of Formula (I) or (la), L1is: In some embodiments of the dendritic l ipid of Formula (I) or (la), L1is:

[0380] In some embodiments of the dendritic lipid of Formula (I) or (la), L1is:

[0381] In some embodiments of the dendritic lipid of Formula (I) or (la), X6is absent. In some embodiments of the dendritic lipid of Formula (I) or (la), X6is -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or - NHC(O)NH-.

[0382] In some embodiments of the dendritic lipid of Formula (I) or (la), X7is -C(1-16)alkyl- or - C(1-8)alkyl-S-S-C(1-8)alkyl-. In some embodiments of the dendritic lipid of Formula (I) or (la), X7is -C(1-16)alkyl-. In some embodiments of the dendritic lipid of Formula (I) or (la), X7is -C(1-8)alkyl-S-S-C(1-8)alkyl-.

[0383] In some embodiments of the dendritic lipid of Formula (I) or (la), X8is absent. In some embodiments of the dendritic lipid of Formula (I) or (la), X8is -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or - NHC(O)NH-.

[0384] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN1is a dendritic monomeric unit of 2,2-bis(hydroxymethyl) propionic acid (bis-MPA), poly(amido-amine) (PAMAM), poly(ethyleneimine) (PEI), polyester, polylysine, polypropyleneimine (PPI), diaminobutane amine polypropylenimine tetramine (DAB-Am 4), pentaerythritol, aliphatic polyether, or aromatic polyether (e.g., poly(benzyl ether)).

[0385] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN1is:

[0386] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN1

[0387] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN1 In some embodiments of the dendritic lipid of Formula (I) or (la), DEN1is:

[0388] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN1is:

[0389] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN1is:

[0390] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN1is:

[0391] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN1is:

[0392] In some embodiments of the dendritic lipid of Formula (I) or (la), nl is 2. In some embodiments of the dendritic lipid of Formula (I) or (la), nl is 3. In some embodiments of the dendritic lipid of Formula (I) or (la), each A1is:

[0393] In some embodiments of the dendritic lipid of Formula (I) or (la), each A1is:

[0394] In some embodiments of the dendritic lipid of Formula (I) or (la), each A1is:

[0395] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN2is a dendritic monomeric unit of 2,2-bis(hydroxymethyl) propionic acid (bis-MPA), poly(amido-amine) (PAMAM), poly(ethyleneimine) (PEI), polyester, polylysine, polypropyleneimine (PPI), diaminobutane amine polypropylenimine tetramine (DAB-Am 4), pentaerythritol, aliphatic polyether, or aromatic polyether (e.g., poly(benzyl ether)).

[0396] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN2is:

[0397] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN2is:

[0398] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN2is:

[0399] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN2is: In some embodiments of the dendritic lipid of Formula (I) or (la), DEN2is:

[0400] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN2is:

[0401] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN2is:

[0402] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN2is:

[0403] In some embodiments of the dendritic lipid of Formula (I) or (la), n2 is 2. In some embodiments of the dendritic lipid of Formula (I) or (la), n2 is 3.

[0404] In some embodiments of the dendritic lipid of Formula (I) or (la), each A2is:

[0405] In some embodiments of the dendritic lipid of Formula (I) or (la), each A2is: In some embodiments of the dendritic lipid of Formula (I) or (la), each A2is:

[0406] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN3is a dendritic monomeric unit of 2,2-bis(hydroxymethyl) propionic acid (bis-MPA), poly(amido-amine) (PAMAM), poly(ethyleneimine) (PEI), polyester, polylysine, polypropyleneimine (PPI), diaminobutane amine polypropylenimine tetramine (DAB-Am 4), pentaerythritol, aliphatic polyether, or aromatic polyether (e.g., poly(benzyl ether)).

[0407] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN3is:

[0408] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN3is:

[0409] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN3is: In some embodiments of the dendritic lipid of Formula (I) or (la), DEN3is:

[0410] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN3is: In some embodiments of the dendritic lipid of Formula (I) or (la), DEN3is:

[0411] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN3is:

[0412] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN3is:

[0413] In some embodiments of the dendritic lipid of Formula (I) or (la), n3 is 2. In some embodiments of the dendritic lipid of Formula (I) or (la), n3 is 3.

[0414] In some embodiments of the dendritic lipid of Formula (I) or (la), each A3is:

[0415] In some embodiments of the dendritic lipid of Formula (I) or (la), each A3is:

[0416] In some embodiments of the dendritic lipid of Formula (I) or (la), each A3is: In some embodiments of the dendritic lipid of Formula (I) or (la), DEN4is a dendritic monomeric unit of 2,2-bis(hydroxymethyl) propionic acid (bis-MPA), poly(amido-amine) (PAMAM), poly(ethyleneimine) (PEI), polyester, polylysine, polypropyleneimine (PPI), diaminobutane amine polypropylenimine tetramine (DAB-Am 4), pentaerythritol, aliphatic polyether, or aromatic polyether (e.g., poly(benzyl ether)).

[0417] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN4is:

[0418] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN4is:

[0419] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN4is:

[0420] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN4is:

[0421] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN4is:

[0422] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN4is:

[0423] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN4is:

[0424] In some embodiments of the dendritic lipid of Formula (I) or (la), DEN4is:

[0425] In some embodiments of the dendritic lipid of Formula (I) or (la), n4 is 2. In some embodiments of the dendritic lipid of Formula (I) or (la), n4 is 3.

[0426] In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid has a structure according to Formula (la- 1 ):

[0427] (la-1), or a pharmaceutically acceptable salt thereof.

[0428] In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid has a structure according to Formula (la- 1.5):

[0429] (la- 1.5). or a pharmaceutically acceptable salt thereof.

[0430] In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid has a structure according to Formula (la-2): or a pharmaceutically acceptable salt thereof.

[0431] In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid has a structure according to Formula (la-3): or a pharmaceutically acceptable salt thereof.

[0432] In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid has a structure according to Formula (la-4):

[0433] (la-4), or a pharmaceutically acceptable salt thereof.

[0434] In some embodiments of the dendritic lipid of Formula (I), the dendritic lipid has a structure according to Formula (lb): (Ib), or a pharmaceutically acceptable salt thereof.

[0435] In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises between 2 and 24 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises between 2 and 16 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises between 2 and 9 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises between 2 and 8 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 2, 3, or 4 TERM groups.

[0436] In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 2 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 3 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 4 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 5 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 6 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 7 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 8 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 9 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 10 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 11 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 12 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 13 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 14 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 15 TERM groups. In some embodiments of the dendritic lipid of Formula (I) or (la), the dendritic lipid comprises 16 TERM groups.

[0437] In some embodiments of the dendritic lipid of Formula (I) or (la), L2independently for each occurrence is absent. In some embodiments of the dendritic lipid of Formula (I) or (la), L2independently for each occurrence is not absent. In some embodiments of the dendritic lipid of Formula (I) or (la), L2independently for each occurrence is -C(1-60)alkyl-, wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O-, -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, - OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, and - NHC(O)NH-. In some embodiments of the dendritic lipid of Formula (I) or (la), L2independently for each occurrence is -C(1-30)alkyl-, wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O-, -NH-, -S-, -S-S-, - C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, - NHC(O)O-, and -NHC(O)NH-.

[0438] In some embodiments of the dendritic lipid of Formula (I) or (la), L2independently for each occurrence is -O-, -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, - C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-. In some embodiments of the dendritic lipid of Formula (I) or (la), L2independently for each occurrence is -S-S-, - C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, - NHC(O)O-, or -NHC(O)NH-.

[0439] In some embodiments of the dendritic lipid of Formula (I) or (la), L2independently for each occurrence comprises an ethylene glycol chain. In some embodiments of the dendritic lipid of Formula (I) or (la), L2comprises an ethylene glycol chain having between 1 and 8 - CH2CH2O- units. In some embodiments of the dendritic lipid of Formula (I) or (la), L2comprises an ethylene glycol chain having between 2 and 6 -CH2CH2O- units. In some embodiments of the dendritic lipid of Formula (I) or (la), L2comprises an ethylene glycol chain having between 2 and 4 -CH2CH2O- units.

[0440] In some embodiments of the dendritic lipid of Formula (I) or (la), L2independently for each occurrence is: wherein:

[0441] X3’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0442] X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m' is 1, 2, 3, 4, 5, 6, 7, or 8;

[0443] X5’ is absent, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, - C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl- NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-;

[0444] X6’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0445] X7is -C(1-16)alkyl-, -C(1-8)alkyl-S-S-C(1-8)alkyl-, -C(1-8)alkyl-C(O)O-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)-C(1-8)alkyl-, -C(1-8)alkyl-C(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)-C(1-8)alkyl-, - C(1-8)alkyl-C(O)S-C(1-8)alkyl-, -C(1-8)alkyl-SC(O)-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)O-C(1-8)alkyl-, - C(1-8)alkyl-OC(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)O-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)NH- C(1-8)alkyl-; and

[0446] X8’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-.

[0447] In some embodiments of the dendritic lipid of Formula (I) or (la), L2independently for each occurrence is: m'

[0448] In some embodiments of the dendritic lipid of Formula (I) or (la), X3is absent. In some embodiments of the dendritic lipid of Formula (I) or (la), X3is -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or - NHC(O)NH-. In some embodiments of the dendritic lipid of Formula (I) or (la), X3is absent or - C(O)NH-.

[0449] In some embodiments of the dendritic lipid of Formula (I) or (la), X4is absent. In some embodiments of the dendritic lipid of Formula (I) or (la), X4is -C(1-6)alkylO-, -C(1-6)alkylNH-, - C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl- OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-. In some embodiments of the dendritic lipid of Formula (I) or (la), X4is -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-

[0450] 6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-.

[0451] In some embodiments of the dendritic lipid of Formula (I) or (la), m’ is 1, 2, 3, 4, 5, or 6. In some embodiments of the dendritic lipid of Formula (I) or (la), m’ is 1, 2, 3, or 4. In some embodiments of the dendritic lipid of Formula (I) or (la), m’ is 1. In some embodiments of the dendritic lipid of Formula (I) or (la), m’ is 2. In some embodiments of the dendritic lipid of Formula (I) or (la), m’ is 3. In some embodiments of the dendritic lipid of Formula (I) or (la), m’ is 4. In some embodiments of the dendritic lipid of Formula (I) or (la), m’ is 5. In some embodiments of the dendritic lipid of Formula (I) or (la), m’ is 6. In some embodiments of the dendritic lipid of Formula (I) or (la), m’ is 7. In some embodiments of the dendritic lipid of Formula (I) or (la), m’ is 8.

[0452] In some embodiments of the dendritic lipid of Formula (I) or (la), X5is absent. In some embodiments of the dendritic lipid of Formula (I) or (la), X5is -C(O)-, -C(O)O-, -C(O)NH-, - C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, -C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-. In some embodiments of the dendritic lipid of Formula (I) or (la), X5is -C(O)-, -C(O)O-, - C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, or -C(O)NHC(1-6)alkyl. In some embodiments of the dendritic lipid of Formula (I) or (la), X5is -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, - C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl- OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-. In some embodiments of the dendritic lipid of Formula (I) or (la), X5is absent or -C(1-6)alkylC(O)-.

[0453] In some embodiments of the dendritic lipid of Formula (I) or (la), each linker is:

[0454] H '

[0455] In some embodiments of the dendritic lipid of Formula (I) or (la), each linker is:

[0456] In some embodiments of the dendritic lipid of Formula (I) or (la), each linker is:

[0457] In some embodiments of the dendritic lipid of Formula (I) or (la), each linker is:

[0458] In some embodiments of the dendritic lipid of Formula (I) or (la), each linker is:

[0459] In some embodiments of the dendritic lipid of Formula (I) or (la), X6is absent. In some embodiments of the dendritic lipid of Formula (I) or (la), X6is -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or - NHC(O)NH-.

[0460] In some embodiments of the dendritic lipid of Formula (I) or (la), X7is -C(1-16)alkyl- or - C(1-8)alkyl-S-S-C(1-8)alkyl-. In some embodiments of the dendritic lipid of Formula (I) or (la), X7is -C(1-16)alkyl-. In some embodiments of the dendritic lipid of Formula (I) or (la), X7is -C(1-8)alkyl-S-S-C(1-8)alkyl-.

[0461] In some embodiments of the dendritic lipid of Formula (I) or (la), X8is absent. In some embodiments of the dendritic lipid of Formula (I) or (la), X8is -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or - NHC(O)NH-.

[0462] In some embodiments of the dendritic lipid of Formula (I) or (la), each linker is:

[0463] In some embodiments of the dendritic lipid of Formula (I) or (la), each linker is: In some embodiments of the dendritic lipid of Formula (I) or (la), each L2is identical. In some embodiments, each L2is not identical.

[0464] In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is an alcohol. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is a polyol (e.g., a sugar moiety). In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is an ethylene glycol chain. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is a polyoxazoline polymer. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is a peptide (e.g., sarcosine).

[0465] In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is a sugar moiety, an ethylene glycol chain, or a peptide. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is a sugar moiety, an ethylene glycol chain, or polysarcosine.

[0466] In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is polyol. In some embodiments, the polyol is a sugar moiety. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is a sugar moiety. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is a monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is a monosaccharide, a disaccharide, or a trisaccharide. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is a monosaccharide or a disaccharide. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is a monosaccharide. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is a disaccharide.

[0467] In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is selected from the group consisting of glucose, galactofuranose, galactose, mannose, allose, altrose, gulose, idose, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, 6-deoxyaltrose, 6-deoxygulose, 6-deoxytalose, fucose, rhamnose, quinovose, 2- deoxyglucose, 2-deoxyribose, olivose, tyvelose, ascarylose, abequose, paratose, digitoxose, colitose, glucosamine, galactosamine, mannosamine, allosamine, altrosamine, gulosamine, idosamine, talosamine, N-acetylglucosamine, N-acetylgalactosamine, N-acetylmannosamine, N- acetylallosamine, N-acetylaltrosamine, N-acetylgulosamine, N-acetylidosamine, N- acetyltalosamine, N-acetylfucosamine, N-acetylrhamnosamine, N-acetylquinovasoamine, N- acetyl-6-deoxyaltrosamine, N-acetyl-6-deoxytalosamine, glucuronic acid, galacturonic acid, mannuronic acid, alluronic acid, altruronic acid, guluronic acid, iduronic acid, taluronic acid, sialic acid, neuraminic acid, N-acetylneuraminic acid, N-glycolylneuraminic acid, psicose, fructose, sorbose, tagatose, xlulose, sedoheptulose, apiose, bacillosamine, thevetose, acofriose, cymarose, muramic acid, N-acetylmuramic acid, N-glycolylmuramic acid, 3-deoxy-lyxo- heptulosaric acid, ketodeoxyoctonic acid, ketodeoxynononic acid, pseudaminic acid, acinetaminic acid, legionaminic acid, 4-epilegionaminic acid, sucrose, lactose, maltose, trehalose, cellobiose, chitobiose, kojibiose, nig erose, isomaltose, sophorose, laminaribiose, gentiobiose, trehalulose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melibiose, allolactose, melibiulose, lactulose, rutinose, rutinulose, and xylobiose. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is selected from the group consisting of glucose, fructose, mannose, mannobiose, galactose, sucrose, lactose, maltose, trehalose, neuraminic acid, cellobiose, N-acetylglucosamine, N-acetylgalactosamine, N-acetylneuraminic acid, and a trisaccharide comprising three sugar molecules selected from the group consisting of glucose, fructose, and mannose. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is selected from the group consisting of glucose, fructose, mannose, galactose, sucrose, lactose, maltose, trehalose, neuraminic acid, cellobiose, N-acetylglucosamine, N- acetylgalactosamine, and N-acetylneuraminic acid. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is selected from the group consisting of glucose, mannose, and trehalose. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is glucose. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is mannose. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is mannobiose. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is trehalose. In some embodiments, each terminal group is a trisaccharide comprising three sugar molecules selected from the group consisting of glucose, fructose, and mannose. In some embodiments, each terminal group is a trisaccharide comprising three mannose molecules.

[0468] In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence has a structure selected from the group consisting of:

[0469] In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence has a structure selected from the group consisting of: In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is an ethylene glycol chain, a polyoxazoline polymer, or a peptide. In some embodiments of the dendritic lipid of Formula (I) or (la), TERM independently for each occurrence is an ethylene glycol chain or polysarcosine.

[0470] In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is an ethylene glycol chain. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is an ethylene glycol chain having between 1 and 8 -CH2CH2O- units. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is an ethylene glycol chain having between 2 and 8 -CH2CH2O- units. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is an ethylene glycol chain having between 2 and 6 -CH2CH2O- units. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is an ethylene glycol chain having between 2 and 4 -CH2CH2O- units. In some embodiments, each ethylene glycol chain terminates in -OH or alkoxy. In some embodiments, each ethylene glycol chain terminates in -OH or -OCH3. In some embodiments, each ethylene glycol chain terminates in -OH. In some embodiments, each ethylene glycol chain terminates in -OCH3.

[0471] In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is a polyoxazoline polymer. In some embodiments, the polyoxazoline polymer has the following structure: wherein RPOZ1is alkyl (e.g., C1-3alkyl, such as methyl, ethyl, iso-propyl, or n-propyl), and nPOZis 2-200. In some embodiments, the polyoxazoline polymer terminates in -H, -OH, -SH, -NH2, - NH(alkyl), -N(alkyl)2, -CN, -N3, -COOH, halogen, alkyl, alkynyl, alkoxy, -OC(O)-alkyl, -C(O)- alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -NHC(O)-alkyl, or -N(alkyl)C(O)-alkyl. In some embodiments, the polyoxazoline polymer terminates in hydrogen or alkyl. In some embodiments, the polyoxazoline polymer terminates in -H, C1-3alkyl, -OH, -N3, C2-6alkynyl, - 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, or - OC(O)(CH2)2COOH. Further examples of polyoxazoline polymers are described in WO 2023 / 166099.

[0472] In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is a peptide. In some embodiments, the peptide comprises naturally occurring and non-naturally occurring amino acids. In some embodiments, the peptide comprises naturally occurring amino acids. In some embodiments, the peptide comprises non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 50 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 45 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 35 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 25 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 15 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 8 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 6 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide comprises between 2 and 4 naturally occurring or non-naturally occurring amino acids. In some embodiments, the peptide is polysarcosine.

[0473] In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is polysarcosine. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is polysarcosine having between 2 and 45 sarcosine units. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is poly sarcosine having between 2 and 35 sarcosine units. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is polysarcosine having between 2 and 25 sarcosine units. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is poly sarcosine having between 2 and 15 sarcosine units. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is polysarcosine having between 2 and 8 sarcosine units. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is polysarcosine having between 2 and 6 sarcosine units. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is polysarcosine having between 2 and 4 sarcosine units.

[0474] In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is identical. In some embodiments of the dendritic lipid of Formula (I) or (la), each TERM is not identical.

[0475] In some embodiments, the present disclosure provides a dendritic lipid having a structure according to Formula (la-1):

[0476] (la-1), or a pharmaceutically acceptable salt thereof, wherein:

[0477] LIP is

[0478]

[0479] R1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, or « ;

[0480] X1is -C(6-14)alkyl or -C(6-14)alkenyl;

[0481] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -

[0482] OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0483] X3is -C(6-14)alkyl or -C(6-14)alkenyl m is 1, 2, 3, 4, 5, 6, 7, or 8;

[0484] L2independently for each occurrence is selected from the group consisting of m' is 1, 2, 3, 4, 5, 6, 7, or 8; and

[0485] TERM independently for each occurrence is selected from the group consisting of sucrose, lactose, maltose, trehalose, cellobiose, glucose, fructose, mannose, mannobiose, galactose, an ethylene glycol chain, polysarcosine, or a trisaccharide comprising three sugar molecules selected from the group consisting of glucose, frutose, and mannose. In some embodiments, the present disclosure provides a dendritic lipid having a structure according to Formula (la- 1 ): or a pharmaceutically acceptable salt thereof, wherein:

[0486] LIP is

[0487] R1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, or

[0488] X1is -C(6-14)alkyl or -C(6-14)alkenyl;

[0489] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -

[0490] OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0491] X3is -C(6-14)alkyl or -C(6-14)alkenyl m is 1, 2, 3, 4, 5, 6, 7, or 8; L2independently for each occurrence is selected from the group consisting of m' is 1, 2, 3, 4, 5, 6, 7, or 8; and

[0492] TERM independently for each occurrence is selected from the group consisting of

[0493] OH OH

[0494] In some embodiments, the present disclosure provides a dendritic lipid having a structure according to Formula (la-2):

[0495] TERM (la-2), or a pharmaceutically acceptable salt thereof, wherein:

[0496] LIP is

[0497] R1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, or ;

[0498] X1is -C(6-14)alkyl or -C(6-14)alkenyl;

[0499] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -

[0500] OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0501] X3is -C(6-14)alkyl or -C(6-14)alkenyl m is 1, 2, 3, 4, 5, 6, 7, or 8;

[0502] L2independently for each occurrence is selected from the group consisting of m' is 1, 2, 3, 4, 5, 6, 7, or 8; and

[0503] TERM independently for each occurrence is selected from the group consisting of sucrose, lactose, maltose, trehalose, cellobiose, glucose, fructose, mannose, mannobiose, galactose, an ethylene glycol chain, polysarcosine, or a trisaccharide comprising three sugar molecules selected from the group consisting of glucose, frutose, and mannose. In some embodiments, the present disclosure provides a dendritic lipid having a structure according to Formula (la-2): or a pharmaceutically acceptable salt thereof, wherein:

[0504] LIP is , or a sterol; R1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, or ?

