Lipid nanoparticle formulations

Abstract

Provided herein are lipid nanoparticles (LNPs) comprising an ionizable or cationic lipid, a helper lipid, a structural lipid, and a stealth lipid. The LNPs provided herein can be useful for delivery and expression of mRNA and encoded protein 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] 772787: SA9-887PC / / PAT24318-WO-PCT

[0002] LIPID NANOPARTICLE FORMULATIONS

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Application No. 63 / 737,910, filed December 23, 2024, the disclosure of which is incorporated herein by reference in its entirety.

[0004] BACKGROUND

[0005] Effective 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.

[0006] 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 or cationic lipids, phospholipids including polyunsaturated 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 having improved efficacy.

[0007] SUMMARY

[0008] The present disclosure provides, inter alia, a lipid nanoparticle (LNP) comprising (1) an ionizable or cationic lipid that constitutes from about 35 mol% to about 50 mol% of the total lipid content of the lipid nanoparticle;

[0009] (2) a helper lipid that constitutes from about 10 mol% to about 18 mol% of the total lipid content of the lipid nanoparticle;

[0010] (3) a structural lipid that constitutes from about 35 mol% to about 50 mol% of the total lipid content of the lipid nanoparticle; and

[0011] (4) a stealth lipid that constitutes from about 1 mol% to about 3 mol% of the total lipid content of the lipid nanoparticle.

[0012] In some embodiments, the ionizable or cationic lipid has a structure according to Formula CAT-I:

[0013] 1

[0014] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0015]

[0016] (CAT-I),

[0017] or a pharmaceutically acceptable salt thereof, wherein A1, Z1, R1A, R1B, a, and b are as defined herein. In some embodiments, the ionizable or cationic lipid of Formula CAT-I has a structure according to Formula CAT-Ia, CAT-Ib, or CAT-Ic. In some embodiments, the ionizable or cationic lipid of Formula CAT-I is GL-HEPES-E3-E12-DS-4-E10.

[0018] In some embodiments, the ionizable or cationic lipid has a structure according to Formula CAT-II:

[0019]

[0020] (CAT-II)

[0021] or a pharmaceutically acceptable salt thereof, wherein, A1, Z1, R, and a are as defined herein. In some embodiments, the ionizable or cationic lipid of Formula CAT-I has a structure according to Formula CAT-IIa, CAT-IIb, CAT-IIb-i, CAT-IIc-i, CAT-IIc-ii, CAT-IIc-iii, CAT-IIc-iv, CAT-IId, CAT-IIe, CAT-IIf-i, CAT-IIf-ii, CAT-IIg, CAT-IIh, CAT-IIi, CAT-IIj, CAT-IIk, or CAT-IIm. In some embodiments, the ionizable or cationic lipid of Formula CAT-II is Compound CII-3.

[0022] In some embodiments, the helper lipid has a structure according to Formula HLP-I:

[0023] 2

[0024] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0025]

[0026] O

[0027] (HLP-I)

[0028] or a pharmaceutically acceptable salt thereof, wherein Y, Ra, R1, and R2are as defined herein. In some embodiments, the helper lipid of Formula HLP-I has a structure according to Formula HLP-Ia, HLP-Ia-i, HLP-Ia-ii, HLP-Ia-iii, HLP-Ia-iv, HLP-Ib, HLP-Ic, HLP-Id, HLP-Id-i, HLP-Idii, HLP-Id-iii, HLP-Id-iv, HLP-Ie, HLP-Ie-i, HLP-Ie-ii, HLP-Ie-iii, or HLP-Ie-iv. In some embodiments, the helper lipid of Formula HLP-I is selected from the group consisting of Compounds HI-6, HI-12, HI-18, HI-24, HI-27, and HI-31.

[0029] In some embodiments, the helper lipid has a structure according to Formula HLP-II:

[0030] R2AO

[0031] / J / -R1A

[0032] R2BO^ IX NDD

[0033] d ) OH IR

[0034]

[0035] R2C^ '" R1 C

[0036] (HLP-II),

[0037] or a pharmaceutically acceptable salt thereof, wherein X, Y, R1A, R1B, R1C, R2A, R2B, R2C, and n are as defined herein. In some embodiments, the helper lipid of Formula HLP-II has a structure according to Formula HLP-II’, HLP-IIa, HLP-IIa-i, HLP-IIa-ii, HLP-IIb, HLP-IIb-i, HLP-IIb-ii, HLP-IIb-iii, HLP-IIb-iv, HLP-IIc, HLP-IIc-i, or HLP-IIc-ii. In some embodiments, the helper lipid of Formula HLP-II is selected from the group consisting of Compounds HII-13, HII-14, and HII-23.

[0038] In some embodiments, the helper lipid is DOPE. In some embodiments the helper lipid is a combination of DOPE and a lipid of Formula HLP-I. In some embodiments the helper lipid is a combination of DOPE and a lipid of Formula HLP-II. In some embodiments, the structural lipid is cholesterol, P-amyrin, or a combination thereof. In some embodiments, the structural lipid is cholesterol. In some embodiments, the stealth lipid is DMG-PEG2000.

[0039] 3

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[0041] The present disclosure further provides a pharmaceutical composition comprising an LNP described herein. In some embodiments, the LNP the LNP encapsulates an mRNA encoding a peptide or protein.

[0042] The present disclosure further provides a pharmaceutical composition described herein for use in therapy.

[0043] The present disclosure further provides a method for treating or preventing a disease wherein said method comprises administering to a subject in need thereof a pharmaceutical composition described herein.

[0044] DETAILED DESCRIPTION

[0045] The present disclosure provides, inter alia, lipid nanoparticle formulations capable of providing improved in vivo delivery of therapeutic agents, such as nucleic acids. The lipid nanoparticles of the present disclosure have been found to provide high levels of peptide or protein expression when delivering mRNA encoding for said peptide or protein. It is contemplated that the presently disclosed lipid nanoparticles are capable of highly effective in vivo delivery of therapeutic agents and vaccines (e.g., for influenza or respiratory syncytial virus (RSV)).

[0046] I. Definitions

[0047] 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.

[0048] 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.

[0049] 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%,

[0050] 4

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[0052] 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).

[0053] 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).

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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).

[0059] 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 5

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[0061] optionally non-cationic lipid(s), optionally cholesterol-based lipid(s), and / or optionally PEG-modified lipid(s).

[0062] 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, C 5 -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., phosphorothioates and 5'-N-phosphoramidite linkages).

[0063] 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.

[0064] 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.

[0065] 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 6

[0066] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0067] (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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; 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.

[0073] 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 7

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[0075] 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.

[0076] As used herein, the term “cationic lipid” or “ionizable lipid” refers to lipid species that have a net positive charge at a selected pH, such as physiological pH. Several cationic and ionizable lipids have been described in the literature, many of which are commercially available. Suitable additional cationic and ionizable lipids for use in the compositions include the cationic and ionizable lipids as described in the literature.

[0077] The term “helper lipid” as used herein refers to any neutral or zwitterionic lipid material. Without wishing to be held to a particular theory, helper lipids may add stability, rigidity, and / or fluidity within lipid bilayers / nanoparticles.

[0078] As used herein, the term “acyl” refers to RZ-(C=O)-, wherein Rzis, for example, any alkyl, alkenyl, or alkynyl.

[0079] As used herein, the term “alkyl” means acyclic linear and branched hydrocarbon groups, e.g. “(C1-C30) alkyl” refers to alkyl groups having 1-30 carbons. An alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl tert-pentylhexyl, isohexyl, etc. The term “lower alkyl" means an alkyl group straight chain or branched alkyl having 1 to 6 carbon atoms. Other alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. An alkyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR”, -CO2H, -CO2R”, -CN, -OH, -OR”, -OCOR”, -OCO2R”, -NH2, -NHR”, -N(R”)2, -SR” or -SO2R”, wherein each instance of R” independently is (Ci-C20) aliphatic (e.g., (C1-C20) alkyl, (C1-C15) alkyl, (C1-C10) alkyl, or (C1-C3) alkyl). In embodiments, R” independently is an unsubstituted alkyl e.g., unsubstituted (C1-C20) alkyl, (C1-C15) alkyl, (C1-C10) alkyl, or (C1-C3) alkyl). In embodiments, R” independently is unsubstituted (C1-C3) alkyl. In embodiments, the alkyl is substituted e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). In embodiments, an alkyl group is substituted with a -OH group and may also be referred to herein as a “hydroxyalkyl” group, where the prefix denotes the -OH group and “alkyl” is as described herein.

[0080] As used herein, “alkyl” also refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 50 carbon atoms (“(C1-C50) alkyl”). In some embodiments, an alkyl group has 1 to 40 carbon atoms (“(C1-C40) alkyl”). In some embodiments, an alkyl group has 1 to 30 carbon atoms (“(C1-C30) alkyl”). In some

[0081] 8

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[0083] embodiments, an alkyl group has 1 to 20 carbon atoms (“(C1-C20) alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“(C1-C10) alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“(C1-C9) alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“(Ci-Cs) alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“(C1-C7) alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“(Ci-Ce) alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“(C1-C5) alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“(C1-C4) alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“(C1-C3) alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“(C1-C2) alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“(C2-C6) alkyl”). Examples of (Ci-Ce) alkyl groups include, without limitation, methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tertbutyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (Ce). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents. In certain embodiments, the alkyl group is an unsubstituted (C1-C50) alkyl. In certain embodiments, the alkyl group is a substituted (C1-C50) alkyl.

[0084] As used herein, “alkenyl” means any linear or branched hydrocarbon chains having one or more unsaturated carbon-carbon double bonds that may occur in any stable point along the chain, e.g. “(C2-C30) alkenyl” refers to an alkenyl group having 2-30 carbons. For example, an alkenyl group includes 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. In embodiments, the alkenyl comprises 1, 2, or 3 carbon-carbon double bond. In embodiments, the alkenyl comprises a single carbon-carbon double bond. In embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. An alkenyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkenyl group may be substituted with one or more e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR”, -CO2H, -CO2R”, -CN, -OH, -OR”, -OCOR”, -OCO2R”, -NH2, -NHR”, -N(R”)2, -SR” or -SO2R”, wherein each instance of R” independently is (C1-C20) aliphatic e.g., (Ci-C20) alkyl, (C1-C15) alkyl, (C1-C10) alkyl, or (C1-C3) alkyl). In embodiments, R” independently is an unsubstituted alkyl e.g., unsubstituted (C1-C20) alkyl, (C1-C15) alkyl, (Ci- 9

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[0086] Cio) alkyl, or (C1-C3) alkyl). In embodiments, R” independently is unsubstituted (C1-C3) alkyl. In embodiments, the alkenyl is unsubstituted. In embodiments, the alkenyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). In embodiments, an alkenyl group is substituted with a-OH group and may also be referred to herein as a “hydroxyalkenyl” group, where the prefix denotes the -OH group and “alkenyl” is as described herein.

[0087] As used herein, “alkenyl” also refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 50 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds) (“(C2-C50) alkenyl”). In some embodiments, an alkenyl group has 2 to 40 carbon atoms (“(C2-C40) alkenyl”). In some embodiments, an alkenyl group has 2 to 30 carbon atoms (“(C2-C30) alkenyl”). In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“(C2-C20) alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“(C2-C10) alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“(C2-C9) alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“(C2-Cs) alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“(C2-C7) alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“(C2-C6) alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“(C2-C5) alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“(C2-C4) alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“(C2-C3) alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“(C2) alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of (C2-C4) alkenyl groups include, without limitation, ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of (C2-C6) alkenyl groups include the aforementioned (C2-C4) alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted (C2-C50) alkenyl. In certain embodiments, the alkenyl group is a substituted (C2-C50) alkenyl.

[0088] As used herein, “alkynyl” means any hydrocarbon chain of either linear or branched configuration, having one or more carbon-carbon triple bonds occurring in any stable point along the chain, e.g., “(C2-C30) alkynyl”, refers to an alkynyl group having 2-30 carbons. Examples of an alkynyl group include prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2 -ynyl, 3- 10

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[0090] methylpent-4-ynyl, hex-2 -ynyl, hex-5-ynyl, etc. In embodiments, an alkynyl comprises one carbon-carbon triple bond. An alkynyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkynyl group may be substituted with one or more (e.g, 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR”, -CO2H, -CO2R”, -CN, -OH, -OR”, -OCOR”, -OCO2R”, -NH2, -NHR”, -N(R”)2, -SR” or -SO2R”, wherein each instance of R” independently is (C1-C20) aliphatic (e.g, (C1-C20) alkyl, (C1-C15) alkyl, (C1-C10) alkyl, or (C1-C3) alkyl). In embodiments, R” independently is an unsubstituted alkyl (e.g., unsubstituted (C1-C20) alkyl, (C1-C15) alkyl, (Ci-C10) alkyl, or (C1-C3) alkyl). In embodiments, R” independently is unsubstituted (C1-C3) alkyl. In embodiments, the alkynyl is unsubstituted. In embodiments, the alkynyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein).

[0091] As used herein, “alkynyl” also refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 50 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) and optionally one or more double bonds (e.g., 1, 2, 3, or 4 double bonds) (“(C2-C50) alkynyl”). An alkynyl group that has one or more triple bonds, and one or more double bonds is also referred to as an “ene-yne”. In some embodiments, an alkynyl group has 2 to 40 carbon atoms (“(C2-C40) alkynyl”). In some embodiments, an alkynyl group has 2 to 30 carbon atoms (“(C2-C30) alkynyl”). In some embodiments, an alkynyl group has 2 to 20 carbon atoms (“(C2-C20) alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“(C2-C10) alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“(C2-C9) alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“(C2-Cs) alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“(C2-C7) alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“(C2-Ce) alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“(C2-C5) alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“(C2-C4) alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“(C2-C3) alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“(C2) alkynyl”). The one or more carbon— carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of (C2-C4) alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of (C2-Ce) alkenyl groups include the aforementioned (C2-C4) alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a 11

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[0093] “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted (C2-C50) alkynyl. In certain embodiments, the alkynyl group is a substituted (C2-C50) alkynyl.

[0094] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0095] The term “alkylene,” as used herein, represents a saturated divalent straight or branched chain hydrocarbon group and is exemplified by methylene, ethylene, isopropylene and the like. Likewise, the term “alkenylene” as used herein represents an unsaturated divalent straight or branched chain hydrocarbon group having one or more unsaturated carbon-carbon double bonds that may occur in any stable point along the chain, and the term “alkynylene” herein represents an unsaturated divalent straight or branched chain hydrocarbon group having one or more unsaturated carbon-carbon triple bonds that may occur in any stable point along the chain. In certain embodiments, an alkylene, alkenylene, or alkynylene group may comprise one or more cyclic aliphatic and / or one or more heteroatoms such as oxygen, nitrogen, or sulfur and may optionally be substituted with one or more substituents such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester or amide. For example, an alkylene, alkenyl ene, or alkynylene may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR”, -CO2H, -CO2R”, -CN, -OH, -OR”, -OCOR”, -OCO2R”, -NH2, -NHR”, -N(R”)2, -SR” or -SO2R”, wherein each instance of R” independently is (C1-C20) aliphatic e.g., (C1-C20) alkyl, (C1-C15) alkyl, (C1-C10) alkyl, or (C1-C3) alkyl). In embodiments, R” independently is an unsubstituted alkyl e.g., unsubstituted (C1-C20) alkyl, (C1-C15) alkyl, (C1-C10) alkyl, or (C1-C3) alkyl). In embodiments, R” independently is unsubstituted (C1-C3) alkyl. In certain embodiments, an alkylene, alkenylene, or alkynylene is unsubstituted. In certain embodiments, an alkylene, alkenylene, or alkynylene does not include any heteroatoms.

[0096] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein said ring system has a single point of attachment to the rest of the molecule, at least one ring in the system is aromatic and wherein each ring in the system contains 4 to 7 ring members. In embodiments, an aryl group has 6 ring carbon atoms (“(Ce) aryl,” e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“(C10) 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 12

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[0098] 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. Exemplary aryls include phenyl, naphthyl, and anthracene.

[0099] As used herein, “aryl” also 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 it electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“(Ce-Cu) aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“(Ce) aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“(Cio) aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“(Cu) 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. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted (Ce-Cu) aryl. In certain embodiments, the aryl group is a substituted (Ce-Cu) aryl.

[0100] The term “arylene” as used herein refers to an aryl group that is divalent (that is, having two points of attachment to the molecule). Exemplary arylenes include phenylene (e.g., unsubstituted phenylene or substituted phenylene).

[0101] As used herein, the term “halogen” means fluorine, chlorine, bromine, or iodine. 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-C10) carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“(Cs-Cs) carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“(C3-C7) carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“(Cs-Ce) carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“(C4-Ce) carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“(Cs-Ce) carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“(C5-C10) carbocyclyl”). Exemplary (Cs-Ce) carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl 13

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[0103] (Ce), and the like. Exemplary (Cs-Cs) carbocyclyl groups include, without limitation, the aforementioned (Cs-Ce) carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary (C3-C10) carbocyclyl groups include, without limitation, the aforementioned (Cs-Cs) carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), 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 carboncarbon 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. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-C10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted (C3-C10) carbocyclyl.

[0104] In some embodiments, “carbocyclyl” or “carbocyclic” is referred to as a “cycloalkyl”, i.e., a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“(C3-C10) cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“(Cs-Cs) cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“(Cs-Ce), cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“(C4-C6) cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“(Cs-Ce) cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“(C5-C10) cycloalkyl”). Examples of (C5-Ce) cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of (Cs-Ce) cycloalkyl groups include the aforementioned (Cs-Ce) cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of (Cs-Cs) cycloalkyl groups include the aforementioned (Cs-Ce) cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”)

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[0107] with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted (C3-C10) cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted (C3-C10) cycloalkyl.

[0108] As used herein, “heterocyclyl” or “heterocyclic” or “heterocycloalkyl” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0109] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-6

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[0112] membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1 or more (e.g., 1, 2, or 3) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6 membered heterocyclyl has 1 or 2 ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus.

[0113] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.

[0114] Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1, 8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-b] pyrrolyl, 5,6-dihydro-4 l-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b ]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo-[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4, 5,6,7-tetrahydrothieno [3,2- b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

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[0117] 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

[0118] 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.

[0119] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, 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 C5-6 alkyl.

[0120] 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.

[0121] 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).

[0122] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.

[0123] As understood from the above, alkyl, alkenyl, alkynyl, 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.,

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[0126] “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl. “substituted” or “unsubstituted” heterocyclyl, “substituted” or “un substituted” 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.

[0127] 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)NRbbSO2Raa, — NRbbSO2Raa, — SO2N(Rbb)2, — SO2Raa, — SO2ORaa, — OSO2Raa, — S(=O)Raa, — OS(=O)Raa, — Si(Raa)3 — OSi(Raa)3 — C(=S)N(Rbb)2, — C(=O)SRaa, — 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), Cl-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;

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[0130] or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc;

[0131] each instance of Raa is, independently, selected from Cl -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;

[0132] 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, Cl-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;

[0133] each instance of Rcc is, independently, selected from hydrogen, Cl-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;

[0134] 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, Cl-50 alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 5-10 membered

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[0137] 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 =0 or =S;

[0138] each instance of Ree is, independently, selected from Cl -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;

[0139] each instance of Rff is, independently, selected from hydrogen, Cl-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

[0140] each instance of Rgg is, independently, halogen, — CN, — NO2, — N3, — SO2H, — SO3H, —OH, — OC1-50 alkyl, — ON(C1-50 alkyl)2, — N(Cl-50 alkyl)2, — N(Cl-50 alkyl)3+X—, — NH(Cl-50 alkyl)2+X—, — NH2(C1-5O alkyl)+X—, — NH3+X—, — N(OC1-50 alkyl)(Cl-50 alkyl), — N(OH)(C1-50 alkyl), — NH(OH), — SH, -SC1-50 alkyl, — SS(C1-5O alkyl), — C(=O)(Cl-50 alkyl), — CO2H, — CO2(Cl-50 alkyl), — OC(=O)(C1-50 alkyl), — OCO2(Cl-50 alkyl), — C(=0)NH2, — C(=O)N(Cl-50 alkyl)2, — OC(=O)NH(Cl-50 alkyl), — NHC(=O)(Cl-50 alkyl), — N(Cl-50 alkyl)C(=O)(Cl-50 alkyl), — NHCO2(Cl-50 alkyl), — NHC(=O)N(Cl-50 alkyl)2, — NHC(=0)NH(C1-50 alkyl), — NHC(=0)NH2, — C(=NH)O(Cl-50 alkyl), — OC(=NH)(C1-50 alkyl), — OC(=NH)OC1-50 alkyl, — C(=NH)N(Cl-50 alkyl)2, — C(=NH)NH(Cl-50 alkyl), — C(=NH)NH2, — OC(=NH)N(Cl-50alkyl)2, — OC(NH)NH(C1-50 alkyl), — 0C(NH)NH2, — NHC(NH)N(Cl-50 alkyl)2, — NHC(=NH)NH2, — NHSO2 (Cl-50 alkyl), — SO2N(Cl-50 alkyl)2, — SO2NH(Cl-50 alkyl), — SO2NH2, — SO2C1-50 alkyl, — SO2OC1-50 alkyl, — OSO2C1-6 alkyl, — SOC1-6 alkyl, — Si(Cl-50 alkyl)3, — OSi(Cl-6 alkyl)3-C(=S)N(Cl-50 alkyl)2, C(=S)NH(Cl-50 alkyl), C(=S)NH2, — C(=O)S(Cl-6 alkyl), — C(=S)SCl-6 alkyl, — SC(=S)SCl-6 alkyl, — P(=O)2(Cl-50 alkyl), — P(=O)(Cl-50 alkyl)2, — OP(=O)(Cl-50 alkyl)2, — OP(=O)(OCl-50 alkyl)2, Cl-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 =0 or =S;

[0141] wherein X — is a counteranion.

[0142] 20

[0143] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0144] 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, Cl-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.

[0145] 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. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0146] 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.

[0147] II. Lipid Nanoparticle Formulations

[0148] The present disclosure provides a lipid nanoparticle (LNP) comprising:

[0149] (1) an ionizable or cationic lipid that constitutes from about 35 mol% to about 50 mol% of the total lipid content of the lipid nanoparticle;

[0150] (2) a helper lipid that constitutes from about 10 mol% to about 18 mol% of the total lipid content of the lipid nanoparticle;

[0151] 21

[0152] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0153] (3) a structural lipid that constitutes from about 35 mol% to about 50 mol% of the total lipid content of the lipid nanoparticle; and

[0154] (4) a stealth lipid that constitutes from about 1 mol% to about 3 mol% of the total lipid content of the lipid nanoparticle;

[0155] provided that at least one of the following is true:

[0156] (i) the ionizable or cationic lipid has a structure according to Formula (CAT-I), as described herein:

[0157]

[0158] R1A

[0159] (CAT-I),

[0160] or a pharmaceutically acceptable salt thereof;

[0161] (ii) the ionizable or cationic lipid has a structure according to Formula (CAT-II), as described herein:

[0162]

[0163] (CAT-II),

[0164] or a pharmaceutically acceptable salt thereof;

[0165] (iii) the helper lipid has a structure according to Formula (HLP-I), as described herein:

[0166] 22

[0167] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0168]

[0169] o (HLP-I)

[0170] or a pharmaceutically acceptable salt thereof; or

[0171] (iv) the helper lipid has a structure according to Formula (HLP-II), as described herein:

[0172]

[0173] (HLP-II)

[0174] or a pharmaceutically acceptable salt thereof.

[0175] A. lonizable / Cationic Lipids of Formula (CAT-I)

[0176] 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.

[0177] In some embodiments, the ionizable or cationic lipid has a structure according to Formula CAT-I:

[0178]

[0179] (CAT-I),

[0180] or a pharmaceutically acceptable salt thereof,

[0181] wherein:

[0182] 23

[0183] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0184] A1is selected from

[0185]

[0186] wherein the left hand side of each depicted structure is bound to the -(CH2)a-;

[0187] O O

[0188] Z is selected from

[0189]

[0190] ?ur, r o r, and ° wherein the right hand side of each depicted structure is bound to the -(CH2)a-;

[0191] R1Aand R1Bare each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, and -W1-X1-Y1;

[0192] each W1is independently selected from optionally substituted alkyl and optionally substituted alkenyl;

[0193] 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,

[0194] 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;

[0195] b is 1, 2, 3, 4, or 5; and

[0196] each a is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0197] In some embodiments, the lipid of Formula CAT-I has a structure according to Formula CAT-Ia:

[0198]

[0199] (CAT-Ia),

[0200] or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the lipid of Formula CAT-I has a structure according to Formula CAT-Ib:

[0202] 24

[0203] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0204]

[0205] or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the lipid of Formula CAT-I has a structure according to Formula CAT-Ic:

[0207]

[0208] or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments of the lipid of Formula CAT-I, A1and Z1are the same. In some embodiments of the lipid of Formula CAT-I, A1and Z1are different.

[0210] In some embodiments of the lipid of Formula CAT-I, A1is

[0211]

[0212] wherein the left hand side of the depicted structure is bound to the -(CH2)a-. In some embodiments of the

[0213] lipid of Formula CAT-I, A1is

[0214]

[0215] , wherein the left hand side of the depicted structure is bound to the -(CH2)a-. In some embodiments of the lipid of Formula CAT-I, A1is

[0216]

[0217] , wherein the left hand side of the depicted structure is bound to the -(CH2)a-.