[0505] X1is -C(6-14)alkyl or -C(6-14)alkenyl;

[0506] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0507] X3is -C(6-14)alkyl or -C(6-14)alkenyl m is 1, 2, 3, 4, 5, 6, 7, or 8;

[0508] L2independently for each occurrence is selected from the group consisting of m' is 1, 2, 3, 4, 5, 6, 7, or 8; and

[0509] TERM independently for each occurrence is selected from the group consisting of

[0510] In some embodiments, the present disclosure provides a dendritic lipid having a structure according to Formula (lb):

[0511] LIP — L or a pharmaceutically acceptable salt thereof, wherein: LIP is R1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, or

[0512] X1is -C(6-14)alkyl or -C(6-14)alkenyl;

[0513] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -

[0514] OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0515] X3is -C(6-14)alkyl or -C(6-14)alkenyl m is 1, 2, 3, 4, 5, 6, 7, or 8;

[0516] L2independently for each occurrence is selected from the group consisting of m' is 1, 2, 3, 4, 5, 6, 7, or 8; and TERM independently for each occurrence is selected from the group consisting of sucrose, lactose, maltose, trehalose, cellobiose, glucose, fructose, mannose, mannobiose, galactose, an ethylene glycol chain, polysarcosine, or a trisaccharide comprising three sugar molecules selected from the group consisting of glucose, frutose, and mannose. In some embodiments, the present disclosure provides a dendritic lipid having a structure according to Formula (lb): or a pharmaceutically acceptable salt thereof, wherein: R1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, or «

[0517] X1is -C(6-14)alkyl or -C(6-14)alkenyl;

[0518] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -

[0519] OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0520] X3is -C(6-14)alkyl or -C(6-14)alkenyl m is 1, 2, 3, 4, 5, 6, 7, or 8;

[0521] L2independently for each occurrence is selected from the group consisting of m' is 1, 2, 3, 4, 5, 6, 7, or 8; and

[0522] The present disclosure further provides a dendritic lipid having a structure selected from the group consisting of:

[0523]

[0524] The present disclosure further provides a dendritic lipid having a structure selected from the group consisting of:

[0525] The present disclosure further provides a dendritic lipid having a structure selected from the group consisting of:

[0526] The present disclosure further provides a dendritic lipid having a structure selected from

[0527]

[0528] or a pharmaceutically acceptable salt thereof.

[0529] The present disclosure further provides a dendritic lipid having a structure selected from

[0530]

[0531] The present disclosure further provides a dendritic lipid having a structure selected from

[0532]

[0533] III. Dendritic Lipid Synthesis

[0534] The dendritic lipids of the present disclosure (e.g., compounds of Formula (I)) can be prepared according to methods known in the art. Nonlimiting and exemplary synthetic methods are disclosed herein.

[0535] For example, Scheme A provides exemplary synthetic routes for preparing certain dendritic lipids of the present disclosure. Alcohol (1) and 2,2,5-trimethyl-l,3-dioxane-5- carboxylic acid (2) can be reacted in the presence of DCC and a base, such as DMAP, to undergo a Steglich esterification. The resulting cyclic acetal intermediate can be opened in the presence of an acid catalyst, such as a cationic resin (e.g., Dowex50WX8), to provide diol (3). Diol (3) can then be converted to a reactive carbonate intermediate (4). Intermediate (4) can then be reacted with H2N-L2-sugar(PG)in the presence of one or more bases, such as DMAP and D1PEA, to provide intermediate (5). Finally, the Fmoc group of intermediate (5) can be deprotected, e.g., with piperidine; the deprotected compound can be reacted with LIP-C(O)CH2CH2COOH in the presence of a coupling agent, such as HATU, and a base, such as D1PEA to install the lipophilic moiety; and the sugar moieties can be deprotected, e.g., with a cationic resin such as Dowex50WX8, to provide the product (6).

[0536]

[0537] Scheme A (m = 0-8; sugar(PG)is a protected sugar moiety (e.g., a trimethylsilyl sugar moeity); L2and LIP are as defined herein)

[0538] Scheme B provides an exemplary synthetic route for preparing certain ionizable lipids of the present disclosure. Diol (3) and 2,2,5-trimethyl-l,3-dioxane-5-carboxylic acid (2) can be reacted in the presence of DCC and a base, such as DMAP, to undergo two Steglich esterifications. The resulting bicyclic diacetal intermediate can be opened in the presence of an acid catalyst, such as a cationic resin (e.g., Dowex50WX8), to provide intermediate (7). Intermediate (7) can then be converted to a reactive carbonate intermediate (8). Intermediate (8) can then be reacted with H2N-L2-sugar(PG)in the presence of one or more bases, such as DMAP and D1PEA, to provide intermediate (9). Finally, the Fmoc group of intermediate (9) can be deprotected, e.g., with piperidine; the deprotected compound can be reacted with LIP- C(O)CH2CH2COOH in the presence of a coupling agent, such as HATU, and a base, such as D1PEA to install the lipophilic moiety; and the sugar moieties can be deprotected, e.g., with a cationic resin such as Dowex50WX8, to provide the product (10).

[0539] Scheme B (m = 0-8; sugar(PG)is a protected sugar moiety (e.g., a trimethylsilyl sugar moeity); L2and LIP are as defined herein)

[0540] Scheme C provides a further exemplary synthetic route for preparing certain ionizable lipids of the present disclosure. Starting material (11) can be reacted with H2N-L2-sugar(PG)in the presence of a base, such as D1PEA, in the presence of a coupling agent, such as HATU, to provide intermediate (12). Intermediate (12) can then be hydrogenated to afford the corresponding amine (13). Amine (13) can then be reacted with LIP-C(O)CH2CH2COOH in the presence of a coupling agent, such as HATU, and a base, such as D1PEA, to install the lipophilic moiety. Finally, the sugar moieties of intermediate (14) can be deprotected using appropriate conditions to provide the product (15). Scheme C (m = 0-8; sugar(PG)is a protected sugar moiety (e.g., an acetylated sugar moeity); L2and LIP are as defined herein) IV. Lipid Nanoparticles Compositions

[0541] The present disclosure also provides a composition comprising a lipid nanoparticle (LNP), wherein the LNP comprises a dendritic lipid of the present disclosure (e.g., a lipid of Formula (I)) and an ionizable or cationic lipid. The dendritic lipids of the present disclosure provide control over particle size and stability of the nanoparticle, may prevent complex aggregation, and provide a means for increasing circulation lifetime and increasing the delivery of a lipid-nucleic acid pharmaceutical composition to target tissues.

[0542] In some embodiments, the LNP further comprises at least one of a structural lipid or a helper lipid. In some embodiments, the LNP comprises a dendritic lipid of the present disclosure, an ionizable or cationic lipid, and a structural lipid. In some embodiments, the LNP comprises a dendritic lipid of the present disclosure, an ionizable or cationic lipid, and a helper lipid. In some embodiments, the LNP comprises a dendritic lipid of the present disclosure, an ionizable or cationic lipid, a structural lipid, and a helper lipid. A. lonizable / Cationic Lipids

[0543] An ionizable lipid facilitates mRNA encapsulation and may be a cationic lipid. A cationic lipid affords a positively charged environment at low pH to facilitate efficient encapsulation of the negatively charged mRNA drug substance.

[0544] In some embodiments, the cationic lipid has a structure according to Formula CAT-I:

[0545] (CAT-I), or a pharmaceutically acceptable salt thereof, wherein: p is an integer of between 1 and 9, inclusive; each instance of R2is independently hydrogen or optionally substituted C1-6 alkyl; each instance of L is independently an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, or combination thereof; each instance of R6and R7is independently a group of formula (i), (ii), or (iii);

[0546] Formulae (i), (ii), and (iii) are: (III), wherein: each instance of R' is independently hydrogen or optionally substituted alkyl;

[0547] X is O, S, or NRX, wherein Rxis hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;

[0548] Y is O, S, or NRY, wherein RYis hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;

[0549] Rpis hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; and

[0550] RLis optionally substituted C1-50alkyl, optionally substituted C2-50alkenyl, optionally substituted C2-50alkynyl, optionally substituted hetero C1-50alkyl, optionally substituted heteroC2-50alkenyl, optionally substituted hetero C2-50alkynyl, or a polymer.

[0551] In certain embodiments of the lipid of Formula CAT-I, a group of formula (i) represents a group of formula (i-a) or a group of formula (i-b): (i-a), (i-b). wherein each variable is independently as defined above and described herein. In some embodiments of the lipid of Formula CAT-I, a group of formula (i) is a group of formula (i-a). In some embodiments of the lipid of Formula CAT-I, a group of formula (i) is a group of formula (i-b).

[0552] In some embodiments of the lipid of Formula CAT-I, each of R6and R7is independently a group of formula (i). In some embodiments of the lipid of Formula CAT-I, each of R6and R7is independently a group of formula (ii). In some embodiments of the lipid of Formula CAT-I, each of R6and R7is independently a group of formula (iii). In some embodiments of the lipid of Formula CAT-I, each of R6and R7is independently a group of formula (i-a). In some embodiments of the lipid of Formula CAT-I, each of R6and R7is independently a group of formula (i-b).

[0553] In some embodiments of the lipid of Formula CAT-I, each instance of R' is hydrogen.

[0554] In some embodiments of the lipid of Formula CAT-I, L is an optionally substituted alkylene.

[0555] As generally defined above with respec to the lipid of Formula CAT-I, p is an integer of between 1 and 9, inclusive. In certain embodiments of the lipid of Formula CAT-I, p is 1. In certain embodiments of the lipid of Formula CAT-I, p is 2. In certain embodiments of the lipid of Formula CAT-I, p is 3. In certain embodiments of the lipid of Formula CAT-I, p is 4. In certain embodiments of the lipid of Formula CAT-I, p is 5. In certain embodiments of the lipid of Formula CAT-I, p is 6. In certain embodiments of the lipid of Formula CAT-I, p is 7. In certain embodiments of the lipid of Formula CAT-I, p is 8. In certain embodiments of the lipid of Formula CAT-I, p is 9.

[0556] In some embodiments of the lipid of Formula CAT-I, the lipid has a structure according to Formula CAT-Ia:

[0557] (CAT-Ia), or a pharmaceutically acceptable salt thereof, wherein each variable is independently as defined above and described herein. In certain embodiments of the lipid of Formula CAT-I, L is an optionally substituted alkylene; e.g., optionally substituted C1-50alkylene, optionally substituted C1-40alkylene, optionally substituted C1-30alkylene, optionally substituted C1-20alkylene, optionally substituted C4-20alkylene, optionally substituted C6-20alkylene, optionally substituted C8-20alkylene, optionally substituted C10-20alkylene, optionally substituted C1-6alkylene, optionally substituted C2-6alkylene, optionally substituted C3-6alkylene, optionally substituted C4-6alkylene, optionally substituted C4-5alkylene, or optionally substituted C3-4alkylene. In some embodiments of the lipid of Formula CAT-I, L is optionally substituted C1alkylene. In some embodiments of the lipid of Formula CAT-I, L is optionally substituted C2alkylene. In some embodiments of the lipid of

[0558] Formula CAT-I, L is optionally substituted C3alkylene. In some embodiments of the lipid of

[0559] Formula CAT-I, L is optionally substituted C4alkylene. In some embodiments of the lipid of

[0560] Formula CAT-I, L is optionally substituted C5alkylene. In some embodiments of the lipid of

[0561] Formula CAT-I, L is optionally substituted C6alkylene. In some embodiments of the lipid of

[0562] Formula CAT-I, L is optionally substituted C7alkylene. In some embodiments of the lipid of

[0563] Formula CAT-I, L is optionally substituted C8alkylene. In some embodiments of the lipid of

[0564] Formula CAT-I, L is — CH2— . In some embodiments of the lipid of Formula CAT-I, L is — (CH2)2— . In some embodiments of the lipid of Formula CAT-I, L is — (CH2)3— . In some embodiments of the lipid of Formula CAT-I, L is — (CH2)4— . In some embodiments of the lipid of Formula CAT-I, L is — (CH2)5— . In some embodiments of the lipid of Formula CAT-I, L is — (CH2)6— . In some embodiments of the lipid of Formula CAT-I, L is — (CH2)7— . In some embodiments of the lipid of Formula CAT-I, L is — (CH2)8— .

[0565] In certain embodiments of the lipid of Formula CAT-I, L is an optionally substituted alkenylene, e.g., optionally substituted C2-50alkenylene, optionally substituted C2-40alkenylene, optionally substituted C2-30alkenylene, optionally substituted C2-20alkenylene, optionally substituted C4-20alkenylene, optionally substituted C6-20alkenylene, optionally substituted C8-2oalkenylene, optionally substituted C10-20alkenylene, optionally substituted C2-6alkenylene, optionally substituted C3 -6alkenylene, optionally substituted C4-6alkenylene, optionally substituted C4-5alkenylene, or optionally substituted C3-4alkenylene.

[0566] In certain embodiments of the lipid of Formula CAT-I, L is an optionally substituted alkynylene, e.g., optionally substituted C2-50alkynylene, optionally substituted C2-40alkynylene, optionally substituted C2-3oalkynylene, optionally substituted C2-2oalkynylene, optionally substituted C4-20alkynylene, optionally substituted C6-20alkynylene, optionally substituted C8-20alkynylene, optionally substituted C10-20alkynylene, optionally substituted C2-6alkynylene, optionally substituted C3-6alkynylene, optionally substituted C4-6alkynylene, optionally substituted C4-5alkynylene, or optionally substituted C3-4alkynylene.

[0567] In certain embodiments of the lipid of Formula CAT-I, L is an optionally substituted heteroalkylene; e.g., optionally substituted hetero C1-50alkylene, optionally substituted heteroC1-40alkylene, optionally substituted hetero C1-30alkylene, optionally substituted heteroC1-20alkylene, optionally substituted heteroC4-20alkylene, optionally substituted heteroC6-20alkylene, optionally substituted heteroC8-20alkylene, optionally substituted heteroC1-20alkylene, optionally substituted heteroC1-6alkylene, optionally substituted heteroC2-6alkylene, optionally substituted heteroC3-6- alkylene, optionally substituted heteroC4-6alkylene, optionally substituted heteroC4-5alkylene, or optionally substituted heteroC3-4alkylene.

[0568] In certain embodiments of the lipid of Formula CAT-I, L is an optionally substituted heteroalkenylene, e.g., optionally substituted hetero C2-50alkenylene, optionally substituted heteroC2-40alkenylene, optionally substituted heteroC2-30alkenylene, optionally substituted heteroC2-2oalkenylene, optionally substituted heteroC4-20alkenylene, optionally substituted heteroC6-20alkenylene, optionally substituted heteroC8-20alkenylene, optionally substituted heteroC10-20alkenylene, optionally substituted heteroC2-6alkenylene, optionally substituted heteroC3 -6alkenylene, optionally substituted hetero C4-6alkenylene, optionally substituted heteroC4-5alkenylene, or optionally substituted heteroCs -4alkenylene.

[0569] In certain embodiments of the lipid of Formula CAT-I, L is an optionally substituted heteroalkynylene, e.g., optionally substituted heteroC2-50alkynylene, optionally substituted heteroC2-40alkynylene, optionally substituted heteroC2-30alkynylene, optionally substituted heteroC2-2oalkynylene, optionally substituted heteroC4-20alkynylene, optionally substituted heteroC6-20alkynylene, optionally substituted heteroC8-20alkynylene, optionally substituted heteroC10-20alkynylene, optionally substituted heteroC2-6alkynylene, optionally substituted hetero C3-6alkyny I ene, optionally substituted heteroC4-ealkynylene, optionally substituted heteroC4-5alkynylene, or optionally substituted heteroCs-4alkynylene.

[0570] In certain embodiments of the lipid of Formula CAT-I, L is an optionally substituted carbocyclylene, e.g., optionally substituted Cs-iocarbocyclylene, optionally substituted C5-8carbocyclylene, optionally substituted C5-6carbocyclylene, optionally substituted C5carbocyclylene, or optionally substituted C6carbocyclylene.

[0571] In certain embodiments of the lipid of Formula CAT-I, L is an optionally substituted heterocyclylene, e.g., optionally substituted 3-14 membered heterocyclylene, optionally substituted 3-10 membered heterocyclylene, optionally substituted 5-8 membered heterocyclylene, optionally substituted 5-6 membered heterocyclylene, optionally substituted 5- membered heterocyclylene, or optionally substituted 6-membered heterocyclylene.

[0572] In certain embodiments of the lipid of Formula CAT-I, L is an optionally substituted arylene, e.g., optionally substituted phenylene. In some embodiments, L is optionally substituted phenylene. In some embodiments, L is substituted phenylene. In some embodiments, L is unsubstituted phenylene.

[0573] In certain embodiments of the lipid of Formula CAT-I, L is an optionally substituted heteroarylene, e.g., optionally substituted 5-14 membered heteroarylene, optionally substituted 5- 10 membered heteroarylene, optionally substituted 5-6 membered heteroarylene, optionally substituted 5-membered heteroarylene, or optionally substituted 6-membered heteroarylene.

[0574] In some embodiments of the lipid of Formula CAT-I, the lipid has a structure according to Formula CAT-Ib: or a pharmaceutically acceptable salt thereof, wherein each variable is independently as defined above and described herein, and wherein 1 is an integer between 1 and 10.

[0575] In certain embodiments of the lipid of Formula CAT-Ib, q is an integer between 2 and 10, inclusive. In certain embodiments of the lipid of Formula CAT-Ib, q is an integer between 2 and 8, inclusive. In certain embodiments of the lipid of Formula CAT-Ib, q is an integer between 2 and 6, inclusive. In certain embodiments of the lipid of Formula CAT-Ib, q is 3 or 4. In certain embodiments of the lipid of Formula CAT-Ib, q is 1. In certain embodiments of the lipid of Formula CAT-Ib, q is 2. In certain embodiments of the lipid of Formula CAT-Ib, q is 3. In certain embodiments of the lipid of Formula CAT-Ib, q is 4. In certain embodiments of the lipid of Formula CAT-Ib, q is 5. In certain embodiments of the lipid of Formula CAT-Ib, q is 6. In certain embodiments of the lipid of Formula CAT-Ib, q is 7. In certain embodiments of the lipid of Formula CAT-Ib, q is 8.

[0576] In some embodiments of the lipid of Formula CAT-I, R6is a group of formula (i). In some embodiments of the lipid of Formula CAT-I, R6is a group of formula (i-a). In some embodiments of the lipid of Formula CAT-I, R6is a group of formula (i-al ):

[0577] In some embodiments of the lipid of Formula CAT-I, R6is a group of formula (i-b). In some embodiments of the lipid of Formula CAT-I, R6is a group of formula (ii). In some embodiments of the lipid of Formula CAT-I, R6is a group of formula (iii).

[0578] In some embodiments of the lipid of Formula CAT-I, R7is a group of formula (i). In some embodiments of the lipid of Formula CAT-I, R7is a group of formula (i-a). In some embodiments of the lipid of Formula CAT-I, R7is a group of formula (i-al). In some embodiments of the lipid of Formula CAT-I, R7is a group of formula (i-b). In some embodiments of the lipid of Formula CAT-I, R7is a group of formula (ii). In some embodiments of the lipid of Formula CAT-I, R7is a group of formula (iii).

[0579] In some embodiments of the lipid of Formula CAT-I, each instance of R6and R7is independently a group of the formula (i). In some embodiments of the lipid of Formula CAT-I, each instance of R6and R7is independently a group of the formula (i-a). In some embodiments of the lipid of Formula CAT-I, each instance of R6and R7is independently a group of the formula (i-b). In some embodiments of the lipid of Formula CAT-I, each instance of R6and R7is independently a group of the formula (ii). In some embodiments of the lipid of Formula CAT-I, each instance of R6and R7is independently a group of the formula (iii).

[0580] In some embodiments of the lipid of Formula CAT-I, R6and R7are the same. In some embodiments of the lipid of Formula CAT-I, R6and R7are different.

[0581] In some embodiments of the lipid of Formula CAT-I, R6and R7are the same group of formula (i-al): i-al), wherein RLis as defined above and described herein.

[0582] In some embodiments of the lipid of Formula CAT-I, R6and R7are the same group of formula i-al), wherein RLis optionally substituted C1-50alkyl, optionally substituted C1-50alkenyl, optionally substituted C1-50alkynyl, optionally substituted heteroC1-50alkyl, optionally substituted heteroCb-50alkenyl, or optionally substituted heteroC1-50alkynyl.

[0583] In some embodiments of the lipid of Formula CAT-I, R6and R7are the same group of formula i-al), wherein R is optionally substituted C5-25alkyl, optionally substituted C5-25alkenyl, optionally substituted C5-25alkynyl, optionally substituted heteroC5-25alkyl, optionally substituted hetero C5-25alkenyl, or optionally substituted heteroC5-25alkynyl.

[0584] In some embodiments of the lipid of Formula CAT-I, R6and R7are the same group of formula i-al), wherein RLis optionally substituted C5-15alkyl, optionally substituted C5-15alkenyl, optionally substituted C5-15alkynyl, optionally substituted heteroC5-15alkyl, optionally substituted heteroC5-15alkenyl, or optionally substituted heteroC5-15alkynyl.