[0218] In some embodiments of the lipid of Formula CAT-I, Z1is

[0219]

[0220] wherein the right hand side of the depicted structure is bound to the -(CH2)a-. In some embodiments of O

[0221] the lipid of Formula CAT-I, Z1is

[0222]

[0223] , wherein the right hand side of the depicted

[0224] 25

[0225] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0226] structure is bound to the -(CH2)a-. In some embodiments of the lipid of Formula CAT-I, Z1is

[0227]

[0228] , wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0229] In some embodiments of the lipid of Formula CAT-I, A1is

[0230]

[0231] wherein the

[0232] left hand side of the depicted structure is bound to the -(CH2)a-, and Z1is

[0233]

[0234] wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0235] In some embodiments of the lipid of Formula CAT-I, A1is

[0236]

[0237] wherein the

[0238] left hand side of the depicted structure is bound to the -(CH2)a-, and Z1is

[0239]

[0240] wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0241] In some embodiments of the lipid of Formula CAT-I, A1is

[0242]

[0243] wherein the

[0244] left hand side of the depicted structure is bound to the -(CH2)a-, and Z1is

[0245]

[0246] wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0247] O

[0248] In some embodiments of the lipid of Formula CAT-I, A1is

[0249]

[0250] wherein the

[0251] left hand side of the depicted structure is bound to the -(CH2)a-, and Z1is

[0252]

[0253] wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0254] In some embodiments of the lipid of Formula CAT-I, A1is

[0255]

[0256] wherein the O

[0257] left hand side of the depicted structure is bound to the -(CH2)a-, and Z1is

[0258]

[0259] wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0260] 26

[0261] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0262] In some embodiments of the lipid of Formula CAT-I, A1is

[0263]

[0264] wherein the

[0265] left hand side of the depicted structure is bound to the -(CH2)a-, and Z1is

[0266]

[0267] wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0268] In some embodiments of the lipid of Formula CAT-I, A1is

[0269]

[0270] wherein the

[0271] left hand side of the depicted structure is bound to the -(CH2)a-, and Z1is

[0272]

[0273] wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0274] In some embodiments of the lipid of Formula CAT-I, A1is

[0275]

[0276] wherein the

[0277] left hand side of the depicted structure is bound to the -(CH2)a-, and Z1is

[0278]

[0279] wherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0280] .

[0281] In some embodiments of the lipid of Formula CAT-I, A1is wherein the S.

[0282] left hand side of the depicted structure is bound to the -(CH2)a-, and Z1isSwherein the right hand side of the depicted structure is bound to the -(CH2)a-.

[0283] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently selected from:

[0284]

[0285] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0286]

[0287] In some embodiments of the lipid of Formula CAT-I, each a is independently selected from 2, 3 and 4. In some embodiments of the lipid of Formula CAT-I, each a is the same. In some embodiments of the lipid of Formula CAT-I, each a is different.

[0288] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare -W1-X1-Y1. In some embodiments of the lipid of Formula CAT-I, W1-X1-Y1is defined as follows: each W1is independently selected from optionally substituted C1-20 alkyl and optionally substituted C2-20 alkenyl, each X1is independently selected from -*O-(C=O)-optionally substituted C1-20 alkyl, -(*C=O)-O-optionally substituted C1-20 alkyl, -*O-(C=O)-optionally substituted C2-20 alkenyl, and -(*C=O)-O-optionally substituted C2-20 alkenyl, wherein the atom marked with a * is connected to W1, each Y1is independently selected from hydrogen, -*O-(C=O)-optionally substituted C1-20 alkyl, -(*C=O)-O-optionally substituted C1-20 alkyl, -*O-(C=O)-optionally substituted C2-20 alkenyl, and -(*C=O)-O-optionally substituted C2-20 alkenyl, wherein the atom marked with a * is connected to X1.

[0289] In some embodiments of the lipid of Formula CAT-I, -W1-X1-Y1; is defined as follows: each W1is independently selected from optionally substituted CA-Balkyl and optionally substituted CC-Dalkenyl, each X1is independently selected from -*O-(C=O)-optionally substituted CA-Balkyl -(*C=O)-O-optionally substituted CA-Balkyl -*O-(C=O)-

[0290] 28

[0291] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0292] 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.

[0293] In some embodiments of the lipid of Formula CAT-I, CA-B is C1-20 and CC-D is C2-20. In some embodiments CA-B is C1-15 and 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 C3-15 and 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.

[0294] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently selected from optionally substituted C5-50 alkyl, optionally substituted C5-50 alkenyl, optionally substituted C5-50 alkynyl, optionally substituted C5-50 acyl, and -W1-X1-Y1, wherein -W1-X1-Y1is as defined herein.

[0295] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently selected from optionally substituted C5-50 alkyl, optionally substituted C5-50 alkenyl, optionally substituted C5-50 alkynyl, and optionally substituted C5-50 acyl.

[0296] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently selected from optionally substituted C5-30 alkyl, optionally substituted C5-30 alkenyl, optionally substituted C5-30 alkynyl, optionally substituted C5-30 acyl and -W1-X1-Y1, wherein -W1-X1-Y1is as defined herein.

[0297] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently selected from optionally substituted C5-30 alkyl, optionally substituted C5-30 alkenyl, optionally substituted C5-30 alkynyl, and optionally substituted C5-30 acyl.

[0298] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently selected from optionally substituted C5-20 alkyl, optionally substituted C5-20 alkenyl, optionally substituted C5-20 alkynyl, optionally substituted C5-20 acyl, and -W1-X1-Y1, wherein -W1-X1-Y1.

[0299] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently selected from optionally substituted C5-20 alkyl, optionally substituted C5-20 alkenyl, optionally substituted C5-20 alkynyl, and optionally substituted C5-20 acyl.

[0300] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently optionally substituted C5-50 alkyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently optionally substituted C5-30 alkyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently 29

[0301] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0302] optionally substituted C5-20 alkyl. In some embodiments of the lipid of Formula CAT-I, R1Aand RIBare each independently optionally substituted C5-15 alkyl.

[0303] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently C5-50 alkyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently C5-30 alkyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently C5-20 alkyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently C5-15 alkyl.

[0304] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently optionally substituted C5-50 alkenyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently optionally substituted C5-30 alkenyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently optionally substituted C5-20 alkenyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently optionally substituted C5-15 alkenyl.

[0305] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently C5-50 alkenyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently C5-30 alkenyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently C5-20 alkenyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently C5-15 alkenyl.

[0306] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently optionally substituted C5-50 alkynyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently optionally substituted C5-30 alkynyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently optionally substituted C5-20 alkynyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently optionally substituted C5-15 alkynyl.

[0307] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently C5-50 alkynyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently C5-30 alkynyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently C5-20 alkynyl. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare each independently C5-15 alkynyl.

[0308] In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare not optionally substituted. In some embodiments of the lipid of Formula CAT-I, each R1Ais the same. In some embodiments of the lipid of Formula CAT-I, each R1Ais different. In some embodiments of the lipid of Formula CAT-I, each R1Bis the same. In some embodiments of the lipid of Formula CAT-I, each R1Bis different. In some embodiments of the lipid of 30

[0309] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0310] Formula CAT -I, R1Aand RIBare the same. In some embodiments of the lipid of Formula CAT-I, R1Aand R1Bare different.

[0311] In embodiments, the substituents are not optionally substituted.

[0312] In some embodiments, the lipid of Formula CAT-I 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:

[0313]

[0314] In some embodiments, the lipid of Formula CAT-I is 2-(4-(3-((4-(bis((Z)-2-hydroxy octadec-9-en- 1 -yl)amino)butyl)disulfaneyl)propyl)piperazin- 1 -yl)ethyl 4-(bis(2-hydroxydecyl)amino)butanoate, having the following structure:

[0315]

[0316] In some embodiments, the lipid of Formula CAT-I is GL-HEPES-E3-E12-DS-4-E10 (2-(4-(2-((4-(bis(2-hydroxydecyl)amino)butyl)disulfaneyl)ethyl)piperazin-l-yl)ethyl 4-(bis(2-hydroxy dodecyl)amino)butanoate), having the following structure:

[0317]

[0318] 31

[0319] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0320] In some embodiments, the lipid of Formula CAT-I 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:

[0321]

[0322] In some embodiments, the lipid of Formula CAT-I is CL-B (2-(4-(4-((4-(bis((Z)-2-hydroxyoctadec-9-en- 1 -yl)amino)butyl)disulfaneyl)butyl)piperazin- 1 -yl)ethyl 4-(bis(2-hydroxydodecyl)amino)butanoate), having the following structure:

[0323]

[0324] OH Additional examples of ionizable and cationic lipids suitable for LNPs of the present disclosure are described in WO 2022221688, which is incorporated by reference herein in its entirety.

[0325] B. lonizable / Cationic Lipids of Formula (CAT-II)

[0326] In some embodiments, the ionizable or cationic lipid has a structure according to Formula CAT-II:

[0327] 32

[0328] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0329]

[0330] (CAT-II)

[0331] or a pharmaceutically acceptable salt thereof wherein:

[0332] 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-;

[0333] 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-;

[0334] each R is independently selected from:

[0335] O

[0336] ■

[0337]

[0338] v W

[0339] / b, wherein each R1is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0340]

[0341] 0H, 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

[0342] 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;

[0343] 33

[0344] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0345]

[0346] o, wherein each R3is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and

[0347]

[0348] R4

[0349] , wherein each R4is independently selected from optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

[0350] o

[0351] wherein at least three R are independently selected from (

[0352]

[0353] i) / b

[0354] (

[0355]

[0356] ii)0Hor (iii) ®;

[0357] each a is independently selected from 2, 3, 4, and 5;

[0358] each b is independently selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10; and

[0359] each c is independently selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0360] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIa):

[0361]

[0362] (CAT-IIa)

[0363] or a pharmaceutically acceptable salt thereof.

[0364] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIb):

[0365] 34

[0366] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0367]

[0368] OH (CAT-IIb)

[0369] 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 -W^X1,

[0370] wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and

[0371] 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.

[0372] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIb-i):

[0373]

[0374] 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 -W^X1,

[0375] 35

[0376] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0377] wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and

[0378] 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.

[0379] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIc-i):

[0380] OH

[0381]

[0382] OH

[0383] (CAT-IIc-i)

[0384] 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 -W^X1,

[0385] wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and

[0386] 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;

[0387] optionally wherein each a is independently selected from 3 or 4.

[0388] 36

[0389] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0390] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIc-ii):

[0391]

[0392] (CAT-IIc-ii)

[0393] 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;

[0394] optionally wherein i) each a is 2, and / or ii) each b is independently selected from 5 or 7.

[0395] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIc-iii):

[0396]

[0397] (CAT-IIc-iii)

[0398] 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;

[0399] optionally wherein i) each a is 3, and / or ii) each c is 6.

[0400] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIc-iv):

[0401] 37

[0402] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0403]

[0404] o (CAT-IIc-iv)

[0405] or a pharmaceutically acceptable salt thereof, wherein each R2A, R2Cand R2Dis independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W^X1,

[0406] wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and

[0407] 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;

[0408] optionally wherein each a is 3.

[0409] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IId):

[0410]

[0411] (CAT-IId)

[0412] or a pharmaceutically acceptable salt thereof.

[0413] 38

[0414] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0415] In embodiments, the cationic lipids of the present invention include compounds having a structure according to Formula (CAT-IIe):

[0416]

[0417] (CAT-IIe)

[0418] 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 -W^X1,

[0419] wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and

[0420] 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;

[0421] optionally wherein each a is independently selected from 3 or 4.

[0422] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIf-i):

[0423]

[0424] (CAT-IIf-i)

[0425] 39

[0426] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0427] 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 -W^X1,

[0428] wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and

[0429] 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;

[0430] optionally wherein each a is independently selected from 3 or 4.

[0431] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIf-ii):

[0432]

[0433] (CAT-IIf-ii)

[0434] 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;

[0435] optionally wherein each a is 2, and / or ii) each b is independently selected from 5 or 7. In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIg):

[0436] 40

[0437] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0438]

[0439] (CAT-IIg)

[0440] 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 -W^X1,

[0441] wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and

[0442] 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;

[0443] optionally wherein each a is 3.

[0444] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIh):

[0445]

[0446] (CAT-IIh)

[0447] 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 -W^X1,

[0448] 41

[0449] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0450] wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and

[0451] 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.

[0452] In embodiments, A1is -C(=O)NH-, wherein the left hand side of the recited structure is bound to the -(CH2)a-, and Z1is -NHC(=O)-, wherein the right hand side of the recited structure is bound to the -(CH2)a-; optionally wherein each a is 3.

[0453] In embodiments, A1is -OC(=O)NH-, wherein the left hand side of the recited structure is bound to the -(CH2)a-, and Z1is -NHC(=O)O-, wherein the right hand side of the recited structure is bound to the -(CH2)a-; optionally wherein each a is 3.