[0585] In some embodiments of the lipid of Formula CAT-I, R6and R7are the same group of formula i-al), wherein RLis optionally substituted C1-50alkyl.

[0586] In some embodiments of the lipid of Formula CAT-I, R6and R7are the same group of formula (i-al), wherein RLis optionally substituted C5-25alkyl.

[0587] In some embodiments of the lipid of Formula CAT-I, R6and R7are the same group of formula (i-al), wherein RLis optionally substituted C5-2oalkyl.

[0588] In some embodiments of the lipid of Formula CAT-I, R6and R7are the same group of formula i-al), wherein RLis optionally substituted C5-15alkyl.

[0589] In some embodiments of the lipid of Formula CAT-I, R2is hydrogen. In some embodiments of the lipid of Formula CAT-I, at least one instance of R2is hydrogen. In some embodiments of the lipid of Formula CAT-I, each instance of R2is hydrogen.

[0590] In certain embodiments of the lipid of Formula CAT-I, R2is optionally substituted C1-6alkyl, optionally substituted C2-6alkyl, optionally substituted C3-6alkyl, optionally substituted C4-6alkyl, optionally substituted C4-5alkyl, or optionally substituted C3-4alkyl. In certain embodiments of the lipid of Formula CAT-I, at least one instance of R2is optionally substituted C1-6alkyl. As generally defined above with respect to the lipid of Formula CAT-I, each instance of R' is independently hydrogen or optionally substituted alkyl. In some embodiments of the lipid of Formula CAT-I, R' is hydrogen. In some embodiments of the lipid of Formula CAT-I, R' is substituted alkyl. In certain embodiments of the lipid of Formula CAT-I, at least one instance of R' is hydrogen. In certain embodiments of the lipid of Formula CAT-I, at least two instances of R' are hydrogen. In certain embodiments of the lipid of Formula CAT-I, each instance of R' is hydrogen. In certain embodiments of the lipid of Formula CAT-I, at least one instance of R' is optionally substituted alkyl, e.g., methyl. In certain embodiments of the lipid of Formula CAT-I, at least two instances of R' are optionally substituted alkyl, e.g., methyl. In some embodiments of the lipid of Formula CAT-I, at least one instance of R' is hydrogen, and at least one instance of R' is optionally substituted alkyl. In certain embodiments of the lipid of Formula CAT-I, one instance of R' is optionally substituted alkyl, and the rest are hydrogen.

[0591] As generally defined above with respect to the lipid of Formula CAT-I, X is O, S, or NRX. In some embodiments of the lipid of Formula CAT-I, X is O. In some embodiments of the lipid of Formula CAT-I, X is S. In some embodiments of the lipid of Formula CAT-I, X is NRX, wherein Rxis as defined above and described herein.

[0592] As generally defined above with respect to the lipid of Formula CAT-I, Rxis hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group. In some embodiments of the lipid of Formula CAT-I, Rxis hydrogen. In some embodiments of the lipid of Formula CAT- I, Rxis optionally substituted alkyl. In some embodiments of the lipid of Formula CAT-I, Rxis optionally substituted alkenyl. In some embodiments of the lipid of Formula CAT-I, Rxis optionally substituted alkynyl. In some embodiments of the lipid of Formula CAT-I, Rxis optionally substituted carbocyclyl. In some embodiments of the lipid of Formula CAT-I, Rxis optionally substituted heterocyclyl. In some embodiments of the lipid of Formula CAT-I, Rxis optionally substituted aryl. In some embodiments of the lipid of Formula CAT-I, Rxis optionally substituted heteroaryl. In some embodiments of the lipid of Formula CAT-I, Rxis a nitrogen protecting group.

[0593] As generally defined above with respect to the lipid of Formula CAT-I, Y is O, S, or NRY. In some embodiments of the lipid of Formula CAT-I, Y is O. In some embodiments of the lipid of Formula CAT-I, Y is S. In some embodiments of the lipid of Formula CAT-I, Y is NRY, wherein RYis as defined above and described herein.

[0594] As generally defined above with respect to the lipid of Formula CAT-I, RYis hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group. In some embodiments of the lipid of Formula CAT-I, RYis hydrogen. In some embodiments of the lipid of Formula CAT- I, RYis optionally substituted alkyl. In some embodiments of the lipid of Formula CAT-I, RYis optionally substituted alkenyl. In some embodiments of the lipid of Formula CAT-I, RYis optionally substituted alkynyl. In some embodiments of the lipid of Formula CAT-I, RYis optionally substituted carbocyclyl. In some embodiments of the lipid of Formula CAT-I, RYis optionally substituted heterocyclyl. In some embodiments of the lipid of Formula CAT-I, RYis optionally substituted aryl. In some embodiments of the lipid of Formula CAT-I, RYis optionally substituted heteroaryl. In some embodiments of the lipid of Formula CAT-I, RYis a nitrogen protecting group.

[0595] As generally defined above with respect to the lipid of Formula CAT-I, Rpis hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom. In some embodiments of the lipid of Formula CAT-I, Rpis hydrogen. In some embodiments of the lipid of Formula CAT-I, Rpis optionally substituted alkyl. In some embodiments of the lipid of Formula CAT-I, Rpis optionally substituted alkenyl. In some embodiments of the lipid of Formula CAT-I, Rpis optionally substituted alkynyl. In some embodiments of the lipid of Formula CAT-I, Rpis optionally substituted carbocyclyl. In some embodiments of the lipid of Formula CAT-I, Rpis optionally substituted heterocyclyl. In some embodiments of the lipid of Formula CAT-I, Rpis optionally substituted aryl. In some embodiments of the lipid of Formula CAT-I, Rpis optionally substituted heteroaryl. In some embodiments of the lipid of Formula CAT-I, Rpis an oxygen protecting group when attached to an oxygen atom. In some embodiments of the lipid of Formula CAT-I, Rpis a sulfur protecting group when atached to a sulfur atom. In some embodiments of the lipid of Formula CAT-I, Rpis a nitrogen protecting group when atached to a nitrogen atom.

[0596] As generally defined above with respect to the lipid of Formula CAT-I, RLis optionally substituted C1-50alkyl, optionally substituted C2-50alkenyl, optionally substituted C2-50alkynyl, optionally substituted heteroC1-50alkyl, optionally substituted heteroC2-50alkenyl, optionally substituted heteroC2-50alkynyl, or a polymer.

[0597] In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C1-50alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2-

[0598] 30alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2-

[0599] 20alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2-

[0600] 15alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2-

[0601] 10alkyl.

[0602] In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-50alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-

[0603] 30alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-

[0604] 20alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-

[0605] 15alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-

[0606] 10alkyl.

[0607] In some embodiments of the lipid of Formula CAT-I, for example, in any of the above embodiments, RLis a substituted alkyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted alkyl group. In some embodiments of the lipid of Formula CAT-I, RLis an optionally substituted straight-chain alkyl group. In some embodiments of the lipid of Formula CAT-I, RLis a substituted straight-chain alkyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted straight-chain alkyl group. In some embodiments of the lipid of Formula CAT-I, RLis an optionally substituted branched alkyl group. In some embodiments of the lipid of Formula CAT-I, RLis a substituted branched alkyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted branched alkyl group.

[0608] In certain embodiments of the lipid of Formula CAT-I, at least one instance of RLis an unsubstituted alkyl. Exemplary unsubstituted alkyl groups include, but are not limited to, — CH3, — C2H5, — C3H7, — C4H9, — C5H11, — C6H13, — C7H15, — C8H17, — C9H19, — C10H21, — C11H23, - C12H25, - C13H27, - C14H29, - C15H31, - C16H33, - C17H35, - C18H37, - C19H39, - C20H41- C21H43, — C22H45, — C23H47, — C24H49, and — C25H51.

[0609] In certain embodiments of the lipid of Formula CAT-I, at least one instance of RLis a substituted alkyl. For example, in certain embodiments of the lipid of Formula CAT-I, at least one instance of RLis an alkyl substituted with one or more fluorine substituents. Exemplary fluorinated alkyl groups include, but are not limited to:

[0610] 

[0611] In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2-50alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2-30alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2-20alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2-18alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2-15alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2-10alkenyl.

[0612] In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-50alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-30alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-20alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-18alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-15alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-10alkenyl.

[0613] In some embodiments of the lipid of Formula CAT-I, for example, in any of the above embodiments, RLis a substituted alkyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted alkyl group. In some embodiments of the lipid of Formula CAT-I, RLis an optionally substituted straight-chain alkenyl group. In some embodiments of the lipid of Formula CAT-I, RLis a substituted straight-chain alkenyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted straight-chain alkenyl group. In some embodiments of the lipid of Formula CAT-I, RLis an optionally substituted branched alkenyl group. In some embodiments of the lipid of Formula CAT-I, RLis a substituted branched alkenyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted branched alkenyl group.

[0614] Exemplary unsubstituted alkenyl group include, but are not limited to:

[0615] Mynstoleic — (CH2)7CH=CH(CH2)CH3,

[0616] Palmitoliec — (CH2)7CH=CH(CH2)5CH3, • Sapienic — (CH2)4CH=CH(CH2)8CH3,

[0617] . Oleic — (C2)7CH=CH(CH2)7CH3,

[0618] . Linoleic — (CH2)7CH=CHCH2CH=CH(CH2)4CH3.

[0619] . a-Linolenic — (CH2)7CH=CHCH2CH=CHCH2CH=CHCH2CH3,

[0620] • Arachinodonic —

[0621] (CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)4CH3,

[0622] • Eicosapentaenoic — (CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH3,

[0623] • Erucic — (CH2)11CH=H(C(CH2)7CH3, and

[0624] • Docosahexaenoic —

[0625] (CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH—

[0626] CH2CH3.

[0627] In some embodiments of the lipid of Formula CAT-I, wherein RLis defined as a C6-50alkyl or C6-50alkenyl groups, such groups are meant to encompass lipophilic groups (also referred to as a “lipid tail”). Lipophilic groups comprise a group of molecules that include fats, waxes, oils, fatty acids, and the like. Lipid tails present in these lipid groups can be saturated and unsaturated, depending on whether or not the lipid tail comprises double bonds. The lipid tail can also comprise different lengths, often categorized as medium (i.e., with tails between 7-12 carbons, e.g., C7-12alkyl or C7-12alkenyl), long (i.e., with tails greater than 12 carbons and up to 22 carbons, e.g., C13-22alkyl or C13-22alkenyl), or very long (i.e., with tails greater than 22 carbons, e.g., C23-30alkyl or C23-30alkenyl).

[0628] In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2.50alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2.30alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2.20alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2.15alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C2.10alkynyl.

[0629] In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-50alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-30alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-20alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-15alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted C6-10alkynyl.

[0630] In some embodiments of the lipid of Formula CAT-I, for example, in any of the above embodiments, RLis a substituted alkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted alkynyl group. In some embodiments of the lipid of Formula CAT- I, RLis an optionally substituted straight-chain alkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis an optionally substituted straight-chain alkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis a substituted straight- chain alkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted straight-chain alkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis an optionally substituted branched alkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis a substituted branched alkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted branched alkynyl group.

[0631] In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC1-50alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC2-30alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC2-20alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC2-15alkyl. In some embodiments of the lipid of Formula CAT- I, RLis optionally substituted heteroC2-10alky I.

[0632] In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-50alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-30alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-20alkyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-15alkyl. In some embodiments of the lipid of Formula CAT- I, RLis optionally substituted heteroC6-10alkyl.

[0633] In some embodiments of the lipid of Formula CAT-I, for example, in any of the above embodiments, RLis a substituted heteroalkyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted heteroalkyl group. In some embodiments of the lipid of Formula CAT-I, RLis an optionally substituted straight-chain heteroalkyl group. In some embodiments of the lipid of Formula CAT-I, RLis a substituted straight- chain heteroalkyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted straight-chain heteroalkyl group. In some embodiments of the lipid of Formula CAT-I, RLis an optionally substituted branched heteroalkyl group. In some embodiments of the lipid of Formula CAT-I, RLis a substituted branched heteroalkyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted branched heteroalkyl group. Exemplary unsubstituted heteroalkyl groups include, but are not limited to:

[0634] In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC2-50alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC2-30alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC2-20alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC2-15alkeny I. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC2-30alkenyl.

[0635] In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-50alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-50alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-10alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-15alkenyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-10alkenyl.

[0636] In some embodiments of the lipid of Formula CAT-I, for example, in any of the above embodiments, RLis a substituted heteroalkenyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted heteroalkenyl group. In some embodiments of the lipid of Formula CAT-I, RLis an optionally substituted straight-chain heteroalkenyl group. In some embodiments of the lipid of Formula CAT-I, RLis a substituted straight- chain heteroalkenyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted straight-chain heteroalkenyl group. In some embodiments of the lipid of Formula CAT-I, RLis an optionally substituted branched heteroalkenyl group. In some embodiments of the lipid of Formula CAT-I, RLis a substituted branched heteroalkenyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted branched heteroalkenyl group.

[0637] In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC2-50alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC2-30alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC2-20alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC2-15alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC1-ioalkynyl.

[0638] In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-50alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-10alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-10alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-15alkynyl. In some embodiments of the lipid of Formula CAT-I, RLis optionally substituted heteroC6-10alkynyl.

[0639] In some embodiments of the lipid of Formula CAT-I, for example, in any of the above embodiments, RLis a substituted heteroalkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted heteroalkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis an optionally substituted straight-chain heteroalkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis a substituted straight- chain heteroalkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted straight-chain heteroalkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis an optionally substituted branched heteroalkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis a substituted branched heteroalkynyl group. In some embodiments of the lipid of Formula CAT-I, RLis an unsubstituted branched heteroalkynyl group.

[0640] In some embodiments of the lipid of Formula CAT-I, RLis a polymer. As used herein, a “polymer”, in some embodiments, refers to a compound comprised of at least 3 (e.g., at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, etc.) repeating covalently bound structural units. The polymer is in certain embodiments biocompatible (i.e., non-toxic). Exemplary polymers include, but are not limited to, cellulose polymers (e.g., hydroxyethylcellulose, ethylcellulose, carboxymethylcellulose, methylc cellulose, hydroxypropylmethylcellulose (HPMC)), dextran polymers, polymaleic acid polymers, poly(acrylic acid) polymers, poly(vinylalcohol) polymers, polyvinylpyrrolidone (PVP) polymers, and polyethyleneglycol (PEG) polymers, and combinations thereof.

[0641] In some embodiments of the lipid of Formula CAT-I, RLis a lipophilic, hydrophobic and / or non-polar group. In some embodiments of the lipid of Formula CAT-I, RLis a lipophilic group. In some embodiments of the lipid of Formula CAT-I, RLis a hydrophobic group. In some embodiments of the lipid of Formula CAT-I, RLis a non-polar group.

[0642] In some embodiments of the lipid of Formula CAT-I, when an RLgroup is depicted as bisecting a carbon-carbon bond, e.g., of the formula (i), it is understood that RLmay be bonded to either carbon.

[0643] Various combinations of the above embodiments of Formula CAT-I are contemplated herein. In some embodiments, the lipid of Formula CAT-I has a structure according to Formula CAT-Ic:

[0644] OH (CAT-Ic) wherein each of R2and RLis independently as defined above and described herein. In some embodiments, the lipid of Formula CAT-I has a structure according to Formula

[0645] CAT-Id:

[0646] (CAT-Id) wherein each of R2and RLis independently as defined above and described herein. In some embodiments of the lipid of Formula CAT-I, CAT-Ia, CAT-Ib, CAT-Ic, or CAT- Id, RLIS C1-20alkyl or C2-20alkenyl. In some embodiments of the lipid of Formula CAT-I, CAT- Ia, CAT-Ib, CAT-Ic, or CAT-Id, RLis C6-20alkyl or C6-20alkenyl.

[0647] In some embodiments, the lipid of Formula CAT-I is cKK-ElO, having the following structure:

[0648] In some embodiments, the lipid of Formula CAT-I is OF-02, having the following structure: Additional examples of cationic lipids suitable for LNPs of the present disclosure are described in WO 2013063468, WO 2016205691, and WO 2013063468, each of which is incorporated by reference herein in its entirety.

[0649] In some embodiments, the cationic lipid has a structure according to Formula CAT-II: or a pharmaceutically acceptable salt thereof, wherein: A1is selected from wherein the left hand side of each depicted structure is bound to the -(CH2)a-;

[0650] Z1is selected from , , and wherein the right hand side of each depicted structure is bound to the -(CH2)a-;

[0651] R1Aand R1Bare each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, and -W1-X1-Y1; each W1is independently selected from optionally substituted alkyl and optionally substituted alkenyl; each X1is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)- O-optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O- optionally substituted alkenyl, wherein the atom marked with a * is connected to W1, each Y1is independently selected from hydrogen, -*O-(C=O)-optionally substituted alkyl, -(*C=O)-O-optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and - (*C=O)-O-optionally substituted alkenyl, wherein the atom marked with a * is connected to X1; b is 1, 2, 3, 4, or 5; and each a is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0652] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula CAT-IIa: or a pharmaceutically acceptable salt thereof.

[0653] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula CAT-IIb:

[0654] (CAT-IIb), or a pharmaceutically acceptable salt thereof.

[0655] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula CAT-IIc: or a pharmaceutically acceptable salt thereof.

[0656] In some embodiments of the lipid of Formula CAT-II, A1and Z1are the same. In some embodiments of the lipid of Formula CAT-II, A1and Z1are different.

[0657] In some embodiments of the lipid of Formula CAT-II, A1is wherein the left hand side of the depicted structure is bound to the -(CH2)a-. In some embodiments of the lipid of

[0658] Formula CAT-II, A1is , wherein the left hand side of the depicted structure is bound to the -(CH2)a-. In some embodiments of the lipid of Formula CAT-II, A1is wherein the left hand side of the depicted structure is bound to the -(CH2)a-.

[0659] In some embodiments of the lipid of Formula CAT-II, Z1is , wherein the right hand side of the depicted structure is bound to the -(CH2)a-. In some embodiments of the lipid of Formula CAT-II, Z1is wherein the right hand side of the depicted structure is bound to the -(CH2)a-. In some embodiments of the lipid of Formula CAT-II, Z1is , wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0660] In some embodiments of the lipid of Formula CAT-II, A1is wherein the left hand side of the depicted structure is bound to the -(CH2)a-, and Z1 wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0661] In some embodiments of the lipid of Formula CAT-II, A1is wherein the left hand side of the depicted structure is bound to the -(CH2)a-, and Z1is wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0662] In some embodiments of the lipid of Formula CAT-II, A1is wherein the left hand side of the depicted structure is bound to the -(CH2)a-, and Z1 wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0663] In some embodiments of the lipid of Formula CAT-II, A1is wherein the left hand side of the depicted structure is bound to the -(CH2)a-, and Z1is , wherein the right hand side of the depicted structure is bound to the -(CH2)a-. o

[0664] In some embodiments of the lipid of Formula CAT-II, A1is wherein the left o hand side of the depicted structure is bound to the -(CH2)a-, and Z1is , wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0665] O

[0666] In some embodiments of the lipid of Formula CAT-II, A1is , wherein the left hand side of the depicted structure is bound to the -(CH2)a-, and Z1S , wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0667] In some embodiments of the lipid of Formula CAT-II, A1is , wherein the left hand side of the depicted structure is bound to the -(CH2)a-, and Z1wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0668] In some embodiments of the lipid of Formula CAT-II, A1is wherein the left hand side of the depicted structure is bound to the -(CH2)a-, and Z1wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0669] In some embodiments of the lipid of Formula CAT-II, A1is wherein the left hand side of the depicted structure is bound to the -(CH2)a-, and Z1wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0670] In some embodiments of the lipid of Formula CAT-II, R1Aand R1Bare each independently selected from:

[0671]

[0672] In some embodiments of the lipid of Formula CAT-II, each a is independently selected from 2, 3 and 4. In some embodiments of the lipid of Formula CAT-II, each a is the same. In some embodiments of the lipid of Formula CAT-II, each a is different.

[0673] In some embodiments of the lipid of Formula CAT-II, R1Aand R1Bare -W1-X1-Y1.

[0674] In some embodiments of the lipid of Formula CAT-II, W1-X1-Y1is defined as follows: each W1is independently selected from optionally substituted C1-20alkyl and optionally substituted C2-20alkenyl, each X1is independently selected from -*O-(C=O)-optionally substituted C1-20alkyl, -(*C=O)-O-optionally substituted C1-20alkyl, -*O-(C=O)-optionally substituted C2-20alkenyl, and -(*C=O)-O-optionally substituted C2-20alkenyl, wherein the atom marked with a * is connected to W1, each Y1is independently selected from hydrogen, -*O- (C=O)-optionally substituted C1-20alkyl, -(*C=O)-O-optionally substituted C1-20alkyl, -*O- (C=O)-optionally substituted C2-20alkenyl, and -(*C=O)-O-optionally substituted C2-20alkenyl, wherein the atom marked with a * is connected to X1.

[0675] In some embodiments of the lipid of Formula CAT-II, - W1-X1-Y1; is defined as follows: each W1is independently selected from optionally substituted CA-B alkyl and optionally substituted CC-D alkenyl, each X1is independently selected from -*O-(C=O)-optionally substituted CA-B alkyl -(*C=O)-O-optionally substituted CA-B alkyl -*O-(C=O)-optionally substituted CC-D alkenyl and -(*C=O)-O-optionally substituted CC-D alkenyl wherein the atom marked with a * is connected to W1, each Y1is independently selected from hydrogen, -*O- (C=O)-optionally substituted CA-B alkyl, -(*C=O)-O-optionally substituted CA-B alkyl, -*O- (C=O)-optionally substituted CC-D alkenyl, and -(*C=O)-O-optionally substituted CC-D alkenyl, wherein the atom marked with a * is connected to X1.

[0676] In some embodiments of the lipid of Formula CAT-II, CA-B is C1-20and CC-D is C2-20. In some embodiments CA-B is C1-15and CC-D is C2-15. In some embodiments CA-B is C1-10 and CC-D is C2-10. In some embodiments CA-B is C3-15and CC-D is C3-15. In some embodiments CA-B is C3-10 and CC-D is C3-10. In some embodiments CA-B is C3-8 and CC-D is C3-8.

[0677] In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently selected from optionally substituted C5-50alkyl, optionally substituted C5-50 alkenyl, optionally substituted C5-50alkynyl, optionally substituted C5-50 acyl, and -W1-X1-Y1, wherein -W1-X1-Y1is as defined herein.

[0678] In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently selected from optionally substituted C5-50alkyl, optionally substituted C5-50 alkenyl, optionally substituted C5-50alkynyl, and optionally substituted C5-50 acyl.

[0679] In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently selected from optionally substituted C5-30alkyl, optionally substituted C5-30 alkenyl, optionally substituted C5-30alkynyl, optionally substituted C5-30 acyl and -W1-X1-Y1, wherein -W1-X1-Y1is as defined herein. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently selected from optionally substituted C5-30alkyl, optionally substituted C5-30 alkenyl, optionally substituted C5-30alkynyl, and optionally substituted C5-30 acyl.

[0680] In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each: independently selected from optionally substituted C5-20alkyl, optionally substituted C5-20 alkenyl, optionally substituted C5-20alkynyl, optionally substituted C5-20 acyl, and -W1-X1-Y1, wherein -W1-X1-Y1.

[0681] In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently selected from optionally substituted C5-20alkyl, optionally substituted C5-20 alkenyl, optionally substituted C5-20alkynyl, and optionally substituted C5-20 acyl.

[0682] In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently optionally substituted C5-50alkyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently optionally substituted C5-30alkyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently optionally substituted C5-20alkyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently optionally substituted C5-15alkyl.

[0683] In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently C5-50alkyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently C5-30alkyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently C5-20alkyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently C5-15alkyl.

[0684] In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently optionally substituted C5-50alkenyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently optionally substituted C5-30alkenyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently optionally substituted C5-20alkenyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently optionally substituted C5-15alkenyl.

[0685] In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently C5-50alkenyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently C5-30alkenyl. In some embodiments of the lipid of Formula CAT-II, R1A and RIBare each independently C5-20alkenyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently C5-15alkenyl.

[0686] In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently optionally substituted C5-50alkynyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently optionally substituted C5-30alkynyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently optionally substituted C5-20alkynyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently optionally substituted C5-15alkynyl.

[0687] In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently C5-50alkynyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently C5-30alkynyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently C5-20alkynyl. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare each independently C5-15alkynyl.

[0688] In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare not optionally substituted. In some embodiments of the lipid of Formula CAT-II, each R1Ais the same. In some embodiments of the lipid of Formula CAT-II, each R1Ais different. In some embodiments of the lipid of Formula CAT-II, each RIBis the same. In some embodiments of the lipid of Formula CAT-II, each RIBis different. In some embodiments of the lipid of Formula CAT-II, R1Aand RIBare the same. In some embodiments of the lipid of Formula CAT-II, R1Aand R1Bare different.

[0689] In some embodiments, the lipid of Formula CAT-II is GL-HEPES-E3-E10-DS-3-E18-1 (2-(4-(2-((3-(Bis((Z)-2-hydroxyoctadec-9-en-l-yl)amino)propyl)disulfaneyl)ethyl)piperazin-l- yl)ethyl 4-(bis(2-hydroxydecyl)amino)butanoate), having the following structure:

[0690] In some embodiments, the lipid of Formula CAT-II is 2-(4-(3-((4-(bis((Z)-2- hydroxyoctadec-9-en-l-yl)amino)butyl)disulfaneyl)propyl)piperazin-l-yl)ethyl 4-(bis(2- hydroxydecyl)amino)butanoate, having the following structure: In some embodiments, the lipid of Formula CAT-II is GL-HEPES-E3-E12-DS-4-E10 (2-

[0691] (4-(2-((3-(bis(2-hydroxydecyl)amino)butyl)disulfaneyl)ethyl)piperazin-l-yl)ethyl 4-(bis(2- hydroxydodecyl)amino)butanoate), having the following structure:

[0692] In some embodiments, the lipid of Formula CAT-II is GL-HEPES-E3-E12-DS-3-E14 (2- (4-(2-((3-(Bis(2-hydroxytetradecyl)amino)propyl)disulfaneyl)ethyl)piperazin-l-yl)ethyl 4-(bis(2- hydroxydodecyl)amino)butanoate), having the following structure:

[0693]

[0694] Additional examples of cationic lipids suitable for LNPs of the present disclosure are described in WO 2022221688, which is incorporated by reference herein in its entirety.

[0695] Other cationic lipids that can be used include those described, for example, in WO 2016176330, WO 2017049245, and WO 2017075531.

[0696] Accordingly, in some embodiments, the cationic lipid has a structure according to Formula CAT-III:

[0697] (CAT-III), or a pharmaceutically acceptable salt thereof, wherein: one ofL1or L2IS -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, - SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa- or -NRaC(=O)O-, and the other of L1or L2is -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O)X-, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, -NRaC(=O)NRa-, -OC(=O)NRa- or -NRaC(=O)O- or a direct bond; G1and G2are each independently unsubstituted C1-C12alkylene or C1-C12alkenylene;

[0698] G3is C1-C24alkylene, C1-C24alkenylene, C3-C8cycloalkylene, C3-C8cycloalkenylene;

[0699] Rais H or C1-C12alkyl;

[0700] R1and R2are each independently C6-C24alkyl or C6-C24alkenyl;

[0701] R3is H, OR5, CN, — C(=O)OR4, — OC(=O)R4or — NR5C(=O)R4; R4IS C1-C12alkyl;

[0702] R5is H or C1-C6alkyl; and x is 0, 1 or 2.

[0703] Accordingly, in some embodiments, the cationic lipid has a structure according to Formula CAT-IV:

[0704] (CAT-IV), or a pharmaceutically acceptable salt thereof, wherein:

[0705] Ri is selected from the group consisting of C5-30alkyl, C5-20alkenyl, -R* YR", -YR", and - R"M'R';

[0706] R2and R3are independently selected from the group consisting of H, C1-14alkyl, C2-14 alkenyl, -R* YR", -YR", and -R*OR", or R2and R3, together with the atom to which they are attached, form a heterocycle or carbocycle;

[0707] R4is selected from the group consisting of a C3-6carbocycle, -(CH2)nQ, -(CH2)nCHQR, - CHQR, -CQ(R)2, and unsubstituted C1-6alkyl, where Q is selected from a carbocycle, heterocycle, -OR, -O(CH2)nN(R)2, -C(O)OR, -OC(O)R, -CX3, -CX2H, -CXH2, -CN, -N(R)2, - C(O)N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -N(R)C(O)N(R)2, -N(R)C(S)N(R)2, -N(R)R8, - O(CH2)nOR, -N(R)C(=NR9)N(R)2, -N(R)C(=CHR9)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, - N(OR)C(O)R, -N(OR)S(O)2R, -N(OR)C(O)OR, -N(OR)C(O)N(R)2, -N(OR)C(S)N(R)2, - N(OR)C(=NR9)N(R)2, -N(OR)C(=CHR9)N(R)2, -C(=NR9)N(R)2, -C(=NR9)R, -C(O)N(R)OR, and -C(R)N(R)2C(O)OR, and each n is independently selected from 1, 2, 3, 4, and 5; each R5 is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H; each R6is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

[0708] M and M' are independently selected from -C(O)O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -S-S-, an aryl group, and a heteroaryl group; R? is selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;

[0709] Rs is selected from the group consisting of C3-6carbocycle and heterocycle;

[0710] R9 is selected from the group consisting of H, CN, NO2, C1-6alkyl, -OR, -S(O)2R, - S(O)2N(R)2, C2-6alkenyl, C3-6carbocycle and heterocycle; each R is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and

[0711] H; each R' is independently selected from the group consisting of C1-18alkyl, C2-18alkenyl, - R*YR", -YR", and H; each R" is independently selected from the group consisting of C3-14 alkyl and C3-14alkenyl; each R* is independently selected from the group consisting of C1-12 alkyl and C2-12alkenyl; each Y is independently a C3-6 carbocycle; each X is independently selected from the group consisting of F, Cl, Br, and I; and m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13.

[0712] In some embodiments, the cationic lipid has a structure according to Formula CAT-V-I:

[0713] (CAT-V-I) or a pharmaceutically acceptable salt thereof wherein:

[0714] A1is selected from -C(=O)O-, -C(=O)S-, -C(=O)NH-, -OC(=O)O-, -OC(=O)NH-, - NHC(=O)O-, -SC(=O)NH-, -OCH2CH2O-, -OCH2O-, -OCH(CH3)O-, -S- and -S-S-, wherein the left hand side of each recited structure is bound to the -(CH2)a-; Z1is selected from -OC(=O)-, -SC(=O)-, -NHC(=O)-, -OC(=O)O-, -NHC(=O)O-, - OC(=O)NH-, -NHC(=O)S-, -OCH2CH2O-, -OCH2O-, -OCH(CH3)O-, -S- and -S-S-, wherein the right hand side of each recited structure is bound to the -(CH2)a-; each R is independently selected from: (i) , wherein each R1is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0715] (ii) , wherein each R2is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W1-X1, wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X1is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)-O- optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O- optionally substituted alkenyl, wherein the atom marked with a * is connected to W1; , wherein each R3is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and

[0716] (iv) , wherein each R4is independently selected from optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; wherein at least three R are independently selected from or (iii) each a is independently selected from 2, 3, 4, and 5; each b is independently selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10; and each c is independently selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0717] In some embodiments of the lipid of Formula CAT-V-I, the lipid has a structure according to Formula CAT-V-IBla:

[0718] (CAT-V-IBla) or a pharmaceutically acceptable salt thereof, wherein each R2A, R2B, R2Cand R2Dis independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W1-X1, wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X1is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)-

[0719] O-optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O- optionally substituted alkenyl, wherein the atom marked with a * is connected to W1; optionally wherein each a is independently selected from 3 or 4. In some embodiments of the lipid of Formula CAT-V-I, the lipid has a structure according to Formula CAT-V-IBlb:

[0720] (CAT-V-IBlb) or a pharmaceutically acceptable salt thereof, wherein each R1A, R1B, R1Cand R1Dis independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; optionally wherein i) each a is 2, and / or ii) each b is independently selected from 5 or 7.

[0721] In some embodiments of the lipid of Formula CAT-V-I, the lipid has a structure according to Formula CAT-V-IBlc:

[0722] (CAT-V-IBlc) or a pharmaceutically acceptable salt thereof, wherein each R3A, R3B, R3Cand R3Dis independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; optionally wherein i) each a is 3, and / or ii) each c is 6.

[0723] In some embodiments of the lipid of Formula CAT-V-I, the lipid has a structure according to Formula CAT-V-IB2a:

[0724] (CAT-V-IB2a) or a pharmaceutically acceptable salt thereof, wherein each R2A, R2B, R2Cand R2Dis independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W1-X1, wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X1is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)- O-optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O- optionally substituted alkenyl, wherein the atom marked with a * is connected to W1; optionally wherein each a is independently selected from 3 or 4.

[0725] In some embodiments of the lipid of Formula CAT-V-I, the lipid has a structure according to Formula CAT-V- ICla: (CAT-V-ICla) or a pharmaceutically acceptable salt thereof, wherein each R2A, R2B, R2Cand R2Dis independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W1-X1, wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X1is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)- O-optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O- optionally substituted alkenyl, wherein the atom marked with a * is connected to W1; optionally wherein each a is independently selected from 3 or 4.

[0726] In some embodiments of the lipid of Formula CAT-V-I, the lipid has a structure according to Formula CAT-V-IClb:

[0727] (CAT-V-IClb) or a pharmaceutically acceptable salt thereof, wherein each R1A, R1B, R1Cand R1Dis independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; optionally wherein each a is 2, and / or ii) each b is independently selected from 5 or 7.

[0728] In some embodiments of the lipid of Formula CAT-V-I, the lipid has a structure according to Formula CAT-V-IC2a:

[0729] (CAT-V-IC2a) or a pharmaceutically acceptable salt thereof, wherein each R2A, R2B, R2Cand R2Dis independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W1-X1, wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and each X1is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)- O-optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O- optionally substituted alkenyl, wherein the atom marked with a * is connected to W1; optionally wherein each a is 3. In some embodiments, the cationic lipid has a structure according to Formula CAT-V-II:

[0730] (CAT-V-II) or a pharmaceutically acceptable salt thereof wherein: each R is independently selected from:

[0731] , wherein each R1is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and wherein each R3is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; each a is independently selected from 2, 3, 4, and 5; each b is independently selected from 2, 3, 4, 5, 6, and 7; and each c is independently selected from 2, 3, 4, 5, 6, and 7.

[0732] In some embodiments of the lipid of Formula CAT-V-II, the lipid has a structure according to Formula CAT-V-IIA:

[0733] (CAT-V-IIA) or a pharmaceutically acceptable salt thereof, wherein each R3A, R3B, R3Cand R3Dis independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

[0734] In some embodiments of the lipid of Formula CAT-V-II, the lipid has a structure according to Formula CAT-V-IIB:

[0735] (CAT-V-IIB) or a pharmaceutically acceptable salt thereof, wherein each R1A, R1B, R1Cand R1Dis independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

[0736] In some embodiments of the lipid of Formula CAT-V-I or CAT-V-II, the lipid has a

[0737]

[0738] Further cationic lipids are described in WO2023 / 135305, which is incorporated herein by reference in its entirety. In some embodiments, the cationic lipid has a structure according to Formula CAT- VI:

[0739] *-NH-CX-(NH)n-A

[0740] (CAT-VI)

[0741] *- represents a single bond linking said radical of formula (I), directly or not, to one C10to C55lipophilic or hydrophobic tail-group; n is 0 or 1 ;

[0742] X is an oxygen or a sulfur atom, and

[0743] A represents an optionally substituted 5- or 6-membered unsaturated heterocyclic radical or 5- or 6-membered heteroaromatic ring radical, both containing at least one nitrogen atom; or one of the pharmaceutically acceptable salts of said radical of formula (CAT-VI); and with said compound that is in all the possible racemic, enantiomeric and diastereoisomeric isomer forms.

[0744] In some embodiments of the lipid of Formula CAT-VI, the lipid is in a cationic form.

[0745] In some embodiments of the lipid of Formula CAT-VI, X is a sulfur atom and A is a pyridinyl radical. In some embodiments of the lipid of Formula CAT-VI, A is a 3-pyridinyl radical.

[0746] In some embodiments of the lipid of Formula CAT-VI, X is an oxygen atom and A is a 5 membered heteroaromatic ring radical containing at least one nitrogen atom. In some embodiments of the lipid of Formula CAT-VI, A is an imidazolyl radical. In some embodiments of the lipid of Formula CAT-VI, A is a 4-imidazolyl radical.

[0747] In some embodiments of the lipid of Formula CAT-VI, the lipid has a structure according to Formula CAT- VI’:

[0748] Rl-Z-NH-CX-(NH)n-A

[0749] (CAT-VI’) wherein:

[0750] R1 is one C10to C55lipophilic or hydrophobic tail-group;

[0751] Z is a spacer arm having from 2 to 24, for example from 2 to 18, for example from 4 to 12 carbon atoms in a branched or unbranched linear saturated or unsaturated hydrocarbon chain, said chain that is interrupted by one or several atoms of oxygen and / or moieties selected among - S-S- ; -(O=C)- ; -(C=O)-O- ; -O-(O=C)- ; -S- ; -NH- , -NH-(O=C)- ; -(O=C)-NH- and - NH-(C=O)-O- and preferably by -(C=O)-O- ; -O-(O=C)- and -NH-(C=O)-O- and optionally ended by an oxygen atom or a moiety selected among -NH-(O=C)-O-(O=C)- ; - (C=O)-O- ; and -(O=C)- to be linked to the hydrophobic tail-group; p is 0 or 1; or one of the pharmaceutically acceptable salts of said compound of formula ( CAT-VI’); and any of its racemic, enantiomeric and diastereoisomeric isomer forms.

[0752] In some embodiments of the lipid of Formula CAT-VI’, the lipid has an apparent pKa lower than 7. In some embodiments of the lipid of Formula CAT-VI’, the lipid has an apparent pKa ranging from 4.5 to 7.

[0753] In some embodiments of the lipid of Formula CAT-VI’, X is a sulfur atom and A is a pyridinyl radical. In some embodiments of the lipid of Formula CAT-VI’, A is a 3-pyridinyl radical.

[0754] In some embodiments of the lipid of Formula CAT-VI’, X is an oxygen atom and A is a 5 membered heteroaromatic ring radical containing at least one nitrogen atom. In some embodiments of the lipid of Formula CAT-VI’, A is an imidazolyl radical. In some embodiments of the lipid of Formula CAT-VI’, A is a 4-imidazolyl radical.

[0755] In some embodiments of the lipid of Formula CAT-VI or CAT-VI’, the C10to C55lipophilic or hydrophobic tail-group is an optionally substituted, branched or unbranched linear, saturated or unsaturated, C10to C55hydrocarbon radical, and which hydrocarbon skeleton that is optionally interrupted by one or several atoms of oxygen or nitrogen and / or one or several -O- CO- or -CO-O- and which one nitrogen atom if present in the skeleton can be linked, directly or not, to said radical having the formula (CAT-VI).

[0756] In some embodiments of the lipid of Formula CAT-VI or CAT-VI’, the C10to C55lipophilic or hydrophobic tail-group is selected from the group consisting of:

[0757] (R1a)

[0758]

[0759] , and In some embodiments of the lipid of Formula CAT-VI or CAT-VI’, the C10to C55lipophilic or hydrophobic tail-group is selected from the group consisting of: and

[0760] In some embodiments of the lipid of Formula CAT-VI or CAT-VI’, the hydrophobic or lipophilic tail contains at least one amino moiety involved in its bonding to the spacer.

[0761] In some embodiments of the lipid of Formula CAT-VI or CAT-VI’, the hydrophobic or lipophilic tail contains at least three or more hydrocarbon chains.

[0762] In some embodiments of the lipid of Formula CAT-VI or CAT-VI’, the spacer arm Z comprise from 1 to 24, in particular from 2 to 15, more particularly from 3 to 12 ethylene oxide units and preferably incorporates at least one moiety selected among -(C=O)-O- ; -O-(O=C)- ; -NH-(O=C)- ; -(O=C)-NH- and -NH-(C=O)-O-. In some embodiments of the lipid of Formula CAT-VI or CAT-VI’, the spacer arm Z is selected in the group consisting of:

[0763] In some embodiments of the lipid of Formula CAT-VI or CAT-VI’, the spacer arm Z comprises from 1 to 24, in particular from 2 to 15, more particularly from 3 to 12 ethylene oxide units and further incorporates at least one NH — (C=O) — O — . In some embodiments of the lipid of Formula CAT-VI, the lipid has a structure selected from the group consisting of: (XXV

[0764] In some embodiments of the lipid of Formula CAT-VI, the lipid has the following structure:

[0765] In some embodiments of the lipid of Formula CAT-VI, the lipid has the following structure: Further cationic lipids are described in WO2022 / 013443, which is incorporated herein by reference in its entirety.

[0766] In some embodiments, the cationic lipid has a structure according to Formula CAT-VII: Y-(CHR)n-Z-(CHR’)p-Q* (CAT-VII) wherein:

[0767] * is the end linked, directly or not, to one C10to C60and preferably to C10to C55lipophilic or hydrophobic tail-group,

[0768] Y is a radical selected in the group consisting of a C1-C5alkyl, a C1-C5alkoxy, a C1-C5acyl, a C1-C5hydroxyalkyl, a C1-C5aminoalkyl, a C1-C5alkylcarboxyl ester, an acetamido, an N,N-C1-C5alkylamido, a C1-C5fluoroalkyl, for example a C1-C5perfluoroalkyl, for example a trifluoromethyl, an imidazolyl, a triazolyl, a squaramidyl, an ureido, a cyano or is one hydrogen; and preferably is a C1-C5alkoxy and more preferably a methoxy;

[0769] Z is a radical -NH-CH2-CO-O-** or a radical -CR”(NH2)-CO-O-** with ** that is the end closest to Q and R’ ’ that is selected in the group consisting of hydrogen, methyl radical and trifluoromethyl radical -

[0770] Q is a radical -NH-CH2-CO-O-*** or a radical -CR”(NH2)-CO-O-*** with R” selected in the group consisting of hydrogen, methyl radical and trifluoromethyl radical and *** that is the end linked, directly or not, to said lipophilic or hydrophobic tail-group;

[0771] R and R’ are, independently one from the other, one hydrogen, one methyl radical or one trifluoromethyl radical; n and p are independently one from the other 0, 1 or 2; or one of its pharmaceutically acceptable salts and with said compound being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms.