[0454] In embodiments, A1is -SC(=O)NH-, wherein the left hand side of the recited structure is bound to the -(CH2)a-, and Z1is -NHC(=O)S-, wherein the right hand side of the recited structure is bound to the -(CH2)a-; optionally wherein each a is 3.

[0455] In embodiments, A1is -C(=O)S-, wherein the left hand side of the recited structure is bound to the -(CH2)a-, and Z1is -SC(=O)-, wherein the right hand side of the recited structure is bound to the -(CH2)a-; optionally wherein each a is 3.

[0456] In embodiments, A1is -S-S-, and Z1is -S-S-; optionally wherein each a is 3.

[0457] In embodiments, A1is -S-, and Z1is -S-; optionally wherein each a is 4.

[0458] In embodiments, A1is -S-S-, and Z1is -SC(=O)-, wherein the right hand side of the recited structure is bound to the -(CH2)a-; optionally wherein each a is 3.

[0459] In embodiments, A1is -NHC(=O)O-, wherein the left hand side of the recited structure is bound to the -(CH2)a-, and Z1is -OC(=O)NH-, wherein the right hand side of the recited structure is bound to the -(CH2)a-; optionally wherein each a is 3.

[0460] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIi):

[0461] 42

[0462] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0463]

[0464] (CAT-IIi)

[0465] or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from:

[0466] O

[0467] (

[0468]

[0469] i) / b, wherein each R1is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0470] (

[0471]

[0472] ii)0H, 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

[0473] 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;

[0474]

[0475] (iii) °, wherein each R3is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0476] optionally wherein (i) each a is 3 or 4 and / or (ii) each b is 5, 6, or 7.

[0477] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0478] In embodiments, the cationic lipids of the present invention include compounds of Formula (I) having a structure according to Formula (CAT-IIj):

[0479]

[0480] (CAT-IIj)

[0481] 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;

[0482] optionally wherein (i) each a is 4, and / or (ii) each b is independently selected from 5 or 7.

[0483] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIk):

[0484] HO

[0485]

[0486] (CAT-IIk)

[0487] 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 -W^X1,

[0488] 44

[0489] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0490] wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and

[0491] 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;

[0492] optionally wherein each a is 3 or 4.

[0493] In some embodiments, the lipid of Formula CAT-II has a structure according to Formula (CAT-IIm):

[0494] H

[0495]

[0496] (CAT-IIm)

[0497] or a pharmaceutically acceptable salt thereof, wherein d is 0 or 1, and

[0498] 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

[0499] 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;

[0500] optionally wherein each a is 3 or 4.

[0501] In embodiments, A1and Z1are the same. In embodiments, A1and Z1are different. In embodiments, A1is -C(=O)O-, wherein the left hand side of the recited structure is bound to the -(CH2)a-. In embodiments, A1is -OC(=O)O-.

[0502] 45

[0503] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0504] In embodiments, A1is -C(=O)S-, wherein the left hand side of the recited structure is bound to the -(CH2)a-. In embodiments, A1is -C(=O)NH-, wherein the left hand side of the recited structure is bound to the -(CH2)a-. In embodiments, A1is -OC(=O)NH-, wherein the left hand side of the recited structure is bound to the -(CH2)a-. In embodiments, A1is -NHC(=O)O-, wherein the left hand side of the recited structure is bound to the -(CH2)a-. In embodiments, A1is -SC(=O)NH-, wherein the left hand side of the recited structure is bound to the -(CH2)a-. In embodiments, A1is -OCH2CH2O-. In embodiments, A1is -OCH2O-. In embodiments, A1is -OCH(CH3)O-. In embodiments, A1is -S-. In embodiments, A1is -S-S-.

[0505] In embodiments, Z1is -OC(=O)-, wherein the right hand side of the recited structure is bound to the -(CH2)a-. In embodiments, Z1is -OC(=O)O-.

[0506] In embodiments, Z1is -SC(=O)-, wherein the right hand side of the recited structure is bound to the -(CH2)a-. In embodiments, Z1is -NHC(=O)-, wherein the right hand side of the recited structure is bound to the -(CH2)a-. In embodiments, Z1is -NHC(=O)O-, wherein the right hand side of the recited structure is bound to the -(CH2)a-. In embodiments, Z1is -OC(=O)NH-, wherein the right hand side of the recited structure is bound to the -(CH2)a-. In embodiments, Z1is -NHC(=O)S-, wherein the right hand side of the recited structure is bound to the -(CH2)a-. In embodiments, Z1is -OCH2CH2O-. In embodiments, Z1is -OCH2O-. In embodiments, Z1is -OCH(CH3)O-. In embodiments, Z1is -S-. In embodiments, Z1is -S-S-.

[0507] In embodiments, each a is independently selected from 3 and 4. In embodiments, each a is 2. In embodiments, each a is 3. In embodiments, each a is 4. In embodiments, each a is 5. In embodiments, each a is different. In embodiments, the value for the a on the left hand side of the depicted Formula is 3 and the value for the a on the right hand side of the depicted Formula is 4. In embodiments, the value for the a on the left hand side of the depicted Formula is 4 and the value for the a on the right hand side of the depicted Formula is 3.

[0508] In embodiments, the value for the a on the left hand side of the depicted Formula is 2. In embodiments, the value for the a on the left hand side of the depicted Formula is 3. In embodiments, the value for the a on the left hand side of the depicted Formula is 4. In embodiments, the value for the a on the left hand side of the depicted Formula is 5.

[0509] In embodiments, the value for the a on the right hand side of the depicted Formula is 2. In embodiments, the value for the a on the right hand side of the depicted Formula is 3. In embodiments, the value for the a on the right hand side of the depicted Formula is 4. In embodiments, the value for the a on the right hand side of the depicted Formula is 5.

[0510] In embodiments, each b is independently selected from 5, 6, and 7. In embodiments, each b is independently selected from 5 and 7. In embodiments, each b is 2. In embodiments,

[0511] 46

[0512] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0513] each b is 3. In embodiments, each b is 4. In embodiments, each b is 5. In embodiments, each b is 6. In embodiments, each b is 7. In embodiments, each b is 8. In embodiments, each b is 9. In embodiments, each b is 10.

[0514] In embodiments, each c is 2. In embodiments, each c is 3. In embodiments, each c is 4. In embodiments, each c is 5. In embodiments, each c is 6. In embodiments, each c is 7. In embodiments, each c is 8. In embodiments, each c is 9. In embodiments, each c is 10.

[0515] In embodiments, each R4is optionally substituted cycloalkyl. In embodiments, each

[0516] R4is optionally substituted heterocycloalkyl. In embodiments, each

[0517]

[0518] R4is O In embodiments, each R is independently selected from:

[0519] O

[0520]

[0521] 'b, wherein each R1is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0522]

[0523] 0H, 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

[0524] 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; and

[0525]

[0526] , wherein each R3is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

[0527] 47

[0528] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0529] O

[0530] In embodiments, each R is independently selected from

[0531]

[0532] zb wherein each R1is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

[0533] In embodiments, each R1is the same. In embodiments, at least one R1is different. In embodiments, R1A, R1B, R1Cand R1Dare the same. In embodiments, R1Aand R1Bare the same. In embodiments, R1Cand R1Dare the same. In embodiments, R1Aand R1Care the same. In embodiments, R1Band R1Dare the same.

[0534] In embodiments, R1Aand R1Bare the same and R1Cand R1Dare the same, but wherein R1Aand R1Bare different to R1Cand R1D. In embodiments, R1Aand R1Care the same and R1Band R1Dare the same, but wherein R1Aand R1Care different to R1Band R1D.

[0535] In embodiments, each R1or each R1A, R1B, R1Cand R1D, when present, is independently selected from optionally substituted (C5-C25) alkyl, optionally substituted (C5-C25) alkenyl, and optionally substituted (C5-C25) alkynyl.

[0536] In embodiments, each R1or each R1A, R1B, R1Cand R1D, when present, is independently selected from optionally substituted alkyl. In embodiments, each R1or each R1A, R1B, R1Cand R1D, when present, is independently selected from optionally substituted (C5-C25) alkyl. In embodiments, each R1or each R1A, R1B, R1Cand R1D, when present, is independently selected from optionally substituted (C10-C20) alkyl.

[0537] In embodiments, each R1A, when present, is optionally substituted alkyl. In embodiments, each R1A, when present, is optionally substituted (C5-C25) alkyl. In embodiments, each R1A, when present, is optionally substituted (C10-C20) alkyl.

[0538] In embodiments, each R1B, when present, is optionally substituted alkyl. In embodiments, each R1B, when present, is optionally substituted (C5-C25) alkyl. In embodiments, each R1B, when present, is optionally substituted (C10-C20) alkyl.

[0539] In embodiments, each R1C, when present, is optionally substituted alkyl. In embodiments, each R1C, when present, is optionally substituted (C5-C25) alkyl. In embodiments, each R1C, when present, is optionally substituted (C10-C20) alkyl.

[0540] In embodiments, each R1D, when present, is optionally substituted alkyl. In embodiments, each R1D, when present, is optionally substituted (C5-C25) alkyl. In embodiments, each R1D, when present, is optionally substituted (C10-C20) alkyl.

[0541] 48

[0542] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0543] In embodiments, each R1or each R1A, R1B, R1Cand R1D, when present, is independently selected from optionally substituted alkenyl. In embodiments, each R1or each R1A, R1B, R1Cand R1D, when present, is independently selected from optionally substituted (C5-C25) alkenyl. In embodiments, each R1or each R1A, R1B, R1Cand R1D, when present, is independently selected from optionally substituted (C10-C20) alkenyl.

[0544] In embodiments, each R1A, when present, is optionally substituted alkenyl. In embodiments, each R1A, when present, is optionally substituted (C5-C25) alkenyl. In embodiments, each R1A, when present, is optionally substituted (C10-C20) alkenyl.

[0545] In embodiments, each R1B, when present, is optionally substituted alkenyl. In embodiments, each R1B, when present, is optionally substituted (C5-C25) alkenyl. In embodiments, each R1B, when present, is optionally substituted (C10-C20) alkenyl.

[0546] In embodiments, each R1C, when present, is optionally substituted alkenyl. In embodiments, each R1C, when present, is optionally substituted (C5-C25) alkenyl. In embodiments, each R1C, when present, is optionally substituted (C10-C20) alkenyl.

[0547] In embodiments, each R1D, when present, is optionally substituted alkenyl. In embodiments, each R1D, when present, is optionally substituted (C5-C25) alkenyl. In embodiments, each R1D, when present, is optionally substituted (C10-C20) alkenyl.

[0548] In embodiments, each R1or each R1A, R1B, R1Cand R1D, when present, is independently selected from optionally substituted alkynyl. In embodiments, each R1or each R1A, R1B, R1Cand R1D, when present, is independently selected from optionally substituted (C5-C25) alkynyl. In embodiments, each R1or each R1A, R1B, R1Cand R1D, when present, is independently selected from optionally substituted (C10-C20) alkynyl.

[0549] In embodiments, each R1A, when present, is optionally substituted alkynyl. In embodiments, each R1A, when present, is optionally substituted (C5-C25) alkynyl. In embodiments, each R1A, when present, is optionally substituted (C10-C20) alkynyl.

[0550] In embodiments, each R1B, when present, is optionally substituted alkynyl. In embodiments, each R1B, when present, is optionally substituted (C5-C25) alkynyl. In embodiments, each R1B, when present, is optionally substituted (C10-C20) alkynyl.

[0551] In embodiments, each R1C, when present, is optionally substituted alkynyl. In embodiments, each R1C, when present, is optionally substituted (C5-C25) alkynyl. In embodiments, each R1C, when present, is optionally substituted (C10-C20) alkynyl.

[0552] In embodiments, each R1D, when present, is optionally substituted alkynyl. In embodiments, each R1D, when present, is optionally substituted (C5-C25) alkynyl. In embodiments, each R1D, when present, is optionally substituted (C10-C20) alkynyl.

[0553] 49

[0554] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0555] In embodiments, each R1or each R1A, R1B, R1Cand R1D, when present, is independently selected from:

[0556]

[0557] , optionally wherein each R1or each R1A, R1B, R1Cand R1D, when present, is independently selected from options (i) and (ii).

[0558] In embodiments, each R1or each R1A, R1B, R1Cand R1D, when present, is

[0559]

[0560] . In embodiments, each R1or each R1A, R1B, R1Cand R1D, when present, is

[0561]

[0562] . In embodiments, each R1or each R1A,

[0563]

[0564]

[0565] embodiments, each R1A, when present, is

[0566] 50

[0567] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0568] In embodiments, each R1B, when present, is

[0569]

[0570] embodiments, each R1B, when present, is

[0571]

[0572]

[0573] each R2is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and -W1-X1,

[0574] wherein each W1is independently selected from optionally substituted alkylene and optionally substituted alkenylene, and

[0575] each X1is independently selected from -*O-(C=O)-optionally substituted alkyl, - (*C=O)-O-optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -

[0576] 51

[0577] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0578] (*C=O)-O-optionally substituted alkenyl, wherein the atom marked with a * is connected to W1.