[0772] In some embodiments of the lipid of Formula CAT-VII, Z and Q are both one radical - NH-CH2-CO-O. In some embodiments of the lipid of Formula CAT-VII, n and p are both 2.

[0773] In some embodiments of the lipid of Formula CAT-VII, Z and Q are different and one of them is one radical -NH-CH2-CO-O- and the other one is one radical -CH(NH2)-CO-O-. In some embodiments of the lipid of Formula CAT-VII, n and p are different and equal to 1 or 2. In some embodiments of the lipid of Formula CAT-VII, Z is -CR”(NH2)-CO-O- and Q is -NH-CH2- CO- O-.

[0774] In some embodiments of the lipid of Formula CAT-VII, Z and Q are both one radical - CR”(NH2)-CO-O-. In some embodiments of the lipid of Formula CAT-VII, R” is an hydrogen. In some embodiments of the lipid of Formula CAT-VII, n and p are both 1. In some embodiments of the lipid of Formula CAT-VH, the lipid has a structure according to Formula CAT-VIF:

[0775] Y-(CHR)n-Z-(CHR’)p-Q-A-Ri

[0776] (CAT-VIF) wherein:

[0777] Y is a radical selected in the group consisting of a C1-C5alkyl, a C1-C5alkoxy, a C1- C5acyl, a C1-C5hydroxyalkyl, a C1-C5aminoalkyl, a C1-C5alkylcarboxyl ester, an acetamido, an N,N-C1-C5alkylamido, a C1-C5fluoroalkyl, for example a C1-C5perfluoroalkyl, for example a trifluoromethyl, an imidazolyl, a triazolyl, a squaramidyl, an ureido, a cyano or is one hydrogen; and preferably is a C1-C5alkoxy and more preferably a methoxy;

[0778] Z is a radical -NH-CH2-CO-O-** or a radical -CR”(NH2)-CO-O-** with ** that is the end closest to Q and R’ ’ that is selected in the group consisting of hydrogen, methyl radical and trifluoromethyl radical -

[0779] Q is a radical -NH-CH2-CO-O-*** or a radical -CR”(NH2)-CO-O-*** with R” selected in the group consisting of hydrogen, methyl radical and trifluoromethyl radical and *** that is the end linked, directly or not, to said lipophilic or hydrophobic tail-group;

[0780] R and R’ are, independently one from the other, one hydrogen, one methyl radical or one trifluoromethyl radical; n and p are independently one from the other 0, 1 or 2; or one of its pharmaceutically acceptable salts and with said compound being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms.

[0781] Ri is a C10to C60and preferably a C10to C55lipophilic or hydrophobic tail-group; and

[0782] A is a spacer arm having from 2 to 24, for example from 2 to 18, for example from 4 to 12 carbon atoms, or for example from 2 to 12 carbon atoms, in a branched or unbranched linear saturated or unsaturated hydrocarbon chain, said chain being interrupted by one or several atoms of oxygen and / or moieties selected among -S-S- ; (C=O)-O- ; -O-(O=C)- ; -(C=O)-NH- ; - NH-(C=O)-O- ; — S — ; -NH-(O=C)- ; and -O-(O=C)-NH- , and / or optionally having a terminal atom of oxygen or one moiety like -(C=O)-O- ; -O-(O=C)- ; -NH-(C=O)- ; -NH- (C=O)-O- or -O-(O=C)-NH- ; to its end to be linked to the lipophilic or hydrophobic tail- group, or one of its pharmaceutically acceptable salts and anyone of its racemic, enantiomeric and diastereoisomeric isomer forms. In some embodiments of the lipid of Formula CAT-VH, the lipid has a structure according to Formula CAT- VII”:

[0783] Y-(CHR)n-NH-CH2-CO-O-(CHR’)p-NH-CH2-CO-O-A-Ri

[0784] (CAT-VII”) wherein:

[0785] Y is a radical selected in the group consisting of a C1-C5alkyl, a C1-C5alkoxy, a C1- C5acyl, a C1-C5hydroxyalkyl, a C1-C5aminoalkyl, a C1-C5alkylcarboxyl ester, an acetamido, an N,N-C1-C5alkylamido, a C1-C5fluoroalkyl, for example a C1-C5perfluoroalkyl, for example a trifluoromethyl, an imidazolyl, a triazolyl, a squaramidyl, an ureido, a cyano or is one hydrogen; and preferably is a C1-C5alkoxy and more preferably a methoxy;

[0786] R and R’ are, independently one from the other, one hydrogen, one methyl radical or one trifluoromethyl radical; n and p are independently one from the other 0, 1 or 2; or one of its pharmaceutically acceptable salts and with said compound being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms.

[0787] Ri is a C10to C60and preferably a C10to C55lipophilic or hydrophobic tail-group; and

[0788] A is a spacer arm having from 2 to 24, for example from 2 to 18, for example from 4 to 12 carbon atoms, or for example from 2 to 12 carbon atoms, in a branched or unbranched linear saturated or unsaturated hydrocarbon chain, said chain being interrupted by one or several atoms of oxygen and / or moieties selected among -S-S- ; (C=O)-O- ; -O-(O=C)- ; -(C=O)-NH- ; - NH-(C=O)-O- ; — S— ; -NH-(O=C)- ; and -O-(O=C)-NH- , and / or optionally having a terminal atom of oxygen or one moiety like -(C=O)-O- ; -O-(O=C)- ; -NH-(C=O)- ; -NH- (C=O)-O- or -O-(O=C)-NH- ; to its end to be linked to the lipophilic or hydrophobic tail- group; or one of its pharmaceutically acceptable salts and anyone of its racemic, enantiomeric and diastereoisomeric isomer forms.

[0789] In some embodiments of the lipid of Formula CAT-VII”, n and p are both 2.

[0790] In some embodiments of the lipid of Formula CAT-VII”, Y is a radical methoxy.

[0791] In some embodiments of the lipid of Formula CAT-VII, the C10to C60and preferably C10to C55lipophilic or hydrophobic tail-group is one optionally substituted, branched or unbranched linear, saturated or unsaturated, C10to C60and preferably C10to C55hydrocarbon radical, and which hydrocarbon skeleton being optionally interrupted by one or several atoms of oxygen or nitrogen and / or one or several -O-CO- or -CO-0 groups.

[0792] In some embodiments of the lipid of Formula CAT-VH, the hydrophobic or lipophilic tail is an optionally substituted branched or unbranched linear saturated or unsaturated C10to C60and preferably C10to C55hydrocarbon radical, and which hydrocarbon skeleton that is optionally interrupted by one or several atoms of oxygen and / or one or several -O-CO- or -CO-O- groups and if one nitrogen atom is present in the skeleton it is present under a form that cannot be protonated and is linked, directly or not, and preferably directly linked to the spacer, A. In particular, it may form an amide moiety with the -C=O terminal moiety of said spacer. In some embodiments of the lipid of Formula CAT-VH, CAT-VIF, or CAT-VH”, the C10to C60and preferably C10to C55lipophilic or hydrophobic tail-group is selected in the group consisting of:

[0793]

[0794] , and

[0795]

[0796] In some embodiments of the lipid of Formula CAT-VH, CAT-VH’, or CAT-VH”, the C10to C60and preferably C10to C55lipophilic or hydrophobic tail-group is selected in the group consisting of: and

[0797] In some embodiments of the lipid of Formula CAT-VH, CAT-VH’, or CAT-VH”, the hydrophobic or lipophilic tail comprises at least three, four or more hydrocarbon chains, each one independently being selected from optionally substituted C4-C24, for example C5-C20, alkyl chain and optionally substituted C4-C24, for example C10-C20, alkenyl chain.

[0798] In some embodiments of the lipid of Formula CAT-VH, CAT-VIF, or CAT-VH”, the hydrophobic or lipophilic tail comprises at least two, three, four or more hydrocarbon C4- C24 chains, with at least one chain and preferably at least two chains being interrupted by at least one oxygen atom and / or at least one moiety selected among -O-(O=C)- and -(C=O)-O-

[0799] In some embodiments of the lipid of Formula CAT-VH, CAT-VIF, or CAT-VH”, the hydrophobic or lipophilic tail comprises at least three, four or more hydrocarbon chains, with at least two chains being optionally substituted C4-C24, for example C5-C20alkylene chain with optionally each one being independently interrupted by at least one moiety selected among -O- (O=C)- and -(C=O)-O-.

[0800] In some embodiments of the lipid of Formula CAT-VH, CAT-VH’, or CAT-VH”, the hydrophobic or lipophilic tail comprises at least three, four or more hydrocarbon chains, with all chains being optionally substituted C4-C24, for example C5-C20alkyl chains with optionally each one being or not independently interrupted by at least one moiety selected among -O-(O=C)- and -(C=O)-O-

[0801] In some embodiments of the lipid of Formula CAT-VH’ or CAT-VII”, the spacer arm A has 2 to 24 in particular from 2 to 12 carbon atoms, comprises at least one or several ethylene oxide units and optionally one or several moieties selected among -OCO-; COO-, -NHCOO-, - OCONH- and -SS-.

[0802] In some embodiments of the lipid of Formula CAT-VIF or CAT-VII”, the spacer arm A has the following structure: which right end being the one linked to the hydrophobic or lipophilic tail and wherein:

[0803] 1 is 0 or 1 ; m ranges from 2 to 12, preferably from 2 to 10 or for example is 2, 3, 4, 5, 6, 7, 8, or 9; p is 0 or 1 ; and

[0804] R’ represents, when p is 1, a group selected from -O-(O=C)- ; -(C=O)-O- ; -NH- (C=O)-O- or -O-(O=C)-NH- ; -NH-(C=O)-O-; -O-CH2-C(=O)-O- ; -O-C(=O)-(CH2)2- C(=O)-and -S-S-.

[0805] In some embodiments of the lipid of Formula CAT-VII’ or CAT-VII”, the spacer arm A is selected in the group consisting of:

[0806] wherein the right end of each structure is linked to the lipophilic or hydrophobic tail-group. In some embodiments of the lipid of Formula CAT-VH, the lipid has a structure selected from the group consisting of:

[0807]

[0808] , and

[0809] Further cationic lipids are described in W02022 / 013439, which is incorporated herein by reference in its entirety.

[0810] In some embodiments, the cationic lipid is MC3, having the following structure:

[0811] In some embodiments, the cationic lipid is SM-102 (9-heptadecanyl 8- {(2- hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino} octanoate), having the following structure: In some embodiments, the cationic lipid is ALC-0315 [(4- hydroxybutyl)azanediyl]di(hexane-6,l-diyl) bis(2-hexyldecanoate), having the following structure: In some embodiments, the cationic lipid is cOrn-EEl, having the following structure:

[0812] In some embodiments, the cationic lipid is bis(3-(bis(2-hydroxydodecyl)amino)propyl) 2,2'-(methylazanediyl)diacetate, having the following structure: In some embodiments, the cationic lipid is bis(3-(bis(2-hydroxydodecyl)amino)propyl) 3- hydroxy-3 -methylpentanedi oate, having the following structure:

[0813] In some embodiments, the cationic lipid is (2, 5 -dimethylpiperazine- 1 ,4-diyl)bis(ethane- 2,1 -diyl) bis(5-(bis(2-hydroxydodecyl)amino)pentanoate), having the following structure:

[0814] In some embodiments, the cationic lipid is tris(5-(octanoyloxy)pentyl) 2-((3-

[0815] (dimethylamino)propanoyl)oxy)propane-1,2,3-tricarboxylate, havinlg the following structure: In some embodiments, the cationic lipid may be selected from the group comprising

[0816] CKK-E12; cKK-ElO; OF-02; [(6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl] 4- (dimethylamino)butanoate (D-Lin-MC3-DMA); 2,2-dihnoleyl-4-dimethylaminoethyl-[l,3]- dioxolane (DLin-KC2-DMA); 1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane (DLin-DMA); di((Z)-non-2-en-l-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319); 9- heptadecanyl 8- {(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino} octanoate (SM-102); [(4- hydroxybutyl)azanediyl]di(hexane-6,l-diyl) bis(2-hexyldecanoate) (ALC-0315); [3- (dimethylamino)-2-[(Z)-octadec-9-enoyl] oxypropyl] (Z)-octadec-9-enoate (DODAP); 2,5-bis(3- aminopropylamino)-N-[2-[di(heptadecyl)amino]-2-oxoethyl]pentanamide (DOGS); [(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]- 2, 3, 4, 7, 8, 9,1 l,12,14,15,16,17-dodecahydro-lH-cyclopenta[a]phenanthren-3-yl] N-[2-

[0817] (dimethylamino)ethyl] carbamate (DC-Chol); tetrakis(8-methylnonyl) 3, 3', 3", 3"'- (((methylazanediyl) bis(propane-3,l diyl))bis (azanetriyl))tetrapropionate (3060il0); decyl (2- (dioctylammonio)ethyl) phosphate (9A1P9); ethyl 5,5-di((Z)-heptadec-8-en-l-yl)-l-(3- (pyrrolidin-l-yl)propyl)-2,5-dihydro-lH-imidazole-2-carboxylate (A2-Iso5-2DC18); bis(2- (dodecyldisulfanyl)ethyl) 3,3'-((3-methyl-9-oxo-10-oxa-13,14-dithia-3,6- diazahexacosyl)azanediyl)dipropionate (BAME-016B); 1 , 1 '-((2-(4-(2-((2-(bis(2- hydroxydodecyl)amino)ethyl) (2-hydroxydodecyl)amino)ethyl) piperazin- 1 -yl)ethyl)azanediyl) bis(dodecan-2-ol) (C12-200); 3, 6-bis(4-(bis(2-hydroxydodecyl)amino)butyl)piperazine-2, 5-dione (cKK-E12); hexa(octan-3-yl) 9, 9', 9", 9"', 9"", 9"'"- ((((benzene-l,3,5-tricarbonyl)yris(azanediyl)) tris (propane-3,1 -diyl)) tris(azanetriyl))hexanonanoate (FTT5); (((3,6-dioxopiperazine-2,5- diyl)bis(butane-4, 1 -diyl))bis(azanetriyl))tetrakis(ethane-2, 1 -diyl) (9Z,9'Z,9"Z,9"'Z,12Z,12'Z,12"Z,12"'Z)-tetrakis (octadeca-9,12-di enoate) (OF-Deg-Lin); TT3; N1,N3,N5-tris(3-(didodecylamino)propyl)benzene-1,3,5-tricarboxamide; Nl-[2-((lS)-l-[(3- aminopropyl)amino] -4- [ di (3 -aminopropyl)amino] butylcarboxamido)ethyl] -3 ,4-di [oleyloxy] - benzamide (MVL5); heptadecan-9-yl 8-((2-hydroxyethyl)(8-(nonyloxy)-8- oxooctyl)amino)octanoate (Lipid 5); GL-HEPES-E3-E10-DS-3-E18-1; GL-HEPES-E3-E12-DS- 4-E10; GL-HEPES-E3-E12-DS-3-E14; and combinations thereof.

[0818] In some embodiments, the cationic lipid is biodegradable. In some embodiments, the cationic lipid is not biodegradable. In some embodiments, the cationic lipid is cleavable. In some embodiments, the cationic lipid is not cleavable. Cationic lipids are described in further detail in Dong et al. (PNAS. 111(11):3955-60.

[0819] 2014); Fenton et al. (Adv Mater. 28:2939. 2016); U.S. Pat. No. 9,512,073; U.S. Pat. No. 10,201,618; EP 22307007.9; EP 22307007.9; WO 2022 / 221688; WO 2022 / 066916; and WO 2022 / 0257716, each of which is incorporated herein by reference.

[0820] B. Structural Lipids

[0821] A structural lipid component provides stability to the lipid bilayer structure within the lipid nanoparticle. In some embodiments, the LNP comprises one or more structural lipid. In some embodiments, the structural lipid is a cholesterol-based lipid. Suitable cholesterol-based lipids include, for example: DC-Choi (N,N-dimethyl-N-ethylcarboxamidocholesterol), 1,4-bis(3- N-oleylamino-propyl)piperazine (Gao et al., Biochem Biophys Res Comm. (1991) 179:280; Wolf et al., BioTechniques (1997) 23:139; U.S. Pat. 5,744,335), imidazole cholesterol ester (“ICE”; WO2011 / 068810), sitosterol (22,23 -dihydrostigmasterol), β-sitosterol, sitostanol, fucosterol, stigmasterol (stigmasta-5,22-dien-3-ol), ergosterol, desmosterol (3B-hydroxy-5,24- cholestadiene), lanosterol (8,24-lanostadien-3b-ol), 7-dehydrocholesterol (A5,7-cholesterol), dihydrolanosterol (24,25-dihydrolanosterol), zymosterol (5a-cholesta-8,24-dien-3B-ol), lathosterol (5α-cholest-7-en-3β-ol), diosgenin ((3β,25R)-spirost-5-en-3-ol), campesterol (campest-5-en-3B-ol), campestanol (5a-campestan-3b-ol), 24-methylene cholesterol (5,24(28)- cholestadien-24-methylen-3B-ol), cholesteryl margarate (cholest-5-en-3B-yl heptadecanoate), cholesteryl oleate, cholesteryl stearate and other modified forms of cholesterol.

[0822] In some embodiments, the structural lipid is cholesterol.

[0823] C. Helper Lipids

[0824] A helper lipid enhances the structural stability of the LNP and helps the LNP in endosomal escape. A helper lipid may improve uptake and release of an mRNA drug payload encapsulated in the LNP. In some embodiments, the helper lipid is a zwitterionic lipid. Without wishing to be bound by theory, the helper lipid can have fusogenic properties for enhancing uptake and release of the drug payload. Examples of helper lipids are 1,2-dioleoyl-SN-glycero-3- phosphoethanolamine (DOPE); 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); 1,2- dioleoyl-sn-glycero-3-phospho-L-serine (DOPS); 1 ,2-dielaidoyl-sn-glycero-3- phosphoethanolamine (DEPE); and 1,2-dioleoyl-sn-glycero-3 -phosphocholine (DPOC), dipalmitoylphosphatidylcholine (DPPC), 1,2-dilauroyl-sn-glycero-3 -phosphocholine (DLPC), 1,2-Distearoylphosphatidylethanolamine (DSPE), and 1,2-dilauroyl-sn-glycero-3- phosphoethanolamine (DLPE).

[0825] Other exemplary helper lipids are dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-l-carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), phosphatidylserine, sphingolipids, cerebrosides, gangliosides, 16-O-monomethyl PE, 16-O-dimethyl PE, 18-1 -trans PE, l-stearoyl-2-oleoyl-phosphatidy ethanolamine (SOPE), or a combination thereof.

[0826] In particular embodiments, the helper lipid is 1,2-dioleoyl-SN-glycero-3- phosphoethanolamine (DOPE). D. Stealth Lipids

[0827] A stealth lipid component provides control over particle size and stability of the nanoparticle. The addition of such components may prevent complex aggregation and provide a means for increasing circulation lifetime and increasing the delivery of a lipid-nucleic acid pharmaceutical composition to target tissues. Typically, the stealth lipid is a polyethylene glycol- conjugated (PEGylated) lipid. These components may be selected to rapidly exchange out of the pharmaceutical composition in vivo (see, e.g., U.S. Pat. 5,885,613).

[0828] In some embodiments, the composition does not further comprise a polyethylene glycol- conjugated (PEGylated) lipid.

[0829] In some embodiments, the composition further comprises a polyethylene glycol- conjugated (PEGylated) lipid.

[0830] Contemplated PEGylated lipids include, but are not limited to, a polyethylene glycol (PEG) chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C20(e.g., C8, C10, C12, C14, C16, or C18) length, such as a derivatized ceramide (e.g., N-octanoyl- sphingosine-l-[succinyl(methoxypoly ethylene glycol)] (C8 PEG ceramide)). In some embodiments, the PEGylated lipid is 1,2-dimyristoyl-rac-glycero-3-methoxypoly ethylene glycol (DMG-PEG); 1,2-distearoyl-sn-glycero-3 -phosphoethanolamine-poly ethylene glycol (DSPE- PEG); 1 ,2-dilauroyl-sn-glycero-3 -phosphoethanolamine-poly ethylene glycol (DLPE-PEG); or 1,2-distearoyl-rac-glycero-polyethelene glycol (DSG-PEG).

[0831] In some embodiments, the PEG has a high molecular weight, e.g., 2000-2400 g / mol. In some embodiments, the PEG is PEG2000 (or PEG-2K). In some embodiments, the PEGylated lipid is DMG-PEG2000, DSPE-PEG2000, DLPE-PEG2000, DSG-PEG2000, or C8 PEG2000. In some embodiments, the PEGylated lipid is dimyristoyl-PEG2000 (DMG-PEG2000).

[0832] E. Combinations of Lipid Components and Molar Ratios

[0833] In some embodiments, the LNP comprises a dendritic lipid of the present disclosure, a cationic or ionizable lipid, and a structural lipid. In some embodiments, the LNP comprises a dendritic lipid of the present disclosure, a cationic or ionizable lipid, and a helper lipid. In some embodiments, the LNP comprises a dendritic lipid of the present disclosure, a cationic or ionizable lipid, a structural lipid, and a helper lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (I), a cationic or ionizable lipid, and a structural lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (I), a cationic or ionizable lipid, and a helper lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (I), a cationic or ionizable lipid, a structural lipid, and a helper lipid.

[0834] In some embodiments, the LNP comprises a dendritic lipid of Formula (la), a cationic or ionizable lipid, and a structural lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (la), a cationic or ionizable lipid, and a helper lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (la), a cationic or ionizable lipid, a structural lipid, and a helper lipid.