[0579] In embodiments, each R2is the same. In embodiments, at least one R2is different. In embodiments, R2A, R2B, R2Cand R2Dare the same. In embodiments, R2Aand R2Bare the same. In embodiments, R2Cand R2Dare the same. In embodiments, R2Aand R2Care the same. In embodiments, R2Band R2Dare the same.

[0580] In embodiments, R2Aand R2Bare the same and R2Cand R2Dare the same, but wherein R2Aand R2Bare different to R2Cand R2D. In embodiments, R2Aand R2Care the same and R2Band R2Dare the same, but wherein R2Aand R2Care different to R2Band R2D.

[0581] In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from optionally substituted (C5-C25) alkyl, optionally substituted (C5-C25) alkenyl, optionally substituted (C5-C25) alkynyl, and -W1-X1,

[0582] wherein each W1is independently selected from optionally substituted (C1-C10) alkylene and optionally substituted (C2-C10) alkenylene, and

[0583] each X1is independently selected from -*O-(C=O)-optionally substituted (C5-C25) alkyl, -(*C=O)-O-optionally substituted (C5-C25) alkyl, -*O-(C=O)-optionally substituted (C5-C25) alkenyl, and -(*C=O)-O-optionally substituted (C5-C25) alkenyl, wherein the atom marked with a * is connected to W1.

[0584] In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from optionally substituted (C5-C25) alkyl, for example optionally substituted (C5-C20) alkyl, and -W^X1,

[0585] wherein each W1is independently selected from optionally substituted (C1-C10) alkylene, for example optionally substituted (C2-C6) alkylene, and optionally substituted (C2-C10) alkenylene, for example optionally substituted (C2-C6) alkenylene, and

[0586] each X1is independently selected from -*O-(C=O)-optionally substituted (C5-C25) alkyl, for example -*O-(C=O)-optionally substituted (C8-C20) alkyl, -(*C=O)-O-optionally substituted (C5-C25) alkyl, for example -(*C=O)-O-optionally substituted (C8-C20) alkyl, -*O-(C=O)-optionally substituted (C5-C25) alkenyl, for example -*O-(C=O)-optionally substituted (C8-C20) alkenyl, and -(*C=O)-O-optionally substituted (C5-C25) alkenyl, for example -(*C=O)-O-optionally substituted (C8-C20) alkenyl, wherein the atom marked with a * is connected to W1.

[0587] In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from optionally substituted alkyl and -W1-X1, optionally wherein each W1is independently selected from optionally substituted alkylene, and

[0588] 52

[0589] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0590] each X1is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)-O-optionally substituted alkyl, and -(*C=O)-O-optionally substituted alkenyl, wherein the atom marked with a * is connected to W1.

[0591] In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from optionally substituted alkyl. In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from optionally substituted (C5-C25) alkyl. In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from optionally substituted (C5-C20) alkyl.

[0592] In embodiments, each R2A, when present, is optionally substituted alkyl. In embodiments, each R2A, when present, is optionally substituted (C5-C25) alkyl. In embodiments, each R2A, when present, is optionally substituted (C5-C20) alkyl.

[0593] In embodiments, each R2B, when present, is optionally substituted alkyl. In embodiments, each R2B, when present, is optionally substituted (C5-C25) alkyl. In embodiments, each R2B, when present, is optionally substituted (C5-C20) alkyl.

[0594] In embodiments, each R2C, when present, is optionally substituted alkyl. In embodiments, each R2C, when present, is optionally substituted (C5-C25) alkyl. In embodiments, each R2C, when present, is optionally substituted (C5-C20) alkyl.

[0595] In embodiments, each R2D, when present, is optionally substituted alkyl. In embodiments, each R2D, when present, is optionally substituted (C5-C25) alkyl. In embodiments, each R2D, when present, is optionally substituted (C5-C20) alkyl.

[0596] In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from optionally substituted alkenyl. In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from optionally substituted (C5-C25) alkenyl.

[0597] In embodiments, each R2A, when present, is optionally substituted alkenyl. In embodiments, each R2A, when present, is optionally substituted (C5-C25) alkenyl.

[0598] In embodiments, each R2B, when present, is optionally substituted alkenyl. In embodiments, each R2B, when present, is optionally substituted (C5-C25) alkenyl.

[0599] In embodiments, each R2C, when present, is optionally substituted alkenyl. In embodiments, each R2C, when present, is optionally substituted (C5-C25) alkenyl.

[0600] In embodiments, each R2D, when present, is optionally substituted alkenyl. In embodiments, each R2D, when present, is optionally substituted (C5-C25) alkenyl.

[0601] In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from optionally substituted alkynyl. In embodiments, each R2or each 53

[0602] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0603] R2A, R2B, R2Cand R2D, when present, is independently selected from optionally substituted (C5-C25) alkynyl.

[0604] In embodiments, each R2A, when present, is optionally substituted alkynyl. In embodiments, each R2A, when present, is optionally substituted (C5-C25) alkynyl.

[0605] In embodiments, each R2B, when present, is optionally substituted alkynyl. In embodiments, each R2B, when present, is optionally substituted (C5-C25) alkynyl.

[0606] In embodiments, each R2C, when present, is optionally substituted alkynyl. In embodiments, each R2C, when present, is optionally substituted (C5-C25) alkynyl.

[0607] In embodiments, each R2D, when present, is optionally substituted alkynyl. In embodiments, each R2D, when present, is optionally substituted (C5-C25) alkynyl.

[0608] In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from -W^X1.

[0609] In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from -W^X1, wherein

[0610] each W1is independently selected from optionally substituted alkylene, and each X1is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)-O-optionally substituted alkyl, and -(*C=O)-O-optionally substituted alkenyl, wherein the atom marked with a * is connected to W1.

[0611] In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from -W^X1,

[0612] wherein each W1is independently selected from optionally substituted (C1-C10) alkylene and optionally substituted (C2-C10) alkenylene, and

[0613] each X1is independently selected from -*O-(C=O)-optionally substituted (C5-C25) alkyl, -(*C=O)-O-optionally substituted (C5-C25) alkyl, -*O-(C=O)-optionally substituted (C5-C25) alkenyl, and -(*C=O)-O-optionally substituted (C5-C25) alkenyl, wherein the atom marked with a * is connected to W1.

[0614] In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from -W^X1,

[0615] wherein each W1is independently selected from optionally substituted (C1-C10) alkylene, for example optionally substituted (C2-C6) alkylene, and optionally substituted (C2-C10) alkenylene, for example optionally substituted (C2-C6) alkenylene, and

[0616] each X1is independently selected from -*O-(C=O)-optionally substituted (C5-C25) alkyl, for example -*O-(C=O)-optionally substituted (C8-C20) alkyl, -(*C=O)-O-optionally substituted (C5-C25) alkyl, for example -(*C=O)-O-optionally substituted (C8-C20) alkyl, -*O- 54

[0617] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0618] (C=O)-optionally substituted (C5-C25) alkenyl, for example -*O-(C=O)-optionally substituted (C8-C20) alkenyl, and -(*C=O)-O-optionally substituted (C5-C25) alkenyl, for example -(*C=O)-O-optionally substituted (C8-C20) alkenyl, wherein the atom marked with a * is connected to W1.

[0619] In embodiments, each R2A, when present, is -W1-X1.

[0620] In embodiments, each R2B, when present, is -W1-X1.

[0621] In embodiments, each R2C, when present, is -W1-X1.

[0622] In embodiments, each R2D, when present, is -W1-X1.

[0623] In embodiments, each W1is independently selected from optionally substituted alkylene. In embodiments, each W1is independently selected from optionally substituted (C1-C10) alkylene. In embodiments, each W1is independently selected from optionally substituted (C2-C6) alkylene.

[0624] In embodiments, each W1is independently selected from optionally substituted alkenylene. In embodiments, each W1is independently selected from optionally substituted (C2-C10) alkenylene. In embodiments, each W1is independently selected from optionally substituted (C2-C6) alkenylene.

[0625] In embodiments, each X1is independently selected from -*O-(C=O)-optionally substituted alkyl, wherein the atom marked with a * is connected to W1. In embodiments, each X1is independently selected from -*O-(C=O)-optionally substituted (C5-C25) alkyl, wherein the atom marked with a * is connected to W1. In embodiments, each X1is independently selected from -*O-(C=O)-optionally substituted (C8-C20) alkyl, wherein the atom marked with a * is connected to W1.

[0626] In embodiments, each X1is independently selected from -(*C=O)-O-optionally substituted alkyl, wherein the atom marked with a * is connected to W1. In embodiments, each X1is independently selected from -(*C=O)-O-optionally substituted (C5-C25) alkyl, wherein the atom marked with a * is connected to W1. In embodiments, each X1is independently selected from -(*C=O)-O-optionally substituted (C8-C20) alkyl, wherein the atom marked with a * is connected to W1.

[0627] In embodiments, each X1is independently selected from -*O-(C=O)-optionally substituted alkenyl, wherein the atom marked with a * is connected to W1. In embodiments, each X1is independently selected from -*O-(C=O)-optionally substituted (C5-C25) alkenyl, wherein the atom marked with a * is connected to W1. In embodiments, each X1is independently selected from -*O-(C=O)-optionally substituted (C8-C20) alkenyl, wherein the atom marked with a * is connected to W1.

[0628] 55

[0629] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0630] In embodiments, each X1is independently selected from -(*C=O)-O-optionally substituted alkenyl, wherein the atom marked with a * is connected to W1. In embodiments, each X1is independently selected from -(*C=O)-O-optionally substituted (C5-C25) alkenyl, wherein the atom marked with a * is connected to W1. In embodiments, each X1is independently selected from -(*C=O)-O-optionally substituted (C8-C20) alkenyl, wherein the atom marked with a * is connected to W1.

[0631] In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is independently selected from:

[0632]

[0633] In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is

[0634] . In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is. In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present,

[0635]

[0636] is In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is

[0637]

[0638] In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is

[0639]

[0640] jnembodiments, each R2or each R2A,

[0641] 56

[0642] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0643] R2B, R2Cand R2D, when present, is

[0644]

[0645] . In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is

[0646] o. In embodiments, each R2or each R2A, R2B,

[0647]

[0648] R2Cand R2D, when present, is O. In embodiments, each R2or each R2A, R2B, R2Cand R2D, when present, is

[0649] o. In embodiments, each R2or each

[0650]

[0651] R2A, R2B, R2Cand R2D, when present, is

[0652] In embodiments, each R2A, when present, is

[0653]

[0654] . In embodiments, each R2A, when present, is

[0655]

[0656] . In embodiments, each R2A, when present, is. In embodiments, each R2A, when present, is

[0657] . In embodiments, each R2A, when present, is

[0658] . In embodiments, each R2A, when present, is

[0659]

[0660] . In embodiments, each R2A, when present, is

[0661] . In embodiments, each R2A, when present, is

[0662] . In embodiments, each R2A, when present, is

[0663] . In embodiments, each R2A, when

[0664]

[0665] present, is

[0666] 57

[0667] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0668] In embodiments, each R2B, when present, is. In embodiments, each R2B, when present, is

[0669]

[0670] . In embodiments, each R2B, when present, is. In embodiments, each R2B, when present, is. In embodiments, each R2B, when present, is

[0671] . In embodiments, each R2B, when present, is

[0672]

[0673] . In embodiments, each R2B, when present, is

[0674] . In embodiments, each R2B, when present, is

[0675] . In embodiments, each R2B, when present, is

[0676] . In embodiments, each R2B, when

[0677]

[0678] present, is

[0679] In embodiments, each R2C, when present, is

[0680]

[0681] . In embodiments, each R2C, when present, is

[0682]

[0683] . In embodiments, each R2C, when present, is. In embodiments, each R2C, when present, is. In embodiments, each R2C, when present, is

[0684] . In embodiments, each R2C, when present, is

[0685]

[0686] . In embodiments, each R2C, when present, is

[0687] . In embodiments, each R2C, when present, is

[0688]

[0689] 0. In embodiments, each R2C, when present, is

[0690] 58

[0691] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0692] . In embodiments, each R2C, when

[0693]

[0694] In embodiments, each R2D, when present, is

[0695]

[0696] . In embodiments, each R2D, when present, is

[0697]

[0698] . In embodiments, each R2D, when present, is. In embodiments, each R2D, when present, is. In embodiments, each R2D, when present, is

[0699] . In embodiments, each R2D, when present, is

[0700]

[0701] . In embodiments, each R2D, when present, is

[0702] . In embodiments, each R2D, when present, is

[0703] °. In embodiments, each R2D, when present, is

[0704] . In embodiments, each R2D, when

[0705]

[0706] present, is

[0707]

[0708] In embodiments, each R is independently selected from wherein each R3is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

[0709] In embodiments, each R3is the same. In embodiments, at least one R3is different. In embodiments, R3A, R3B, R3Cand R3Dare the same. In embodiments, R3Aand R3Bare the same. In embodiments, R3Cand R3Dare the same. In embodiments, R3Aand R3Care the same. In embodiments, R3Band R3Dare the same.

[0710] 59

[0711] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0712] In embodiments, R3Aand R3Bare the same and R3Cand R3Dare the same, but wherein R3Aand R3Bare different to R3Cand R3D. In embodiments, R3Aand R3Care the same and R3Band R3Dare the same, but wherein R3Aand R3Care different to R3Band R3D.

[0713] In embodiments, each R3or each R3A, R3B, R3Cand R3D, when present, is independently selected from optionally substituted (C5-C25) alkyl, optionally substituted (C5-C25) alkenyl, and optionally substituted (C5-C25) alkynyl.

[0714] In embodiments, each R3or each R3A, R3B, R3Cand R3D, when present, is independently selected from optionally substituted alkyl. In embodiments, each R3or each R3A, R3B, R3Cand R3D, when present, is independently selected from optionally substituted (C5-C25) alkyl. In embodiments, each R3or each R3A, R3B, R3Cand R3D, when present, is independently selected from optionally substituted (C10-C20) alkyl.

[0715] In embodiments, each R3A, when present, is optionally substituted alkyl. In embodiments, each R3A, when present, is optionally substituted (C5-C25) alkyl. In embodiments, each R3A, when present, is optionally substituted (C10-C20) alkyl.

[0716] In embodiments, each R3B, when present, is optionally substituted alkyl. In embodiments, each R3B, when present, is optionally substituted (C5-C25) alkyl. In embodiments, each R3B, when present, is optionally substituted (C10-C20) alkyl.

[0717] In embodiments, each R3C, when present, is optionally substituted alkyl. In embodiments, each R3C, when present, is optionally substituted (C5-C25) alkyl. In embodiments, each R3C, when present, is optionally substituted (C10-C20) alkyl.

[0718] In embodiments, each R3D, when present, is optionally substituted alkyl. In embodiments, each R3D, when present, is optionally substituted (C5-C25) alkyl. In embodiments, each R3D, when present, is optionally substituted (C10-C20) alkyl.

[0719] In embodiments, each R3or each R3A, R3B, R3Cand R3D, when present, is independently selected from optionally substituted alkenyl. In embodiments, each R3or each R3A, R3B, R3Cand R3D, when present, is independently selected from optionally substituted (C5-C25) alkenyl. In embodiments, each R3or each R3A, R3B, R3Cand R3D, when present, is independently selected from optionally substituted (C10-C20) alkenyl.

[0720] In embodiments, each R3A, when present, is optionally substituted alkenyl. In embodiments, each R3A, when present, is optionally substituted (C5-C25) alkenyl. In embodiments, each R3A, when present, is optionally substituted (C10-C20) alkenyl.

[0721] In embodiments, each R3B, when present, is optionally substituted alkenyl. In embodiments, each R3B, when present, is optionally substituted (C5-C25) alkenyl. In embodiments, each R3B, when present, is optionally substituted (C10-C20) alkenyl.

[0722] 60

[0723] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0724] In embodiments, each R3C, when present, is optionally substituted alkenyl. In embodiments, each R3C, when present, is optionally substituted (C5-C25) alkenyl. In embodiments, each R3C, when present, is optionally substituted (C10-C20) alkenyl.

[0725] In embodiments, each R3D, when present, is optionally substituted alkenyl. In embodiments, each R3D, when present, is optionally substituted (C5-C25) alkenyl. In embodiments, each R3D, when present, is optionally substituted (C10-C20) alkenyl.

[0726] In embodiments, each R3or each R3A, R3B, R3Cand R3D, when present, is independently selected from optionally substituted alkynyl. In embodiments, each R3or each R3A, R3B, R3Cand R3D, when present, is independently selected from optionally substituted (C5-C25) alkynyl. In embodiments, each R3or each R3A, R3B, R3Cand R3D, when present, is independently selected from optionally substituted (C10-C20) alkynyl.

[0727] In embodiments, each R3A, when present, is optionally substituted alkynyl. In embodiments, each R3A, when present, is optionally substituted (C5-C25) alkynyl. In embodiments, each R3A, when present, is optionally substituted (C10-C20) alkynyl.

[0728] In embodiments, each R3B, when present, is optionally substituted alkynyl. In embodiments, each R3B, when present, is optionally substituted (C5-C25) alkynyl. In embodiments, each R3B, when present, is optionally substituted (C10-C20) alkynyl.

[0729] In embodiments, each R3C, when present, is optionally substituted alkynyl. In embodiments, each R3C, when present, is optionally substituted (C5-C25) alkynyl. In embodiments, each R3C, when present, is optionally substituted (C10-C20) alkynyl.

[0730] In embodiments, each R3D, when present, is optionally substituted alkynyl. In embodiments, each R3D, when present, is optionally substituted (C5-C25) alkynyl. In embodiments, each R3D, when present, is optionally substituted (C10-C20) alkynyl.

[0731] In embodiments, each R3or each R3A, R3B, R3Cand R3D, when present, is independently selected from:

[0732] , or

[0733]

[0734] , optionally wherein each R3or each R3A, R3B, R3Cand R3D, when present, is option (iii).

[0735] 61

[0736] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT In embodiments, each R3or each R3A, R3B, R3Cand R3D, when present, is

[0737]

[0738] . In embodiments, each R3or each R3A, R3B, R3Cand R3D, when present, is

[0739]

[0740] . In embodiments, each R3or each R3A,

[0741]

[0742] R3B, R3Cand R3D, when present, is

[0743]

[0744] In embodiments, each R3A, when present, is. In embodiments, each R3A, when present, is

[0745]

[0746] . In

[0747] embodiments, each R3A, when present,

[0748]

[0749] is

[0750]

[0751] In embodiments, each R3B, when present, is. In embodiments, each R3B, when present, is

[0752]

[0753] . In

[0754] embodiments, each R3B, when present,

[0755]

[0756] is

[0757]

[0758] In embodiments, each R3C, when present, is. In embodiments, each R3C, when present, is

[0759]

[0760] . In

[0761] embodiments, each R3C, when present,

[0762]

[0763] is

[0764] 62

[0765] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0766] \

[0767] I

[0768] \ \;. j

[0769] o z —x

[0770] / / < ( x

[0771] ) >

[0772] In embodiments, the subst ( < Oi -— / tuents are not optionally substituted.

[0773] Xo z—

[0774] In some embodiments, the ionizable or cationic lipid has a structure selected from the group consisting of:

[0775] <^ o °

[0776] ^< O= \^o- OH

[0777] / x Z\ xx, OH "\ O'!

[0778] r H, Px0>x^x^X^x^ <z

[0779] CII-1 ^01p o

[0780] j ) II A >

[0781] x 0 H 1, IH0-'K / \^x / x^x O / \ T PZ

[0782] ^o-— H~“

[0783] )7

[0784] O

[0785] O / / .””

[0786] ! v>

[0787] CII-2 < <

[0788] i > ) 1 _

[0789] } >

[0790] \ \

[0791] OH < < / x xOH 1

[0792] T H„ Px Q

[0793] CII-3

[0794] ° -0 H i

[0795] OH

[0796] CII-4

[0797]

[0798] 63

[0799] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0800] o

[0801] J 1

[0802] CII-5 V "y-q OH

[0803] OH O-A ) A zx zx / X z-v.z'

[0804] H i r

[0805] 0xZ\ A

[0806] r i

[0807] 0 z-k Z\ z\ Z\ z~x Z\ z' OH

[0808] . v

[0809] ^ ^

[0810] CII-6 OH H ^ ^

[0811] O / 'k ■ Z^x,z'A,

[0812] ^ ^

[0813] H CII-7 X / X-7"'"- •• ■"''■ •'• "'■■ •■'"" '•■■' ■'OH ^A' A

[0814] OH

[0815] OH

[0816] \

[0817] A A A CII-8 y.-.qQH

[0818] H' r

[0819] O

[0820] L A CII-9 j A

[0821] j

[0822] ^ ^ ^^

[0823] OHOZV0- Xz^xzZX / X / yOx / Xz^xAoO HO. J OH

[0824] CII-10 6 0 N zx A A A I

[0825] A

[0826]

[0827] 64

[0828] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT O OH

[0829] . A X X

[0830] O' O

[0831] „N,, / x A

[0832] .,... A _.1 ' '

[0833] CII-11 xx x / 0- v -0H / x

[0834] \,0 / OH O ''

[0835] H Q A X„X x,x i JA - -,x -• J. A.

[0836] ° ' HO' 1 XX-, X,x1’ Q-. Xx- V XX- Xx X. X

[0837] _ J

[0838] CII-12 'x. x-XxX~x. / X^.. X X A. x-,x Jx,, KA

[0839] \? OH A A. AxvxA-A ' ■ A \. ■, ■..., I •. ■. ■ - •X? X- Xff‘. X rC‘

[0840] X x-X xx„ XX x x->x X I kJ, '

[0841] CII-13 - - - - - ¥ - - - AA - <^x^

[0842] ■ i V A / X. x-X X‘x A x-x x-. x'X. X kA '1'..

[0843] >«-^x.x^x.~x. -..,.,--. '

[0844] ~ OH 0

[0845] 1; - '-' X 0

[0846] 0 HO..L

[0847] h

[0848] _,o.

[0849] X. x-'x x-X, x-=X -O. x-x., x-X A

[0850] CII-14 x X- X- X}fx -XOx / OH

[0851] '\ xl XX XX.,.x^ X- O 1- 0 '-• XX.1 xxx A

[0852] °' ~ 1.,.

[0853] HO" '■•-"v'x' \z

[0854] -X x-Xxx^X x<=Xx. x0-.. x-Xxx^X x-XxOH

[0855] V] H. O~, OH

[0856] ° K 1 — A l! °> 1 A A A, O A f ' / v-x - x-.^ x- / CII-15 -X X X-X^ -x-'X X Z=\ X, AXKZ\ X. / x XvX-X-xYxx’ 0 A O)' H A j -^x'? A.

[0857] O OH J HO" ^^S / X^z^x /

[0858]

[0859] 65

[0860] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT OH O

[0861] •x~ „,.0Ol~ \ |j >

[0862] [1.. H, O / / CII-16 1 ' Y ' ■ Y O \ \

[0863] o -0 H 1 11...

[0864] [f 1 HO'' O'

[0865] 0 OH ( (

[0866] . G P ) X° - d

[0867] x OZ.—' ’

[0868] T CII-17

[0869] Xo= Y...

[0870] J\Lc> °

[0871] o — - / \

[0872] \ T ' ' o p

[0873] X \ O i °

[0874] .. j..

[0875] _1 °

[0876] YYJC' “ ~ X \ /

[0877] o

[0878] CII-18 / \ \ r r° o

[0879] uh..

[0880] \ \ / °x—

[0881] s?X... 7 I X X > XC o

[0882] \ 1' x _

[0883] X / d ft

[0884] / YY p X o“ XQ=

[0885] o

[0886] CII-19 1> O X — \

[0887] \ S Y / o —

[0888] ;r\ \

[0889] $ \

[0890] / /

[0891] 1 _

[0892] CII-20 \

[0893] CII-21

[0894]

[0895] 66

[0896] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0897] OH

[0898] 1 H O-, o X\ / X / \ZXZ'''v / i

[0899] CII-22

[0900] 1)

[0901] > 0 -Q H 1 „ _, <

[0902] / / OH

[0903] 1 < d 7 s7- O z— 7 >

[0904] ; <1

[0905] ' 0' \"

[0906] CII-23 ^ a=s

[0907] J \ p

[0908] 7 ( O — — /

[0909] vr \ / \ T

[0910] 17 O --- ) 2 T \

[0911] AK <

[0912] T

[0913] 4 o o

[0914] o o V^

[0915] b

[0916] CII-24

[0917] ? f \“ o '

[0918] AO\ / ' / o' XX _

[0919] L / 's\ d X _

[0920] / \ p Iz“ d yo=

[0921] ^O■

[0922] V CII-25 ( T

[0923] O

[0924] Vg r

[0925] 77^

[0926] \ > /

[0927] OH

[0928] H oH0' \ <

[0929] CII-26 b. / X / vAXx, J

[0930] li b o N

[0931] OH OH

[0932] -•,OHt

[0933] i H, p—; 0 K

[0934] CII-27 ' ' N - 'OV' '\ d ■ A.- -.. N

[0935] O LOAH°V” 1

[0936] : HO '' '-' ' ' '" "''"' OH

[0937] OH

[0938] 0 QHO

[0939] CII-28

[0940] O -O H

[0941] OH

[0942]

[0943] 67

[0944] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0945] OH

[0946] Y^x^^^x^-'-x^x-x^x-x^x-x '0H[

[0947] -'•' ■-■ yH 0 Qy\Z\zX / \z\zAx / '\ / ' CII-29 ii-xyOy-.OJI^

[0948] 0W H J

[0949] T HO'' \ / \ / V'X / X / Xx-Xx-' OH OH

[0950] x, x-,, x..x, x-...-x.x-, xx. OH:

[0951] ' " " '' T H pY 0

[0952] CII-30 " V -■■•'' 'Yr'%'Y,..xP

[0953] o W H i.z..