[0835] In some embodiments, the LNP comprises a dendritic lipid of Formula (la-1), a cationic or ionizable lipid, and a structural lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (la-1), a cationic or ionizable lipid, and a helper lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (la-1), a cationic or ionizable lipid, a structural lipid, and a helper lipid.

[0836] In some embodiments, the LNP comprises a dendritic lipid of Formula (la-1.5), a cationic or ionizable lipid, and a structural lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (la- 1.5), a cationic or ionizable lipid, and a helper lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (la-1.5), a cationic or ionizable lipid, a structural lipid, and a helper lipid.

[0837] In some embodiments, the LNP comprises a dendritic lipid of Formula (la-2), a cationic or ionizable lipid, and a structural lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (la-2), a cationic or ionizable lipid, and a helper lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (la-2), a cationic or ionizable lipid, a structural lipid, and a helper lipid.

[0838] In some embodiments, the LNP comprises a dendritic lipid of Formula (la-3), a cationic or ionizable lipid, and a structural lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (la-3), a cationic or ionizable lipid, and a helper lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (la-3), a cationic or ionizable lipid, a structural lipid, and a helper lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (la-4), a cationic or ionizable lipid, and a structural lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (la-4), a cationic or ionizable lipid, and a helper lipid. In some embodiments, the LNP comprises a dendritic lipid of Formula (la-4), a cationic or ionizable lipid, a structural lipid, and a helper lipid.

[0839] In some embodiments, the dendritic lipid may comprise a molar ratio from about 0.5% to about 10% of the total lipid present in the lipid nanoparticle. In some embodiments, the dendritic lipid may comprise a molar ratio of about 1.5% of the total lipid present in the lipid nanoparticle. In some embodiments, the dendritic lipid may comprise a molar ratio of about 5% of the total lipid present in the lipid nanoparticle.

[0840] In some embodiments, the ionizable or cationic lipid may comprise a molar ratio from about 22% to about 50% (e.g., from about 35% to about 45%) of the total lipid present in the lipid nanoparticle. In some embodiments, the ionizable or cationic lipid may comprise a molar ratio of about 40% of the total lipid present in the lipid nanoparticle. In some embodiments, the ionizable or cationic lipid may comprise a molar ratio of about 50% of the total lipid present in the lipid nanoparticle.

[0841] In some embodiments, the structural lipid may comprise a molar ratio from about 20% to about 50% (e.g., from about 20% to about 35%) of the total lipid present in the lipid nanoparticle. In some embodiments, the structural lipid may comprise a molar ratio of about 25% of the total lipid present in the lipid nanoparticle. In some embodiments, the structural lipid may comprise a molar ratio of about 30% of the total lipid present in the lipid nanoparticle. In some embodiments, the structural lipid may comprise a molar ratio of about 35% of the total lipid present in the lipid nanoparticle.

[0842] In some embodiments, the helper lipid may comprise a molar ratio from about 5% to about 30% (e.g., from about 20% to about 30%) of the total lipid present in the lipid nanoparticle. In some embodiments, the helper lipid may comprise a molar ratio of about 10% of the total lipid present in the lipid nanoparticle. In some embodiments, the helper lipid may comprise a molar ratio of about 25% of the total lipid present in the lipid nanoparticle. In some embodiments, the helper lipid may comprise a molar ratio of about 28.5% of the total lipid present in the lipid nanoparticle. In some embodiments, the helper lipid may comprise a molar ratio of about 30% of the total lipid present in the lipid nanoparticle. In some embodiments, the LNP comprises the dendritic lipid at a molar ratio between 0.5% and 10%, the ionizable or cationic lipid at a molar ratio between 22% and 50%, the structural lipid at a molar ratio between 20% and 50%, and the helper lipid at a molar ratio between 5% and 30%.

[0843] In some embodiments, the LNP comprises the dendritic lipid at a molar ratio between 0.5% and 7%, the ionizable or cationic lipid at a molar ratio between 35% and 45%, the structural lipid at a molar ratio between 20% and 35%, and the helper lipid at a molar ratio between 20% and 30%.

[0844] In some embodiments, the LNP comprises the dendritic lipid at a molar ratio of about 5%, the ionizable or cationic lipid at a molar ratio of about 40%, the structural lipid at a molar ratio of about 25%, and the helper lipid at a molar ratio of about 30%. In some embodiments, the LNP comprises the dendritic lipid at a molar ratio of about 5%, the ionizable or cationic lipid at a molar ratio of about 50%, the structural lipid at a molar ratio of about 35%, and the helper lipid at a molar ratio of about 10%.

[0845] To calculate the actual amount of each lipid to be put into an LNP formulation, the molar amount of the cationic or ionizable lipid is first determined based on a desired N / P ratio, where N is the number of nitrogen atoms in the cationic lipid and P is the number of phosphate groups in the mRNA to be transported by the LNP. Next, the molar amount of each of the other lipids is calculated based on the molar amount of the cationic lipid and the molar ratio selected. These molar amounts are then converted to weights using the molecular weight of each lipid.

[0846] F. Active Ingredients of the LNPs

[0847] The active ingredient of the present LNP composition may be an mRNA that encodes a polypeptide of interest. In certain embodiments, the polypeptide is an antigen. In certain embodiments, the polypeptide is a therapeutic polypeptide. The therapeutic polypeptide may be an antibody (e.g., an antibody heavy chain or an antibody light chain. The therapeutic polypeptide may be an enzyme.

[0848] The mRNA molecule encapsulated by the present disclosure LNPs may comprise at least one ribonucleic acid (RNA) comprising an ORF encoding a polypeptide of interest. In certain embodiments, the mRNA further comprises at least one 5’ UTR, 3’ UTR, a poly(A) tail, and / or a 5’ cap. i. 5’ Cap

[0849] An mRNA 5’ cap can provide resistance to nucleases found in most eukaryotic cells and promote translation efficiency. Several types of 5’ caps are known. A 7-methylguanosine cap (also referred to as “m7G” or “Cap-0”), comprises a guanosine that is linked through a 5’ - 5’ - triphosphate bond to the first transcribed nucleotide.

[0850] A 5' cap is typically added as follows: first, an RNA terminal phosphatase removes one of the terminal phosphate groups from the 5’ nucleotide, leaving two terminal phosphates; guanosine triphosphate (GTP) is then added to the terminal phosphates via a guanylyl transferase, producing a 5 ‘5 ‘5 triphosphate linkage; and the 7-nitrogen of guanine is then methylated by a methyltransferase. Examples of cap structures include, but are not limited to, m7G(5’)ppp, (5’(A,G(5’)ppp(5’)A, and G(5’)ppp(5’)G. Additional cap structures are described in U.S. Publication No. US 2016 / 0032356 and U.S. Publication No. US 2018 / 0125989, which are incorporated herein by reference.

[0851] 5 ’-capping of polynucleotides may be completed concomitantly during the in vitro- transcription reaction using the following chemical RNA cap analogs to generate the 5’- guanosine cap structure according to manufacturer protocols: 3’-O-Me-m7G(5’)ppp(5’)G (the ARCA cap); G(5’)ppp(5’)A; G(5’)ppp(5’)G; m7G(5’)ppp(5’)A; m7G(5’)ppp(5’)G; m7G(5')ppp(5')(2'OMeA)pG; m7G(5')ppp(5')(2'OMeA)pU; m7G(5')ppp(5')(2'OMeG)pG (New England BioLabs, Ipswich, MA; TriLink Biotechnologies). 5 ’-capping of modified RNA may be completed post-transcriptionally using a vaccinia virus capping enzyme to generate the Cap 0 structure: m7G(5’)ppp(5’)G. Cap 1 structure may be generated using both vaccinia virus capping enzyme and a 2’-0 methyl-transferase to generate: m7G(5’)ppp(5’)G-2’-O-methyl. Cap 2 structure may be generated from the Cap 1 structure followed by the 2’-O-methylation of the 5 ’-antepenultimate nucleotide using a 2’-0 methyl-transferase. Cap 3 structure may be generated from the Cap 2 structure followed by the 2’-O-methylation of the 5’- preantepenultimate nucleotide using a 2’-0 methyl-transferase.

[0852] In certain embodiments, the mRNA of the disclosure comprises a 5’ cap selected from the group consisting of 3’-O-Me-m7G(5’)ppp(5’)G (the ARCA cap), G(5’)ppp(5’)A, G(5’)ppp(5’)G, m7G(5’)ppp(5’)A, m7G(5’)ppp(5’)G, m7G(5')ppp(5')(2'OMeA)pG, m7G(5')ppp(5')(2'OMeA)pU, and m7G(5')ppp(5')(2'OMeG)pG. In certain embodiments, the mRNA of the disclosure comprises a 5’ cap of: ii. Untranslated Region (UTR)

[0853] In some embodiments, the mRNA of the disclosure includes a 5’ and / or 3’ untranslated region (UTR). In mRNA, the 5’ UTR starts at the transcription start site and continues to the start codon but does not include the start codon. The 3’ UTR starts immediately following the stop codon and continues until the transcriptional termination signal.

[0854] In some embodiments, the mRNA disclosed herein may comprise a 5’ UTR that includes one or more elements that affect an mRNA’s stability or translation. In some embodiments, a 5’ UTR may be about 10 to 5,000 nucleotides in length. In some embodiments, a 5’ UTR may be about 50 to 500 nucleotides in length. In some embodiments, the 5’ UTR is at least about 10 nucleotides in length, about 20 nucleotides in length, about 30 nucleotides in length, about 40 nucleotides in length, about 50 nucleotides in length, about 100 nucleotides in length, about 150 nucleotides in length, about 200 nucleotides in length, about 250 nucleotides in length, about 300 nucleotides in length, about 350 nucleotides in length, about 400 nucleotides in length, about 450 nucleotides in length, about 500 nucleotides in length, about 550 nucleotides in length, about 600 nucleotides in length, about 650 nucleotides in length, about 700 nucleotides in length, about 750 nucleotides in length, about 800 nucleotides in length, about 850 nucleotides in length, about 900 nucleotides in length, about 950 nucleotides in length, about 1,000 nucleotides in length, about 1,500 nucleotides in length, about 2,000 nucleotides in length, about 2,500 nucleotides in length, about 3,000 nucleotides in length, about 3,500 nucleotides in length, about 4,000 nucleotides in length, about 4,500 nucleotides in length or about 5,000 nucleotides in length.

[0855] In some embodiments, the mRNA disclosed herein may comprise a 3 ’ UTR comprising one or more of a polyadenylation signal, a binding site for proteins that affect an mRNA’s stability of location in a cell, or one or more binding sites for miRNAs. In some embodiments, a 3’ UTR may be 50 to 5,000 nucleotides in length or longer. In some embodiments, a 3’ UTR may be 50 to 1,000 nucleotides in length or longer. In some embodiments, the 3’ UTR is at least about 50 nucleotides in length, about 100 nucleotides in length, about 150 nucleotides in length, about 200 nucleotides in length, about 250 nucleotides in length, about 300 nucleotides in length, about 350 nucleotides in length, about 400 nucleotides in length, about 450 nucleotides in length, about 500 nucleotides in length, about 550 nucleotides in length, about 600 nucleotides in length, about 650 nucleotides in length, about 700 nucleotides in length, about 750 nucleotides in length, about 800 nucleotides in length, about 850 nucleotides in length, about 900 nucleotides in length, about 950 nucleotides in length, about 1,000 nucleotides in length, about 1,500 nucleotides in length, about 2,000 nucleotides in length, about 2,500 nucleotides in length, about 3,000 nucleotides in length, about 3,500 nucleotides in length, about 4,000 nucleotides in length, about 4,500 nucleotides in length, or about 5,000 nucleotides in length.

[0856] In some embodiments, the mRNA disclosed herein may comprise a 5’ or 3’ UTR that is derived from a gene distinct from the one encoded by the mRNA transcript (i.e., the UTR is a heterologous UTR).

[0857] In certain embodiments, the 5’ and / or 3’ UTR sequences can be derived from mRNA which are stable (e.g., globin, actin, GAPDH, tubulin, histone, or citric acid cycle enzymes) to increase the stability of the mRNA. For example, a 5’ UTR sequence may include a partial sequence of a CMV immediate-early 1 (IE1) gene, or a fragment thereof, to improve the nuclease resistance and / or improve the half-life of the mRNA. Also contemplated is the inclusion of a sequence encoding human growth hormone (hGH), or a fragment thereof, to the 3 ’ end or untranslated region of the mRNA. Generally, these modifications improve the stability and / or pharmacokinetic properties (e.g., half-life) of the mRNA relative to their unmodified counterparts, and include, for example, modifications made to improve such mRNA resistance to in vivo nuclease digestion.

[0858] Exemplary 5’ UTRs include a sequence derived from a CMV immediate-early 1 (IE1) gene (U.S. Publication Nos. 2014 / 0206753 and 2015 / 0157565, each of which is incorporated herein by reference), or the sequence GGGAUCCUACC (SEQ ID NO: 1) (U.S. Publication No. 2016 / 0151409, incorporated herein by reference).

[0859] In various embodiments, the 5’ UTR may be derived from the 5’ UTR of a TOP gene. TOP genes are typically characterized by the presence of a 5 ’-terminal oligopyrimidine (TOP) tract. Furthermore, most TOP genes are characterized by growth-associated translational regulation. However, TOP genes with a tissue specific translational regulation are also known. In certain embodiments, the 5’ UTR derived from the 5’ UTR of a TOP gene lacks the 5’ TOP motif (the oligopyrimidine tract) (e.g., U.S. Publication Nos. 2017 / 0029847, 2016 / 0304883, 2016 / 0235864, and 2016 / 0166710, each of which is incorporated herein by reference).

[0860] In certain embodiments, the 5’ UTR is derived from a ribosomal protein Large 32 (L32) gene (U.S. Publication No. 2017 / 0029847, supra).

[0861] In certain embodiments, the 5 ’ UTR is derived from the 5 ’ UTR of an hydroxysteroid (17-b) dehydrogenase 4 gene (HSD17B4) (U.S. Publication No. 2016 / 0166710, supra).

[0862] In certain embodiments, the 5’ UTR is derived from the 5’ UTR of an ATP5A1 gene (U.S. Publication No. 2016 / 0166710, supra).

[0863] In some embodiments, an internal ribosome entry site (IRES) is used instead of a 5’ UTR.

[0864] In some embodiments, the 5 ’UTR comprises a nucleic acid sequence reproduced below: (SEQ ID NO:2)

[0865] In some embodiments, the 3 ’UTR comprises a nucleic acid sequence reproduced below: (SEQ ID NO:3)

[0866] The 5’ UTR and 3 ’UTR are described in further detail in W02012 / 075040, incorporated herein by reference. iii. Polyadenylated Tail

[0867] As used herein, the terms “poly(A) sequence,” “poly(A) tail,” and “poly(A) region” refer to a sequence of adenosine nucleotides at the 3 ’ end of the mRNA molecule. The poly(A) tail may confer stability to the mRNA and protect it from exonuclease degradation. The poly(A) tail may enhance translation. In some embodiments, the poly(A) tail is essentially homopolymeric. For example, a poly(A) tail of 100 adenosine nucleotides may have essentially a length of 100 nucleotides. In certain embodiments, the poly(A) tail may be interrupted by at least one nucleotide different from an adenosine nucleotide (e.g., a nucleotide that is not an adenosine nucleotide). For example, a poly(A) tail of 100 adenosine nucleotides may have a length of more than 100 nucleotides (comprising 100 adenosine nucleotides and at least one nucleotide, or a stretch of nucleotides, that are different from an adenosine nucleotide). In certain embodiments, the poly(A) tail comprises the sequence (SEQ ID NO: 4)

[0868] The “poly(A) tail,” as used herein, typically relates to RNA. However, in the context of the disclosure, the term likewise relates to corresponding sequences in a DNA molecule (e.g., a “poly(T) sequence”).

[0869] The poly(A) tail may comprise about 10 to about 500 adenosine nucleotides, about 10 to about 200 adenosine nucleotides, about 40 to about 200 adenosine nucleotides, or about 40 to about 150 adenosine nucleotides. The length of the poly(A) (SEQ ID NO: 5) tail may be at least about 10, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, or 500 adenosine nucleotides.

[0870] In some embodiments where the nucleic acid is an RNA, the poly(A) tail of the nucleic acid is obtained from a DNA template during RNA in vitro transcription. In certain embodiments, the poly(A) tail is obtained in vitro by common methods of chemical synthesis without being transcribed from a DNA template. In various embodiments, poly(A) tails are generated by enzymatic polyadenylation of the RNA (after RNA in vitro transcription) using commercially available polyadenylation kits and corresponding protocols, or alternatively, by using immobilized poly(A)polymerases, e.g., using methods and means as described in WO20 16 / 174271.

[0871] The nucleic acid may comprise a poly(A) tail obtained by enzymatic polyadenylation, wherein the majority of nucleic acid molecules comprise about 100 (+ / -20) to about 500 (+ / -50) or about 250 (+ / -20) adenosine nucleotides.

[0872] In some embodiments, the nucleic acid may comprise a poly(A) tail derived from a template DNA and may additionally comprise at least one additional poly(A) tail generated by enzymatic polyadenylation, e.g., as described in W02016 / 091391.

[0873] In certain embodiments, the nucleic acid comprises at least one polyadenylation signal. In various embodiments, the nucleic acid may comprise at least one poly(C) sequence. The term “poly(C) sequence (SEQ ID NO: 6),” as used herein, is intended to be a sequence of cytosine nucleotides of up to about 200 cytosine nucleotides. In some embodiments, the poly(C) sequence comprises about 10 to about 200 cytosine nucleotides, about 10 to about 100 cytosine nucleotides, about 20 to about 70 cytosine nucleotides, about 20 to about 60 cytosine nucleotides, or about 10 to about 40 cytosine nucleotides. In some embodiments, the poly(C) sequence comprises about 30 cytosine nucleotides. iv. Chemical Modification

[0874] The mRNA disclosed herein may be modified or unmodified. In some embodiments, the mRNA may comprise at least one chemical modification. In some embodiments, the mRNA disclosed herein may contain one or more modifications that typically enhance RNA stability. Exemplary modifications can include backbone modifications, sugar modifications, or base modifications. In some embodiments, the disclosed mRNA may be synthesized from naturally occurring nucleotides and / or nucleotide analogues (modified nucleotides) including, but not limited to, purines (adenine (A) and guanine (G)) or pyrimidines (thymine (T), cytosine (C), and uracil (U)). In certain embodiments, the disclosed mRNA may be synthesized from modified nucleotide analogues or derivatives of purines and pyrimidines, such as, e.g., 1-methyl-adenine, 2-methyl-adenine, 2-methylthio-N-6-isopentenyl-adenine, N6-methyl-adenine, N6-isopentenyl- adenine, 2-thio-cytosine, 3-methyl-cytosine, 4-acetyl-cytosine, 5-methyl-cytosine, 2,6- diaminopurine, 1 -methyl-guanine, 2-methyl-guanine, 2,2-dimethyl-guanine, 7-methyl-guanine, inosine, 1 -methyl-inosine, pseudouracil (5-uracil), dihydro-uracil, 2-thio-uracil, 4-thio-uracil, 5- carboxymethylaminomethyl-2-thio-uracil, 5-(carboxyhydroxymethyl)-uracil, 5-fluoro-uracil, 5- bromo-uracil, 5-carboxymethylaminomethyl-uracil, 5-methyl-2-thio-uracil, 5-methyl-uracil, N- uracil-5-oxy acetic acid methyl ester, 5-methylaminomethyl-uracil, 5-methoxyaminomethyl-2- thio-uracil, 5’ -methoxy carbonylmethyl-uracil, 5 -methoxy-uracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), 1 -methyl-pseudouracil, queosine, β-D-mannosyl-queosine, phosphoramidates, phosphorothi oates, peptide nucleotides, methylphosphonates, 7- deazaguanosine, 5-methylcytosine, and inosine.

[0875] In some embodiments, the disclosed mRNA may comprise at least one chemical modification including, but not limited to, pseudouridine, N1 -methylpseudouridine, 2- thiouridine, 4 ’-thiouridine, 5-methylcytosine, 2-thio-l-methyl-1-deaza-pseudouridine, 2-thio-l- methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-l- methyl-pseudouridine, 4-thio-pseudouridine, 5 -aza-uridine, dihydropseudouridine, 5- methyluridine, 5-methyluridine, 5 -methoxy uridine, and 2’-O-methyl uridine.

[0876] In some embodiments, the chemical modification is selected from the group consisting of pseudouridine, N1 -methylpseudouridine, 5-methylcytosine, 5-methoxyuridine, and a combination thereof.

[0877] In some embodiments, the chemical modification comprises N1 -methylpseudouridine.

[0878] In some embodiments, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% of the uracil nucleotides in the mRNA are chemically modified.

[0879] In some embodiments, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% of the uracil nucleotides in the ORF are chemically modified.

[0880] The preparation of such analogues is described, e.g., in U.S. Pat. No. 4,373,071, U.S. Pat. No. 4,401,796, U.S. Pat. No. 4,415,732, U.S. Pat. No. 4,458,066, U.S. Pat. No. 4,500,707, U.S. Pat. No. 4,668,777, U.S. Pat. No. 4,973,679, U.S. Pat. No. 5,047,524, U.S. Pat. No. 5,132,418, U.S. Pat. No. 5,153,319, U.S. Pat. No. 5,262,530, and U.S. Pat. No. 5,700,642. v. mRNA Synthesis

[0881] The mRNAs disclosed herein may be synthesized according to any of a variety of methods. For example, mRNAs according to the present disclosure may be synthesized via in vitro transcription (IVT). Some methods for in vitro transcription are described, e.g., in Geall et al. (2013) Semin. Immunol. 25(2): 152-159; Brunelle et al. (2013) Methods Enzymol. 530: 101- 14. Briefly, IVT is typically performed with a linear or circular DNA template containing a promoter, a pool of ribonucleotide triphosphates, a buffer system that may include DTT and magnesium ions, an appropriate RNA polymerase (e.g., T3, T7, or SP6 RNA polymerase), DNase I, pyrophosphatase, and / or RNase inhibitor. The exact conditions may vary according to the specific application. The presence of these reagents is generally undesirable in a final mRNA product and these reagents can be considered impurities or contaminants which can be purified or removed to provide a clean and / or homogeneous mRNA that is suitable for therapeutic use. While mRNA provided from in vitro transcription reactions may be desirable in some embodiments, other sources of mRNA can be used according to the instant disclosure including wild-type mRNA produced from bacteria, fungi, plants, and / or animals.

[0882] Where desired, the LNP or the LNP formulation may be multi-valent. In some embodiments, the LNP may carry mRNAs that encode more than one polypeptide (e.g., antigen), such as two, three, four, five, six, seven, eight, nine, ten, or more polypeptides. For example, the LNP may carry multiple mRNA molecules, each encoding a different polypeptide; or carry a polycistronic mRNA that can be translated into more than one polypeptide (e.g., each polypeptide-coding sequence is separated by a nucleotide linker encoding a self-cleaving peptide such as a 2A peptide). An LNP carrying different mRNA molecules typically comprises (encapsulate) multiple copies of each mRNA molecule. For example, an LNP carrying or encapsulating two different mRNA molecules typically carries multiple copies of each of the two different mRNA molecules.

[0883] In some embodiments, a single LNP formulation may comprise multiple kinds (e.g., two, three, four, five, six, seven, eight, nine, ten, or more) of LNPs, each kind carrying a different mRNA.

[0884] G. Buffer and Other Components

[0885] To stabilize the nucleic acid and / or LNPs (e.g., to prolong the shelf-life of the vaccine product), to facilitate administration of the LNP pharmaceutical composition, and / or to enhance in vivo expression of the nucleic acid, the nucleic acid and / or LNP can be formulated in combination with one or more carriers, targeting ligands, stabilizing reagents (e.g., preservatives and antioxidants), and / or other pharmaceutically acceptable excipients. Examples of such excipients are parabens, thimerosal, thiomersal, chlorobutanol, bezalkonium chloride, and chelators (e.g., EDTA).

[0886] The LNP compositions of the present disclosure can be provided as a frozen liquid form or a lyophilized form. A variety of cryoprotectants may be used, including, without limitations, sucrose, trehalose, glucose, mannitol, mannose, dextrose, and the like. The cryoprotectant may constitute 5-30% (w / v) of the LNP composition. In some embodiments, the LNP composition comprises trehalose, e.g., at 5-30% (e.g., 10%) (w / v). Once formulated with the cryoprotectant, the LNP compositions may be frozen (or lyophilized and cryopreserved) at -20°C to -80°C.

[0887] The LNP compositions may be provided to a patient in an aqueous buffered solution - thawed if previously frozen, or if previously lyophilized, reconstituted in an aqueous buffered solution at bedside. The buffered solution may be isotonic and suitable for e.g., intramuscular or intradermal injection. In some embodiments, the buffered solution is a phosphate-buffered saline (PBS). In some embodiments, the buffered solution is a Tris buffered solution.

[0888] H. Processes for Making the Present LNP Formulations

[0889] The present LNPs can be prepared by various techniques presently known in the art. For example, multilamellar vesicles (MLV) may be prepared according to conventional techniques, such as by depositing a selected lipid on the inside wall of a suitable container or vessel by dissolving the lipid in an appropriate solvent, and then evaporating the solvent to leave a thin film on the inside of the vessel or by spray drying. An aqueous phase may then be added to the vessel with a vortexing motion that results in the formation of MLVs. Unilamellar vesicles (ULV) can then be formed by homogenization, sonication or extrusion of the multilamellar vesicles. In addition, unilamellar vesicles can be formed by detergent removal techniques.

[0890] Various methods are described in US 2011 / 0244026, US 2016 / 0038432, US 2018 / 0153822, US 2018 / 0125989, and PCT / US2020 / 043223 (filed July 23, 2020) and can be used to practice the present disclosure. One exemplary process entails encapsulating mRNA by mixing it with a mixture of lipids, without first pre-forming the lipids into lipid nanoparticles, as described in US 2016 / 0038432. Another exemplary process entails encapsulating mRNA by mixing pre-formed LNPs with mRNA, as described in US 2018 / 0153822.

[0891] In some embodiments, the process of preparing mRNA-loaded LNPs includes a step of heating one or more of the solutions to a temperature greater than ambient temperature, the one or more solutions being the solution comprising the pre-formed lipid nanoparticles, the solution comprising the mRNA and the mixed solution comprising the LNP-encapsulated mRNA. In some embodiments, the process includes the step of heating one or both of the mRNA solution and the pre-formed LNP solution, prior to the mixing step. In some embodiments, the process includes heating one or more of the solutions comprising the pre-formed LNPs, the solution comprising the mRNA and the solution comprising the LNP-encapsulated mRNA, during the mixing step. In some embodiments, the process includes the step of heating the LNP- encapsulated mRNA, after the mixing step. In some embodiments, the temperature to which one or more of the solutions is heated is or is greater than about 30°C, 37°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, or 70°C. In some embodiments, the temperature to which one or more of the solutions is heated ranges from about 25-70°C, about 30-70°C, about 35-70°C, about 40-70°C, about 45-70°C, about 50-70°C, or about 60-70°C. In some embodiments, the temperature is about 65°C.

[0892] Various methods may be used to prepare an mRNA solution suitable for the present disclosure. In some embodiments, mRNA may be directly dissolved in a buffer solution described herein. In some embodiments, an mRNA solution may be generated by mixing an mRNA stock solution with a buffer solution prior to mixing with a lipid solution for encapsulation. In some embodiments, an mRNA solution may be generated by mixing an mRNA stock solution with a buffer solution immediately before mixing with a lipid solution for encapsulation. In some embodiments, a suitable mRNA stock solution may contain mRNA in water or a buffer at a concentration at or greater than about 0.2 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.8 mg / ml, 1.0 mg / ml, 1.2 mg / ml, 1.4 mg / ml, 1.5 mg / ml, or 1.6 mg / ml, 2.0 mg / m1,2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 mg / ml, or 5.0 mg / ml.

[0893] In some embodiments, an mRNA stock solution is mixed with a buffer solution using a pump. Exemplary pumps include but are not limited to gear pumps, peristaltic pumps and centrifugal pumps. Typically, the buffer solution is mixed at a rate greater than that of the mRNA stock solution. For example, the buffer solution may be mixed at a rate at least lx, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 1 Ox, 15x, or 20x greater than the rate of the mRNA stock solution. In some embodiments, a buffer solution is mixed at a flow rate ranging between about 100-6000 ml / minute (e.g., about 100-300 ml / minute, 300-600 ml / minute, 600-1200 ml / minute, 1200-2400 ml / minute, 2400-3600 ml / minute, 3600-4800 ml / minute, 4800-6000 ml / minute, or 60-420 ml / minute). In some embodiments, a buffer solution is mixed at a flow rate of, or greater than, about 60 ml / minute, 100 ml / minute, 140 ml / minute, 180 ml / minute, 220 ml / minute, 260 ml / minute, 300 ml / minute, 340 ml / minute, 380 ml / minute, 420 ml / minute, 480 ml / minute, 540 ml / minute, 600 ml / minute, 1200 ml / minute, 2400 ml / minute, 3600 ml / minute, 4800 ml / minute, or 6000 ml / minute. In some embodiments, an mRNA stock solution is mixed at a flow rate ranging between about 10-600 ml / minute (e.g., about 5-50 ml / minute, about 10-30 ml / minute, about 30-60 ml / minute, about 60-120 ml / minute, about 120-240 ml / minute, about 240-360 ml / minute, about 360-480 ml / minute, or about 480-600 ml / minute). In some embodiments, an mRNA stock solution is mixed at a flow rate of or greater than about 5 ml / minute, 10 ml / minute, 15 ml / minute, 20 ml / minute, 25 ml / minute, 30 ml / minute, 35 ml / minute, 40 ml / minute, 45 ml / minute, 50 ml / minute, 60 ml / minute, 80 ml / minute, 100 ml / minute, 200 ml / minute, 300 ml / minute, 400 ml / minute, 500 ml / minute, or 600 ml / minute.

[0894] The process of incorporation of a desired mRNA into a lipid nanoparticle is referred to as “loading.” Exemplary methods are described in Lasic et al., FEBS Lett. (1992) 312:255-8. The LNP- incorporated nucleic acids may be completely or partially located in the interior space of the lipid nanoparticle, within the bilayer membrane of the lipid nanoparticle, or associated with the exterior surface of the lipid nanoparticle membrane. The incorporation of an mRNA into lipid nanoparticles is also referred to herein as “encapsulation” wherein the nucleic acid is entirely or substantially contained within the interior space of the lipid nanoparticle.

[0895] Suitable LNPs may be made in various sizes. In some embodiments, decreased size of lipid nanoparticles is associated with more efficient delivery of an mRNA. Selection of an appropriate LNP size may take into consideration the site of the target cell or tissue and to some extent the application for which the lipid nanoparticle is being made.

[0896] A variety of methods known in the art are available for sizing of a population of lipid nanoparticles. Preferred methods herein utilize Zetasizer Nano ZS (Malvern Panalytical) to measure LNP particle size. In one protocol, 10 pl of an LNP sample are mixed with 990 pl of 10% trehalose. This solution is loaded into a cuvette and then put into the Zetasizer machine. The z-average diameter (nm), or cumulants mean, is regarded as the average size for the LNPs in the sample. The Zetasizer machine can also be used to measure the polydispersity index (PD1) by using dynamic light scattering (DLS) and cumulant analysis of the autocorrelation function. Average LNP diameter may be reduced by sonication of formed LNP. Intermittent sonication cycles may be alternated with quasi-elastic light scattering (QELS) assessment to guide efficient lipid nanoparticle synthesis.

[0897] In some embodiments, the majority of purified LNPs, i.e., greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the LNPs, have a size of about 70-150 nm (e.g., about 145 nm, about 140 nm, about 135 nm, about 130 nm, about 125 nm, about 120 nm, about 115 nm, about 110 nm, about 105 nm, about 100 nm, about 95 nm, about 90 nm, about 85 nm, or about 80 nm). In some embodiments, substantially all (e.g., greater than 80 or 90%) of the purified lipid nanoparticles have a size of about 70-150 nm (e.g., about 145 nm, about 140 nm, about 135 nm, about 130 nm, about 125 nm, about 120 nm, about 115 nm, about 110 nm, about 105 nm, about 100 nm, about 95 nm, about 90 nm, about 85 nm, or about 80 nm).

[0898] In some embodiments, the LNPs in the present composition have an average size of less than 150 nm, less than 120 nm, less than 100 nm, less than 90 nm, less than 80 nm, less than 70 nm, less than 60 nm, less than 50 nm, less than 30 nm, or less than 20 nm.

[0899] In some embodiments, greater than about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% of the LNPs in the present composition have a size ranging from about 40-90 nm (e.g., about 45-85 nm, about 50-80 nm, about 55-75 nm, about 60-70 nm), about 40-90 nm (e.g., about 45-85 nm, about 50-80 nm, about 55-75 nm, about 60-70 nm), or about 50-70 nm (e.g., 55- 65 nm) are particular suitable for pulmonary delivery via nebulization.

[0900] In some embodiments, the dispersity, or measure of heterogeneity in size of molecules (PD1), of LNPs in a pharmaceutical composition provided by the present disclosure is less than about 0.5. In some embodiments, an LNP has a PD1 of less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.28, less than about 0.25, less than about 0.23, less than about 0.20, less than about 0.18, less than about 0.16, less than about 0.14, less than about 0.12, less than about 0.10, or less than about 0.08. The PD1 may be measured by a Zetasizer machine as described above.

[0901] In some embodiments, greater than about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the purified LNPs in a pharmaceutical composition provided herein encapsulate an mRNA within each individual particle. In some embodiments, substantially all (e.g., greater than 80% or 90%) of the purified lipid nanoparticles in a pharmaceutical composition encapsulate an mRNA within each individual particle. In some embodiments, a lipid nanoparticle has an encapsulation efficiency of between 50% and 99%; or greater than about 60, 65, 70, 75, 80, 85, 90, 92, 95, 98, or 99%. Typically, lipid nanoparticles for use herein have an encapsulation efficiency of at least 90% (e.g., at least 91, 92, 93, 94, or 95%). In some embodiments, an LNP has a N / P ratio of between 1 and 10. In some embodiments, a lipid nanoparticle has a N / P ratio above 1, about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8. In further embodiments, a typical LNP herein has an N / P ratio of 4.

[0902] In some embodiments, a pharmaceutical composition according to the present disclosure contains at least about 0.5 μg, 1 μg, 5 μg, 10 μg, 100 μg, 500 μg, or 1000 pg of encapsulated mRNA. In some embodiments, a pharmaceutical composition contains about 0.1 μg to 1000 μg, at least about 0.5 μg, at least about 0.8 μg, at least about 1 μg, at least about 5 μg, at least about 8 μg, at least about 10 μg, at least about 50 μg, at least about 100 μg, at least about 500 μg, or at least about 1000 pg of encapsulated mRNA.

[0903] Packaging and Use of the mRNA-LNP

[0904] The mRNA-LNP can be packaged for parenteral (e.g., intramuscular, intradermal, subcutaneous, or intravenous) administration, nasopharyngeal (e.g., intranasal) administration, or mucosal (e.g., intranasal, oral, rectal) administration. The compositions may be in the form of an extemporaneous formulation, where the LNP composition is lyophilized and reconstituted with a physiological buffer (e.g., PBS) just before use. The compositions also may be shipped and provided in the form of an aqueous solution or a frozen aqueous solution and can be directly administered to subjects without reconstitution (after thawing, if previously frozen).

[0905] Accordingly, the present disclosure provides an article of manufacture, such as a kit, that provides the mRNA-LNP in a single container, or provides the mRNA-LNP in one container and a physiological buffer for reconstitution in another container. The container(s) may contain a single-use dosage or multi-use dosage. The containers may be pre-treated glass vials or ampules. The article of manufacture may include instructions for use as well.

[0906] In some embodiments, the present disclosure provides methods of preventing or treating a disease or disorder by administering the composition of the disclosure to a subject in need thereof. In some embodiments, the subject is suffering from or susceptible to an infection.

[0907] In some embodiments, the present disclosure provides methods of eliciting an immune response in a subject in need thereof, comprising administering to the subject a prophylactically effective amount of a composition described herein. In some embodiments, the present disclosure provides methods of preventing an infection or reducing one or more symptoms of an infection in a subject in need thereof, comprising administering to the subject a prophylactically effective amount of the composition.

[0908] In some embodiments of the methods described herein, the composition is administered to the subject mucosally, intramuscularly, intranasally, intravenously, subcutaneously, or intradermally. In some embodiments, the composition is administered mucosally. In some embodiments, the composition is administered intranasally.

[0909] In some embodiments of the methods described herein, the subject is administered one or more doses of the composition, wherein each dose comprises 1-250 pg of mRNA. In some embodiments, each dose comprises 2.5-135 pg of mRNA. In some embodiments, each dose comprises 2.5., 5, 15, 45, or 135, pg of mRNA.

[0910] In some embodiments of the methods described herein, the subject is administered two doses of the composition. In some embodiments, the two doses of the composition are administered with an interval of 1-6 weeks, e.g., 2-6 weeks. In some embodiments, the two doses of the composition are administered with an interval of 1, 2, 3, 4, 5, or 6 weeks. In some embodiments, the two doses of the composition are administered with an interval of 4 weeks.

[0911] In some embodiments of the methods described herein, the subject is administered more than two doses of the composition. For example, the subject is administered three, four, five, or six doses of the composition. In some embodiments, the three, four, five, or six doses of the composition are administered with an interval of 1-6 weeks, e.g., 2-6 weeks. In some embodiments, the three, four, five, or six doses of the composition are administered with an interval of 1, 2, 3, 4, 5, or 6 weeks. In some embodiments, the three, four, five, or six doses of the composition are administered with an interval of 4 weeks.

[0912] As compared to PEG-lipid containing LNP formulations, the dendritic lipid-containing LNP formulations of the present application provide a lower anti-drug antibody response and / or increased expression of mRNA-encoded protein upon subsequent doses. Accordingly, in some embodiments of the methods described herein, said methods are further characterized in that the subject administered the composition exhibits a reduced anti-drug antibody response (e.g., at least 5%, 10%, 15%, 20%, 25%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% less) as compared to said subject being administered a corresponding PEGylated lipid-containing composition. Furthermore, in some embodiments of the methods described herein, said methods are further characterized in that the subject exhibits expression of mRNA- encoded protein (e.g., an antigen such as a viral antigen or a bacterial antigen) upon administration of a second or subsequent dose of the composition that is at least 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, or 60% the expression exhibited upon administration of the first dose of the composition.

[0913] The present disclosure also provides the use of a composition described herein for the manufacture of a medicament for use in any of the methods described herein.

[0914] The present disclosure further provides a kit comprising a composition of the present disclosure. In some embodiments, the kit comprises a containing comprising a single-use or multi-use dosage of the composition. In some embodiments, the containing is a vial. In some embodiments, the container is a pre- filled nasal spray device.

[0915] V. Particular Embodiments

[0916] 1. A dendritic lipid comprising: a lipophilic moiety comprising one or more hydrophobic tails; a generation 1 to generation 4 dendron having a core, a branching portion, and a plurality of terminal groups, each of which terminal group is an alcohol; a polyol, optionally a sugar moiety; an ethylene glycol chain; a polyoxazoline polymer; or a peptide, optionally a polysarcosine; wherein said lipophilic moiety is covalently attached to the core of the dendron, optionally via a spacer; and optionally wherein each terminal group is covalently attached to the branching portion of the dendron via a linker.

[0917] 2. The dendritic lipid of embodiment 1 , wherein the lipophilic moiety comprises one, two, or three hydrophobic tails.

[0918] 3. The dendritic lipid of embodiment 1 or embodiment 2, wherein the lipophilic moiety further comprises a head group, wherein the one or more hydrophobic tails are covalently attached to the head group, and the head group is covalently attached to the core of the dendron, optionally via a spacer.

[0919] 4. The dendritic lipid of embodiment 3, wherein the head group is a glycerol, a phosphatidylglycerol, a sphingosine, a phosphosphingosine, or a dialkylamide.

[0920] 5. The dendritic lipid of any one of embodiments 1-4, wherein the hydrophobic tails each comprise a C(6-24)alkyl, a C(6-24)alkenyl, or a C(6-24)alkynyl group.

[0921] 6. The dendritic lipid of embodiment 5, wherein the hydrophobic tails each comprise a C(12-18)alkyl, a C(12-18)alkenyl, or a C(12-18)alkynyl group.

[0922] 7. The dendritic lipid of any one of embodiments 1 -6, wherein each hydrophobic tail is selected from the group consisting of -C(6-24)alkyl, -C(6-24)alkenyl, -C(6-24)alkynyl, and , wherein the -C(6-24)alkyl, -C(6-24)alkenyl, and -C(6-24)alkynyl are each optionally substituted with one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl; wherein:

[0923] X1is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl;

[0924] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and

[0925] X3is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl.

[0926] 8. The dendritic lipid of embodiment 7, wherein each hydrophobic tail is selected from the group consisting of -C(6-24)alkyl, -C(6-24)alkenyl, and wherein: X1is -C(6-14)alkyl or -C(6-14)alkenyl;

[0927] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and

[0928] X3is -C(6-14)alkyl or -C(6-14)alkenyl.

[0929] 9. The dendritic lipid of embodiment 1 , wherein the lipophilic moiety has a structure selected from: wherein:

[0930] R1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, -C(6-24)alkynyl, or , wherein the -C(6-24)alkyl, -C(6-24)alkenyl, and -C(6-24)alkynyl are each optionally substituted with one to six groups independently selected from halo, -OC(1-6)alkyl, -OC( 2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl;

[0931] X1is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl;

[0932] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and X3is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, - SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl.

[0933] 10. The dendritic lipid of embodiment 9, wherein:

[0934] R1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, or

[0935] X1is -C(6-14)alkyl or -C(6-14)alkenyl;

[0936] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and

[0937] X3is -C(6-14)alkyl or -C(6-14)alkenyl.

[0938] 11. The dendritic lipid of any one of embodiments 1 -7, wherein the lipophilic moiety has the following structure: wherein:

[0939] R1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, -C(6-24)alkynyl, or , wherein the -C(6-24)alkyl, -C(6-24)alkenyl, and -C(6-24)alkynyl are each optionally substituted with one to six groups independently selected from halo, -OC(1-6)alkyl, -OC( 2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl;

[0940] X1is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl;

[0941] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and

[0942] X3is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl. 12. The dendritic lipid of any one of embodiments 1-9, wherein the lipophilic moiety has the following structure: wherein:

[0943] R1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, or

[0944] X1is -C(6-14)alkyl or -C(6-14)alkenyl;

[0945] X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; and

[0946] X3is -C(6-14)alkyl or -C(6-14)alkenyl.