[0954] i HO' •■ ' ' OH OH

[0955] X'"'V""'' P Hz0 0HY<'-xzxx,^^

[0956] CII-31 P'^ / s'x. OVA J„ JI J

[0957] 0 >-d'H

[0958] 6H

[0959] OH

[0960] z-., x'x, xx x*x x-x xO., xx. xx. -OH:

[0961] " •-• [f '- Y H„0 / X / x^X / X, /

[0962] O x—x xCk X 1! 1

[0963] CII-32 N - If V \x-'!x-x... Nx / XZK / X / YA / V / Y / X Z1°l’"p H:

[0964] r if i

[0965] . XX.ZX „-.xo OH

[0966] OH 0 P''-. X'^xzX-'x,x". X....... x...^.... ^. O.... X...z0H;:: J ' ' ’ ' ' H ' 1 H„ P"i 0 ' ' c " ' ' CII-330• ■ ' -X '\.x.;> 1;..

[0967] 'J <; ■ r: o' x' 'x "x0

[0968] xx..xx, xX........ xO. X-....... • •.. X 0 Q H i i;

[0969] 1 11 ' 1 HO’ " " ■'••"' " ' ' " '’O'" " '...• ■ '... ' ' -x ' - xx....x..........:0 OH

[0970] --x / x^ ^

[0971] J Cx XX O V? y-Xx^'x^x^ CII-34 N sx Yu*r' \ xJX. xK X-X -N,

[0972] - "xxx nO-^X-x^XX^.x.-'X A j A 0 1 x,dXHO "-' > 1..

[0973] O OH

[0974] X...... X..... x.. o....... x„ X.,0H 9H9

[0975] O l,.. X,XXP.C;'‘I 9, X-,, XX,. X^..xA&^^

[0976] CII-35 N - X 'S' \zX x.-X. X, H

[0977] -x,^ 6 M -H ° - - 5 „

[0978] 6 OHHC* '0

[0979]

[0980] 68

[0981] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[0982] L - A

[0983] 'N' 0 O

[0984] J! H

[0985] CII-36 CP* OH

[0986] OH O~X A /

[0987] ”O.^.O....'....'T.;

[0988] HCA

[0989] k...^ A

[0990] N O' O

[0991] C,.......... J J

[0992] CII-37H

[0993] ■'" ■-■' ■-.•• -- Y < y- q OH

[0994] OH 0 C ) A.-......,-,............

[0995] H i (

[0996] o.,o „.ry

[0997] S. HO' I x,......,. ~....-.. _

[0998] OH

[0999] o

[1000] f ■^^'•^'0 0

[1001] CII-38 \ A AT'”HO

[1002] OAA

[1003] V.. A

[1004] OH

[1005] 'A.-"..-"'..--'.O

[1006] .. -..........1. V k '--'■......,.x> O

[1007] DrN— < Ao

[1008] ........ ~...........0.,.. J z I • H...o

[1009] CII-39 o - 4< £ A. O,..'■•.

[1010] r - r ' ■'■ ••■ ••■ ■•• ■■ o„,o.. o

[1011] L _...

[1012] ■ I VXX '

[1013] OH < " OHH0^o

[1014] J y

[1015] CII-40 IT i Ak

[1016] ° "-0 HH0J

[1017]

[1018] 69

[1019] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1020] OH

[1021] / X / Xx'X / 'Xz'X. OH [

[1022] I I H H. O-^ o / \xzX / X / VzX /

[1023] CII-41 / /

[1024] ( < Y^V'rV

[1025] ^ xx ) X \.-x, z^x > 0 'H H!

[1026] ( (■ < < i ^A^'X / 'X / ^XZ

[1027] X \ \ X OH

[1028] ) )

[1029] 7 / ( <

[1030] X X

[1031] > ) X \ \ \ x \ X

[1032] / /

[1033] CII-42 k Co / x / T!o z / / — 0 x...........7 X X / " T* \ \ 02— X I \ /

[1034] / X

[1035] d

[1036] \( o= z

[1037] cn zi

[1038] OH P

[1039] 'X / X / W x / X? h HY—X rO V q

[1040] CII-43 \ / ± "o _

[1041] : n X ' \f 1' □N IZ _ S-' N

[1042] 0k-o' H H Vofi ( X q cn rv'

[1043] / OH

[1044] \

[1045] 7

[1046] X-\ x- 7 / X OH

[1047] x X-X. _x\XOH p Xz / • i

[1048] "vT H P^0O z:

[1049] x-,

[1050] < / X -S', >1 IS J ( o— —

[1051] CII-44 N -' Y V V -A^zxA X )

[1052] ' r pi

[1053] x^x.xX-X^x>X^.x-'X_,^.^x-' O '" 0 H! X X

[1054] ) )

[1055] OH? / ( <

[1056] ? <

[1057] < <

[1058] / / CII-45 ( < X \

[1059] 1 _

[1060] OH

[1061] x-X xX ZX x-X,0H j

[1062] CII-46 ~ I Z. s.MX°- 1

[1063] N r' \-" -R'^x / 's'

[1064] / 'x.^\.zx'x^.z'x^x-^^>l-c / H J

[1065] JHQX X / X^Xx-^sz^XZ OH

[1066]

[1067] 70

[1068] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1069] OH

[1070] ^x x-'x x-x x-x / x, OH ■

[1071] I,s.Hx°n g pzxx^ s / CII-47

[1072] / -x x-^ x-x..> -"0 H

[1073] OH

[1074] H CII-48 [ [ X

[1075] L

[1076] 1 1 J —

[1077] _ _ A,-. J I

[1078] CII-49

[1079] XX J x>

[1080] r r _,. Y1 ~X '■' _ ^ XX XXX j

[1081] XXXXJX^..

[1082] CII-50 - x x I Xj j f

[1083] L X w W

[1084] CII-51 y

[1085]

[1086] 71

[1087] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1088] jj

[1089] CII-52 y

[1090] CII-53 ) > O — \— - ^X1o z

[1091] o

[1092] X A CII-54

[1093] r Y exyx °>

[1094] \ / ' T _

[1095] o

[1096] X - °z^\

[1097] CII-55 ' / ) Xo — / / i

[1098] ^

[1099] CII-56

[1100] AZXXAO^^OH?H9 CII-57 x^x o Xx / Akoi?

[1101] o ''O H0

[1102] x vH0'^^° cCCX

[1103]

[1104] 72

[1105] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1106] ° °H

[1107] _0MA 0 HO. \ CII-58

[1108] 0 A / -\A OH A o L 0 A H ° N-0

[1109] OH o XZZXZX^XZZ'

[1110] T H AAo

[1111] CII-591o -- oJ HAI \ n r

[1112] ck o k

[1113] ) >o —- \

[1114] o

[1115] OH

[1116] T / \'

[1117] A 0 OH

[1118] X°oX

[1119] \ / ' o A _

[1120] CII-60

[1121] 5 <

[1122] Q °-O

[1123] \'' l _

[1124] OH

[1125] o ■ OH

[1126] CII-61rN-A -oA j 1 ) / > o ——

[1127] '~X’'°Y^^N'I A ) / o — / / i

[1128] 0H0'''''X^ / '\^^

[1129] CII-62

[1130] CII-63

[1131] ^

[1132] CII-64 9 ° o0

[1133] ^ ^ ^A ^ ^ A ^^ ^^ A

[1134]

[1135] 73

[1136] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1137] OH

[1138] / X / X / X / V / V / OH 1

[1139] TH, P-i o

[1140] CII-65 o \

[1141] 0 <0' H 1 ( \o=

[1142] OH \(o=

[1143] / / i

[1144] \ \ / ° —

[1145] CII-66

[1146] J’

[1147] 9

[1148] / ' \i

[1149] CII-67 JN^ ^ X° °

[1150] oOYL--oV _ l \ / 'X

[1151] H 'O^^''N LJ

[1152] o

[1153] OH I OH

[1154] 0 0HJ

[1155] \ / A * °

[1156] CII-68 9Z

[1157] / / ° —zJ I

[1158] °LoXa 0

[1159] OH O

[1160] / / °

[1161] < O

[1162] | OH 0

[1163] 0 J H, P-, o X 1^X^X'gX 1 ^X^X / X^X CII-69 °xN I '^ II °vX xj,^ '0Jxx / ^Xxz^Nx\nQ V^ / x 0 *—OH 1 n

[1164] [] |HO / x^x'''O / \x^x\.

[1165] 0 OH 1

[1166] X^-xXX^_0HQ

[1167] OH Oxx /

[1168] CII-70

[1169] 1=1NH

[1170] 0< X^X^\NZJ

[1171] OH

[1172]

[1173] 74

[1174] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1175] A / XAAAyH0

[1176] ZS"°\

[1177] CII-71 OH OA A

[1178] 1=1NHHOAAA / XA / A

[1179] OH

[1180] o °

[1181] ¥ H H, P-, 0

[1182] CII-72 ° ¥-^N^,NA^Nr0

[1183] o A H H L X

[1184] Xx^xz-xJ0

[1185] O OH

[1186] . -N. / X J-L

[1187] ] o rN H H

[1188] A> P0H

[1189] CII-73

[1190] T 1 jf

[1191] H NH ^x^^^

[1192] A 1 XX / JK O. -~S /

[1193] OH O

[1194] •x. ^-x x'x. „.^x Ax.xx,,-xZOH i?■

[1195] 'If ■- T H H P-0Ay^x AA^X / X / \ CII-74 ° |!• A 5 K 1 'N' ¥.x x.' N xo

[1196] '■x,.^-Xx.'-'■■■x A....■'■ x,..-x^....~x x'0‘“O' 'H H J 8

[1197] O OH O H HzP-x o

[1198] CII-750S'^N- ryxNJixxxz. Nr

[1199] '■x^z^z=V'°v n "^ / X-^ 0 A HHI v-'Xx-'^ XxO'x= / \ / xz-'x 0

[1200] X / X^Z X 0 X x.?

[1201] I. L,x.. I. V1? A. ■'--■o-"'f'-'-'.... CII-76 N H‘ ■<"z-*-X Z^X. -Ns X Z-~X Z-XvyOx^Aj 6 WX X ‘ l....,-s A Jx. X

[1202] ° i r ' OH 0

[1203] x / ’'’s'x / ’ ^'xx' X A z-'x. z-x... OH:!■

[1204] li " " I H H, P-, o A / '' / XOAAX^'XA'-XXZ-'\ CII-77 '*•-. •'■X" X

[1205] 0A f A A-A o1....

[1206] 's^z- 'x.z' X.z’ x.z' •x.-'.o..xx, x 0 '-.a H H j J:.

[1207] H 1 HO 'x-x XVZ x0..- s x x.z- S..Xs„ o OH i

[1208]

[1209] 75

[1210] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1211] 0 0H

[1212] H H, P-1 0

[1213] CII-78 o r ^^ W -- j I

[1214] O AozHH

[1215] OH / / T o

[1216] \ \ / ° - O Z

[1217] l^ A 0H

[1218] CII-79 / A°\ r0H

[1219] OHA < o — / o4^\ 0 < ^A^^ / XZ ( (cQ> o— / — -1Y A

[1220] '^ OZ

[1221] I

[1222] _ □? \ / x ° °

[1223] Z) (

[1224] co

[1225] co

[1226] CII-80 A rx'

[1227] . r CX°x° °'Xo

[1228] \ / A °H\ / s\ I / 'sI _ _

[1229] ) 7° — co co

[1230] I CII-81 ° 'z~\'

[1231] A 5fo — / / I ozx

[1232] V \ / o —

[1233] / / I

[1234] OH Y H, PY o

[1235] CII-82

[1236] 0A H 1

[1237] OH

[1238] CII-83

[1239] o

[1240] \ / X^x^x^x^oA^xX^o

[1241] X-X^-xo rN-~-sANH

[1242] 1 II 1 I H

[1243] \ / Xz-x^Xo> X^x^x / \ A°

[1244] CII-84

[1245] °AY YXX\ / Xrovxx''x / '-x^^HHNYS^^XNJ O IAJA-X O A^'\^'-'Y°X^^

[1246] o

[1247]

[1248] 76

[1249] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1250] 0

[1251] O 0

[1252] I

[1253] \ \ Y H

[1254] CII-85

[1255] Z 7 oAA

[1256] HHT, A / A / / / / 0 I 0

[1257] x x

[1258] 0

[1259] ( (> O— — /

[1260] \u ooz— \ \ / -r x

[1261] CII-XO z—

[1262] 86

[1263] j

[1264]

[1265] CD \

[1266] or a pharmaceutically acceptable salt thereof. oz <>

[1267] In some embodiments, the lipid of Formula CAT-II has a structure selected from the

[1268] A ° A'ZO>

[1269] group consisting of: \ \ 1 / '' ±'" x _ _

[1270] CD

[1271] \ OH

[1272] xOH CD 5

[1273] - ~ YHO¥ oA

[1274] 1 A-K A II i

[1275] CII-3 « '' r T /

[1276] \ T

[1277] O Z— X

[1278] OH X ) O '; — — o / X /

[1279] \ / ) o ——

[1280] > > / / X

[1281] CII-24 /

[1282]

[1283] or a pharmaceutically acceptable salt thereof. I \

[1284] In some embodiments, the lipid of Formula CAT-II has the following structure: _

[1285] (Compound CII-3),

[1286] or a pharmaceutically acceptable salt thereof.