[0947] 13. The dendritic lipid of any one of embodiments 1-12, wherein the lipophilic moiety has a structure selected from the group consisting of:

[0948] 14. The dendritic lipid of any one of embodiments 1-13, wherein the lipophilic moiety is covalently attached to the core of the dendron via a spacer.

[0949] 15. The dendritic lipid of any one of embodiments 1-14, wherein the spacer is -C(1-60)alkyl-, wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O-, -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, - C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, and -NHC(O)NH-.

[0950] 16. The dendritic lipid of any one of embodiments 1-15, wherein the spacer is -O-, -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-.

[0951] 17. The dendritic lipid of any one of embodiments 1-15, wherein the spacer comprises an ethylene glycol chain.

[0952] 18. The dendritic lipid of any one of embodiments 1-15, wherein the spacer is: wherein:

[0953] X3is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0954] X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1.6)alkyl-NHC(O)NH-; m is 1, 2, 3, 4, 5, 6, 7, or 8;

[0955] X5is absent, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, - C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl- NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-;

[0956] X6is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0957] X7is -C(1-16)alkyl-, -C(1-8)alkyl-S-S-C(1-8)alkyl-, -C(1-8)alkyl-C(O)O-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)-C(1-8)alkyl-, -C(1-8)alkyl-C(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)-C(1-8)alkyl-, - C(1-8)alkyl-C(O)S-C(1-8)alkyl-, -C(1-8)alkyl-SC(O)-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)O-C(1-8)alkyl-, - C(1-8)alkyl-OC(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)O-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)NH-

[0958] C(1-8)alkyl-; and

[0959] X8is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; wherein X3forms a bond with the lipophilic moiety and X5forms a bond with the core of the dendron; or wherein X6forms a bond with the lipophilic moiety and X8forms a bond with the core of the dendron.

[0960] 19. The dendritic lipid of embodiment 18, wherein the spacer is:

[0961] 20. The dendritic lipid of embodiment 19, wherein the spacer is:

[0962] 21. The dendritic lipid of embodiment 19, wherein the spacer is:

[0963] 22. The dendritic lipid of any one of embodiments 1-21, wherein the dendron is a generation 1 to generation 2 dendron.

[0964] 23. The dendritic lipid of embodiment 22, wherein the dendron is a generation 1 dendron.

[0965] 24. The dendritic lipid of embodiment 22, wherein the dendron is a generation 1.5 dendron.

[0966] 25. The dendritic lipid of embodiment 22, wherein the dendron is a generation 2 dendron. 26. The dendritic lipid of any one of embodiments 1-25, wherein the dendron comprises dendritic monomeric units selected from 2,2-bis(hydroxymethyl) propionic acid (bis-MPA), poly(amido-amine) (PAMAM), poly(ethyleneimine) (PEI), polyester, polylysine, polypropyleneimine (PPI), diaminobutane amine polypropylenimine tetramine (DAB-Am 4), pentaerythritol, aliphatic polyether, aromatic polyether, or combinations thereof.

[0967] 27. The dendritic lipid of embodiment 26, wherein the dendron comprises dendritic monomeric units of bis-MPA.

[0968] 28. The dendritic lipid of embodiment 27, wherein the dendron is: wherein:

[0969] L2independently for each occurrence is absent or a linker; and TERM independently for each occurrence is a terminal group.

[0970] 29. The dendritic lipid of any one of embodiments 1-21, 26, or 27, wherein the dendritic lipid comprises between 2 and 24 terminal groups.

[0971] 30. The dendritic lipid of any one of embodiments 1-21, 26, 27, or 29, wherein the dendritic lipid comprises between 2 and 16 terminal groups.

[0972] 31. The dendritic lipid of any one of embodiments 1-22, 26, 27, 29, or 30, wherein the dendritic lipid comprises 2, 3, or 4 terminal groups. 32. The dendritic lipid of any one of embodiments 1-31, wherein each terminal group is covalently attached to the branching portion of the dendron via a linker.

[0973] 33. The dendritic lipid of any one of embodiments 1-32, wherein each linker is independently for each occurrence -C(1-60)alkyl-, wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O-, -NH-, -S-, -S-S-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, - NHC(O)O-, and -NHC(O)NH-.

[0974] 34. The dendritic lipid of any one of embodiments 1-32, wherein each linker is independently for each occurrence -O-, -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, - C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-.

[0975] 35. The dendritic lipid of any one of embodiments 1-32, wherein each linker comprises an ethylene glycol chain.

[0976] 36. The dendritic lipid of any one of embodiments 1-32, wherein each linker independently for each occurrence is: m' wherein:

[0977] X3’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0978] X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m’ is 1, 2, 3, 4, 5, 6, 7, or 8;

[0979] X5’ is absent, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, - C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl- NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-;

[0980] X6’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;

[0981] X7is -C(1-16)alkyl-, -C(1-8)alkyl-S-S-C(1-8)alkyl-, -C(1-8)alkyl-C(O)O-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)-C(1-8)alkyl-, -C(1-8)alkyl-C(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)-C(1-8)alkyl-, - C(1-8)alkyl-C(O)S-C(1-8)alkyl-, -C(1-8)alkyl-SC(O)-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)O-C(1-8)alkyl-, - C(1-8)alkyl-OC(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)O-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)NH- C(1-8)alkyl-; and

[0982] X8’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; wherein X3forms a bond with the branching portion of the dendron and X5forms a bond with the terminal group; or wherein X6forms a bond with the branching portion of the dendron and X8forms a bond with the terminal group.

[0983] 37. The dendritic lipid of embodiment 36, wherein each linker independently for each occurrence is:

[0984] The dendritic lipid of embodiment 37, wherein each linker is: m’ II 0

[0985] The dendritic lipid of embodiment 37, wherein each linker is: 40. The dendritic lipid of embodiment 36, wherein each linker independently for each occurrence is:

[0986] 41. The dendritic lipid of embodiment 40, wherein each linker is:

[0987] 42. The dendritic lipid of any one of embodiments 1-41, wherein each linker is identical.

[0988] 43. The dendritic lipid of any one of embodiments 1-42, wherein each terminal group is a sugar moiety.

[0989] 44. The dendritic lipid of any one of embodiments 1-43, wherein each terminal group is a monosaccharide or a disaccharide.

[0990] 45. The dendritic lipid of any one of embodiments 1-43, wherein each terminal group is selected from the group consisting of:

[0991] 46. The dendritic lipid of any one of embodiments 1-45, wherein each terminal group is independently selected from the group consisting of glucose, fructose, mannose, galactose, sucrose, lactose, maltose, trehalose, neuraminic acid, cellobiose, N-acetylglucosamine, N- acetylgalactosamine, and N-acetylneuraminic acid.

[0992] 47. The dendritic lipid of embodiment 46, wherein each terminal group is independently selected from the group consisting of glucose, mannose, and trehalose.

[0993] 48. The dendritic lipid of any one of embodiments 1-42, wherein each terminal group is an ethylene glycol chain or polysarcosine.

[0994] 49. The dendritic lipid of any one of embodiments 1-48, wherein each terminal group is identical.

[0995] 50. A dendritic lipid of Formula (I):

[0996] (I), or a pharmaceutically acceptable salt thereof, wherein:

[0997] LIP is a lipophilic moiety comprising one or more hydrophobic tails;

[0998] L1is absent or -C(1-60)alkyl- wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O-, -NH-, -S-, -S-S-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, - NHC(O)O-, and -NHC(O)NH-;

[0999] DEN1is a dendritic monomeric unit having nl branching valencies; nl is 2 or 3;

[1000] A1independently for each occurrence is: DEN2independently for each occurrence is a dendritic monomeric unit having n2 branching valencies; n2 independently for each occurrence is 2 or 3;

[1001] A2independently for each occurrence is:

[1002] DEN3independently for each occurrence is a dendritic monomeric unit having n3 branching valencies; n3 independently for each occurrence is 2 or 3;

[1003] A3independently for each occurrence is:

[1004] DEN4independently for each occurrence is a dendritic monomeric unit having n4 branching valencies; n4 independently for each occurrence is 2 or 3;

[1005] A4independently for each occurrence is:

[1006] L2independently for each occurrence is absent or -C(1-60)alkyl- wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O- , -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, - OC(O)O-, -OC(O)NH-, -NHC(O)O-, and -NHC(O)NH-; and

[1007] TERM independently for each occurrence ...

Claims

CLAIMS1. A dendritic lipid comprising: a lipophilic moiety comprising one or more hydrophobic tails; a generation 1 to generation 4 dendron having a core, a branching portion, and a plurality of terminal groups, each of which terminal group is an alcohol; a polyol, optionally a sugar moiety; an ethylene glycol chain; a polyoxazoline polymer; or a peptide, optionally a polysarcosine; wherein said lipophilic moiety is covalently attached to the core of the dendron, optionally via a spacer; and optionally wherein each terminal group is covalently attached to the branching portion of the dendron via a linker.

2. A dendritic lipid of Formula (I):(I), or a pharmaceutically acceptable salt thereof, wherein:LIP is a lipophilic moiety comprising one or more hydrophobic tails;L1is absent or -C(1-60)alkyl- wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O-, -NH-, -S-, -S-S-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, - NHC(O)O-, and -NHC(O)NH-;DEN1is a dendritic monomeric unit having nl branching valencies; nl is 2 or 3;A1independently for each occurrence is:orDEN2independently for each occurrence is a dendritic monomeric unit having n2 branching valencies; n2 independently for each occurrence is 2 or 3;A2independently for each occurrence is:orDEN3independently for each occurrence is a dendritic monomeric unit having n3 branching valencies; n3 independently for each occurrence is 2 or 3;A3independently for each occurrence is:OrDEN4independently for each occurrence is a dendritic monomeric unit having n4 branching valencies; n4 independently for each occurrence is 2 or 3;A4independently for each occurrence is:L2independently for each occurrence is absent or -C(1-60)alkyl- wherein one or more nonconsecutive -CH2- groups are replaced with a group selected from the group consisting of -O-, -NH-, -S-, -S-S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, - OC(O)O-, -OC(O)NH-, -NHC(O)O-, and -NHC(O)NH-; andTERM independently for each occurrence is an alcohol; a polyol, optionally a sugar moiety; an ethylene glycol chain; a polyoxazoline polymer; or a peptide, optionally a polysarcosine.

3. The dendritic lipid of claim 2, or a pharmaceutically acceptable salt thereof, wherein:LIP is a lipophilic moiety comprising one, two, or three hydrophobic tails and a head group, wherein the one or more hydrophobic tails are covalently attached to the head group, and wherein the head group is covalently attached to L1; each hydrophobic tail is selected from the group consisting of -C(6-24)alkyl, -C(6-24)alkenyl,, wherein the -C(6-24)alkyl, -C(6-24)alkenyl, and -C(6-24)alkynyl are each optionally substituted with one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl;X1is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl;X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;X3is -C(6-14)alkyl, -C(6-14)alkenyl, or -C(6-14)alkynyl, each of which is optionally substituted by one to six groups independently selected from halo, -OC(1-6)alkyl, -OC(2-6)alkenyl, -SC(1-6)alkyl, -SC(2-6)alkenyl, and -C(O)OC(1-6)alkyl; the head group is a glycerol, a phosphatidylglycerol, a sphingosine, a phosphosphingosine, or a dialkylamide;L1is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, - SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, -NHC(O)NH-,X3is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;X5is absent, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, - C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl- NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-;X6is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;X7is -C(1-16)alkyl-, -C(1-8)alkyl-S-S-C(1-8)alkyl-, -C(1-8)alkyl-C(O)O-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)-C(1-8)alkyl-, -C(1-8)alkyl-C(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)-C(1-8)alkyl-, - C(1-8)alkyl-C(O)S-C(1-8)alkyl-, -C(1-8)alkyl-SC(O)-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)O-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)O-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)NH- C(1-8)alkyl-;X8is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -0C(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;DEN1is a dendritic monomeric unit having nl branching valencies; nl is 2 or 3;A1independently for each occurrence is:OrDEN2independently for each occurrence is a dendritic monomeric unit having n2 branching valencies; n2 independently for each occurrence is 2 or 3;A2independently for each occurrence is:orDEN3independently for each occurrence is a dendritic monomeric unit having n3 branching valencies; n3 independently for each occurrence is 2 or 3;A3independently for each occurrence is:orDEN4independently for each occurrence is a dendritic monomeric unit having n4 branching valencies; n4 independently for each occurrence is 2 or 3;A4independently for each occurrence is:L2independently for each occurrence is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, - OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, - NHC(O)NH-,orX3’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;X5’ is absent, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, - C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl- NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-;X6’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;X7is -C(1-16)alkyl-, -C(1-8)alkyl-S-S-C(1-8)alkyl-, -C(1-8)alkyl-C(O)O-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)-C(1-8)alkyl-, -C(1-8)alkyl-C(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)-C(1-8)alkyl-, - C(1-8)alkyl-C(O)S-C(1-8)alkyl-, -C(1-8)alkyl-SC(O)-C(1-8)alkyl-, -C(1-8)alkyl-OC(O)O-C(1-8)alkyl-, - C(1-8)alkyl-OC(O)NH-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)O-C(1-8)alkyl-, -C(1-8)alkyl-NHC(O)NH- C(1-8)alkyl-;X8’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; andTERM independently for each occurrence is a monosaccharide, a disaccharide, an ethylene glycol chain, or polysarcosine.

4. The dendritic lipid of claim 2 or claim 3, having a structure according to Formula (la):(la) or a pharmaceutically acceptable salt thereof, wherein:LIP isR1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, orX1is -C(6-14)alkyl or -C(6-14)alkenyl;X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;X3is -C(6-14)alkyl or -C(6-14)alkenylL1is absent,orX3is absent, -C(O)-, -C(O)O-, or -C(O)NH-;X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m is 1, 2, 3, 4, 5, 6, 7, or 8;X5is absent, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, -C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, - C(1-6)alkylO-, -C(1-6)alkylNH-, or -C(1-6)alkylS-;X6is absent, -C(O)-, -C(O)O-, or -C(O)NH-;X7is -C(1-16)alkyl- or -C(1-8)alkyl-S-S-C(1-8)alkyl-;X8is absent, -O-, -NH-, or -S-;A1independently for each occurrence is:orA2independently for each occurrence is:A3independently for each occurrence is:orA4independently for each occurrence is:L2independently for each occurrence is absent, -C(O)-, -C(O)O-, -C(O)NH-,X3’ is absent, -C(O)-, -C(O)O-, or -C(O)NH-;X4is absent, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl-NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-; m' is 1, 2, 3, 4, 5, 6, 7, or 8;X5’ is absent, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)C(1-6)alkyl -, -C(O)OC(1-6)alkyl -, - C(O)NHC(1-6)alkyl -, -C(1-6)alkyl-, -C(1-6)alkylO-, -C(1-6)alkylNH-, -C(1-6)alkylS-, -C(1-6)alkylC(O)-, -C(1-6)alkylC(O)O-, -C(1-6)alkylOC(O)-, -C(1-6)alkylC(O)NH-, -C(1-6)alkylNHC(O)-, -C(1-6)alkylC(O)S-, -C(1-6)alkylSC(O)-, -C(1-6)alkylOC(O)O-, -C(1-6)alkyl-OC(O)NH-, -C(1-6)alkyl- NHC(O)O-, or -C(1-6)alkyl-NHC(O)NH-;X6’ is absent, -C(O)-, -C(O)O-, or -C(O)NH-;X7is -C(1-16)alkyl- or -C(1-8)alkyl-S-S-C(1-8)alkyl-;X8’ is absent, -O-, -NH-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; andTERM independently for each occurrence is selected from the group consisting of sucrose, lactose, maltose, trehalose, cellobiose, glucose, fructose, mannose, galactose, an ethylene glycol chain, or polysarcosine.

5. The dendritic lipid of claim 2 or claim 3, or a pharmaceutically acceptable salt thereof, wherein LIP has the following structure:wherein:X1is -C(6-14)alkyl or -C(6-14)alkenyl;X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-; andX3is -C(6-14)alkyl or -C(6-14)alkenyl.

6. The dendritic lipid of any one of claims 2-5, having the structure according to Formula(Ia-1):(Ia-1);Formula (la-1.5):Formula (la-2):(la-2), or a pharmaceutically acceptable salt thereof.

7. The dendritic lipid of claim 1, having a structure according to Formula (la-1 ):(la-1), or a pharmaceutically acceptable salt thereof, wherein: LIP isR1independently for each occurrence is -C(6-24)alkyl, -C(6-24)alkenyl, orX1is -C(6-14)alkyl or -C(6-14)alkenyl;X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;X3is -C(6-14)alkyl or -C(6-14)alkenyl m is 1, 2, 3, 4, 5, 6, 7, or 8;L2independently for each occurrence is selected from the group consisting of m' is 1, 2, 3, 4, 5, 6, 7, or 8; andTERM independently for each occurrence is selected from the group consisting of sucrose, lactose, maltose, trehalose, cellobiose, glucose, fructose, mannose, mannobiose, galactose, an ethylene glycol chain, polysarcosine, or a trisaccharide comprising three sugar molecules selected from the group consisting of glucose, frutose, and mannose.

8. The dendritic lipid of claim 1, having a structure according to Formula (la-1 ):(la-1), or a pharmaceutically acceptable salt thereof, wherein:LIP isX1is -C(6-14)alkyl or -C(6-14)alkenyl;X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;X3is -C(6-14)alkyl or -C(6-14)alkenyl m is 1, 2, 3, 4, 5, 6, 7, or 8;L2independently for each occurrence is selected from the group consisting of m' is 1, 2, 3, 4, 5, 6, 7, or 8; andTERM independently for each occurrence is selected from the group consisting of 9. The dendritic lipid of claim 1, having a structure according to Formula (la-2):(la-2), or a pharmaceutically acceptable salt thereof, wherein:LIP isX1is -C(6-14)alkyl or -C(6-14)alkenyl;X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, - OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;X3is -C(6-14)alkyl or -C(6-14)alkenyl m is 1, 2, 3, 4, 5, 6, 7, or 8;L2independently for each occurrence is selected from the group consisting of m' is 1, 2, 3, 4, 5, 6, 7, or 8; andTERM independently for each occurrence is selected from the group consisting of sucrose, lactose, maltose, trehalose, cellobiose, glucose, fructose, mannose, mannobiose, galactose, an ethylene glycol chain, polysarcosine, or a trisaccharide comprising three sugar molecules selected from the group consisting of glucose, frutose, and mannose.

10. The dendritic lipid of claim 1, having a structure according to Formula (la-2): or a pharmaceutically acceptable salt thereof, wherein: LIP isX1is -C(6-14)alkyl or -C(6-14)alkenyl;X2is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -C(O)S-, -SC(O)-, -OC(O)O-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;X3is -C(6-14)alkyl or -C(6-14)alkenylm is 1, 2, 3, 4, 5, 6, 7, or 8;L2independently for each occurrence is selected from the group consisting of m' is 1, 2, 3, 4, 5, 6, 7, or 8; andTERM independently for each occurrence is selected from the group consisting of 11. A dendritic lipid having a structure selected from the group consisting of:13. A dendritic lipid having a structure selected from the group consisting of:(Dendritic Lipid #26),(Dendritic Lipid #27),(Dendritic Lipid #28),(Dendritic Lipid #36),(Dendritic Lipid #37),14. A composition comprising a lipid nanoparticle (LNP), wherein the LNP comprises:(I) a cationic lipid; and(II) the dendritic lipid of any one of claims 1-13.

15. The composition of claim 14, wherein the LNP comprises:(I) a cationic lipid;(II) the dendritic lipid of any one of claims 1-13;(III) a structural lipid; and(IV) a helper lipid.

16. The composition of claim 14 or claim 15, further comprising a nucleic acid molecule, wherein the nucleic acid molecule is encapsulated in the LNP, and wherein the nucleic acid molecule is an mRNA molecule.

17. The composition of claim 16, wherein the mRNA molecule encodes an antigen, optionally a viral antigen or a bacterial antigen.

18. The composition of claim 16, wherein the mRNA molecule encodes a protein.

19. The composition of claim 16 or claim 17 for use in eliciting an immune response in a subject in need thereof.

20. The composition of claim 16 or claim 17 for use in preventing an infection or reducing one or more symptoms of an infection in a subject in need thereof.

21. The composition of claim 16 or claim 17 for us in curing an infection or reducing one or more symptoms of an infection.

22. A method of preventing an infection or reducing one or more symptoms of an infection in a subject in need thereof, comprising administering to the subject a prophylactically effective amount of the composition of claim 16 or claim 17.

23. A method of curing an infection or reducing one or more symptoms of an infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the composition of claim 16 or claim 17.

24. The method of claim 22 or claim 23, comprising administering to the subject: two doses of the composition with an interval of 2-6, optionally 4, weeks; or more than two doses, optionally three, four, five, or six doses, of the composition with an interval of 2-6, optionally 4, weeks.

25. The composition of claim 18 for use in delivering the mRNA molecule encoding a protein to a subject in need thereof, optionally wherein the composition is delivered to the subject via intravenous administration.

26. A method of delivering an mRNA molecule encoding a protein to a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the composition of claim 18, optionally wherein the composition is administered intravenously.

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