[1287] In some embodiments, the lipid of Formula CAT-II has the following structure:

[1288] 77

[1289] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1290]

[1291] OH (Compound CII-24),

[1292] or a pharmaceutically acceptable salt thereof.

[1293] C. Helper Lipids of Formula (HLP-I)

[1294] The present disclosure provides helper lipids that provide improved delivery, uptake, and release of mRNA drug payload. In some embodiments, the helper lipid is a phospholipid comprising three aliphatic tails.

[1295] In some embodiments, the helper lipid has a structure according to Formula HLP-I:

[1296] O O

[1297]

[1298] O

[1299] (HLP-I)

[1300] or a pharmaceutically acceptable salt thereof, wherein:

[1301] Y is selected from optionally substituted C2-C6 alkylene or optionally substituted C4-C6 alkenylene;

[1302] Rais absent, or Ra is optionally substituted C1-C10 alkyl, wherein, when Ra is present, the nitrogen to which Ra is bonded bears a positive charge;

[1303] each Ri is independently selected from hydrogen or optionally substituted C1-C10 alkyl; each R2 is independently selected from:

[1304] (i) optionally substituted C4-C24 alkyl, optionally substituted C4-C24 alkenyl, and optionally substituted C4-C24 alkynyl;

[1305] 78

[1306] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1307] O

[1308] RA\ \

[1309] (ii)

[1310]

[1311] 0 Za, wherein each RA is independently selected from optionally substituted C1-C31 alkyl, optionally substituted C2-C31 alkenyl, and optionally substituted C2-C31 alkynyl; and

[1312] wherein each ZA is independently selected from optionally substituted C1-C10 alkylene and optionally substituted C2-C10 alkenylene;

[1313] O

[1314] (iii)

[1315]

[1316] B 5, wherein each RB is independently selected from optionally substituted C1-C31 alkyl, optionally substituted C2-C31 alkenyl, and optionally substituted C2-C31 alkynyl; and

[1317] wherein each ZB is independently selected from optionally substituted C1-C10 alkylene and optionally substituted C2-C10 alkenylene.

[1318] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Ia):

[1319] O O

[1320]

[1321] O (HLP-Ia)

[1322] or a pharmaceutically acceptable salt thereof.

[1323] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Ia-i):

[1324] 79

[1325] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1326] o O

[1327] R2

[1328] OH

[1329]

[1330] (HLP-Ia-i)

[1331] or a pharmaceutically acceptable salt thereof.

[1332] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Ia-ii):

[1333] OH

[1334]

[1335] (HLP-Ia-ii)

[1336] or a pharmaceutically acceptable salt thereof.

[1337] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Ia-iii):

[1338] O O

[1339] OH

[1340] R2- R2

[1341]

[1342] (HLP-Ia-iii)

[1343] or a pharmaceutically acceptable salt thereof.

[1344] 80

[1345] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1346] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Ia-iv):

[1347] O o

[1348]

[1349] O (HLP-Ia-iv)

[1350] or a pharmaceutically acceptable salt thereof.

[1351] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Ib):

[1352] O O

[1353]

[1354] O (HLP-Ib)

[1355] or a pharmaceutically acceptable salt thereof.

[1356] In embodiments, Y is selected from optionally substituted C2-6 alkylene. In embodiments, Y is optionally substituted C2 alkylene. In embodiments, Y is optionally substituted C3 alkylene. In embodiments, Y is optionally substituted C4 alkylene. In embodiments, Y is optionally substituted C5 alkylene. In embodiments, Y is optionally substituted Ce alkylene.

[1357] In a preferred embodiment, Y is -CH2CH2-.

[1358] In embodiments, Y is selected from optionally substituted C4-6 alkenylene. In embodiments, Y is optionally substituted C4 alkenylene. In embodiments, Y is optionally substituted C5 alkenylene. In embodiments, Y is optionally substituted Ce alkenylene.

[1359] 81

[1360] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1361] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Ic):

[1362]

[1363] O (HLP-Ic)

[1364] or a pharmaceutically acceptable salt thereof.

[1365] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Id):

[1366] o oRi

[1367]

[1368] o (HLP-Id)

[1369] or a pharmaceutically acceptable salt thereof.

[1370] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Id-i):

[1371]

[1372] O 82

[1373] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1374] (HLP-Id-i)

[1375] or a pharmaceutically acceptable salt thereof.

[1376] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Id-ii):

[1377] O O

[1378]

[1379] O (HLP-Id-ii)

[1380] or a pharmaceutically acceptable salt thereof.

[1381] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Id-iii):

[1382] O O

[1383]

[1384] o (HLP-Id-iii)

[1385] or a pharmaceutically acceptable salt thereof.

[1386] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Id-iv):

[1387] 83

[1388] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1389]

[1390] o (HLP-Id-iv)

[1391] or a pharmaceutically acceptable salt thereof.

[1392] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Ie):

[1393] O O

[1394]

[1395] O (HLP-Ie)

[1396] or a pharmaceutically acceptable salt thereof.

[1397] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Ie-i):

[1398] O O

[1399]

[1400] O (HLP-Ie-i)

[1401] or a pharmaceutically acceptable salt thereof.

[1402] 84

[1403] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1404] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Ie-ii):

[1405] O O

[1406]

[1407] O (HLP-Ie-ii)

[1408] or a pharmaceutically acceptable salt thereof.

[1409] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Ie-iii):

[1410] O O

[1411]

[1412] O (HLP-Ie-iii)

[1413] or a pharmaceutically acceptable salt thereof.

[1414] In some embodiments of the lipid of Formula HLP-I, the lipid has a structure according to Formula (HLP-Ie-iv):

[1415] O O

[1416]

[1417] O (HLP-Ie-iv)

[1418] 85

[1419] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1420] or a pharmaceutically acceptable salt thereof.

[1421] In embodiments, the stereochemistry of the carbon atom situated between R2C(=O)O-CH2- and -CH2-OP(=O)(OH)-O- is as depicted in the following structure:

[1422]

[1423] In embodiments, the stereochemistry of the carbon atom situated between R2C(=O)O-CH2- and -CH2-OP(=O)(OH)-O- is as depicted in the following structure:

[1424]

[1425] In embodiments, each R2 is the same. In embodiments, each R2 is different.

[1426] In embodiments, each R2 is independently selected from optionally substituted C4-C24 alkyl, optionally substituted C4-C24 alkenyl, and optionally substituted C4-C24 alkynyl. In embodiments, each R2 is independently selected from optionally substituted C5-C20 alkyl, optionally substituted C5-C20 alkenyl, and optionally substituted C5-C20 alkynyl. In embodiments, each R2 is independently selected from optionally substituted Ce-Cis alkyl, optionally substituted Ce-Cis alkenyl, and optionally substituted Ce-Cis alkynyl. In embodiments, each R2 is independently selected from optionally substituted C7-C15 alkyl, optionally substituted C7-C15 alkenyl, and optionally substituted C7-C15 alkynyl.

[1427] In embodiments, each R2 is independently selected from optionally substituted C4-C24 alkyl, for example a branched C4-C24 alkyl. In embodiments, each R2 is independently selected from optionally substituted C5-C20 alkyl, for example a branched C5-C20 alkyl. In embodiments, each R2 is independently selected from optionally substituted Ce-Cis alkyl, for example a branched Ce-Cis alkyl. In embodiments, each R2 is independently selected from optionally substituted C7-C15 alkyl, for example a branched C7-C15 alkyl.

[1428] In embodiments, each R2 is independently selected from

[1429]

[1430] 13, 14, 15, 16 17, 18, 19, 20, 21, 22, and 23,

[1431] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1432]

[1433] In embodiments, each R2 is independently selected from:

[1434]

[1435] is independently selected from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 17, 18, 19, 20, 21, 22, and 23. In embodiments, each n is 3. In embodiments, each n is 4. In embodiments, each n is 5. In embodiments, each n is 6. In embodiments, each n is 7. In embodiments, each n is 8.

[1436] 87

[1437] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1438] In embodiments, each n is 9. In embodiments, each n is 10. In embodiments, each n is 11. In embodiments, each n is 12. In embodiments, each n is 13. In embodiments, each n is 14. In embodiments, each n is 15. In embodiments, each n is 16. In embodiments, each n is 17. In embodiments, each n is 18. In embodiments, each n is 19. In embodiments, each n is 20. In embodiments, each n is 21. In embodiments, each n is 22. In embodiments, each n is 23.

[1439] In embodiments, each R2 is independently selected from

[1440]

[1441] , wherein each n is independently selected from 3-23. In embodiments, each R2 is independently selected from

[1442]

[1443] , wherein each n is independently selected from 5-21. In embodiments, each R2 is

[1444] independently selected from

[1445]

[1446] , wherein each n is independently selected from 7-

[1447] 19. In embodiments, each R2 is independently selected from

[1448]

[1449] , wherein each n is independently selected from 9-17. In embodiments, each R2 is independently selected from

[1450]

[1451] , wherein each n is independently selected from 11-15.

[1452] In embodiments, each R2 is

[1453]

[1454] . In embodiments, each R2 is

[1455] . In embodiments, each R2 is

[1456]

[1457] embodiments, each R2 is

[1458]

[1459] . In embodiments, each R2 is

[1460]

[1461] In embodiments, each R2 is. In

[1462] embodiments, each R

[1463]

[1464] 2 is

[1465] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1466] In embodiments, each R2 is independently selected from optionally substituted C4-C24 alkenyl.

[1467] In embodiments, R2 is independently selected from:

[1468]

[1469] In embodiments, each R2 is. In embodiments, each

[1470]

[1471] . In embodiments, each R2 is

[1472]

[1473] In embodiments, each R2 is independently selected from

[1474] RA\

[1475]

[1476] 0 Za, wherein each RA is independently selected from optionally substituted C1-C31 alkyl, optionally substituted C2-C31 alkenyl, and optionally substituted C2-C31 alkynyl; and wherein each ZA is independently selected from optionally substituted Ci-C10 alkylene and optionally substituted C2-C10 alkenylene.

[1477] In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl, for example optionally substituted C4-C24 alkyl, for example a branched C4-C24 alkyl. In some embodiments each RA is independently selected from optionally substituted C5-C20 alkyl, each RA is independently selected from optionally substituted Cs-Cis alkyl.

[1478] In embodiments, each RA is independently selected from:

[1479] (i)

[1480]

[1481] ", wherein each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30,

[1482] 89

[1483] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1484]

[1485] In embodiments, each RA is independently selected from

[1486]

[1487] wherein each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30. In embodiments, each n is 0. In embodiments, each n is 1. In embodiments, each n is 2. In embodiments, each n is 3. In embodiments, each n is 4. In embodiments, each n is 5. In embodiments, each n is 6. In embodiments, each n is 7. In embodiments, each n is 8. In embodiments, each n is 9. In embodiments, each n is 10. In embodiments, each n is 11. In embodiments, each n is 12. In embodiments, each n is 13. In embodiments, each n is 14. In embodiments, each n is 15. In embodiments, each n is 16. In embodiments, each n is 17. In embodiments, each n is 18. In embodiments, each n is 19. In embodiments, each n is 20. In embodiments, each n is 21. In embodiments, each n is 22. In

[1488] 90

[1489] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1490] embodiments, each n is 23. In embodiments, each n is 24. In embodiments, each n is 25. In embodiments, each n is 26. In embodiments, each n is 27. In embodiments, each n is 28. In embodiments, each n is 29. In embodiments, each n is 30.

[1491] In embodiments, each RA is independently selected from

[1492]

[1493] wherein each n is independently selected from 1-29. In embodiments, each RA is independently selected from

[1494]

[1495] , wherein each n is independently selected from 3-25. In embodiments, each RA is

[1496] independently selected from

[1497]

[1498] 21. In embodiments, each RA is independently selected from wherein each n is independently selected from 7-19.

[1499] In embodiments, each RA is

[1500]

[1501] . In embodiments, each RA is

[1502]

[1503] embodiments, each RA is

[1504]

[1505] . In embodiments, each RA is

[1506] e

[1507]

[1508] mbodiments, each RA is

[1509] In embodiments, each RA is independently selected from optionally substituted C2-C31 alkenyl, for example optionally substituted C4-C24 alkenyl.

[1510] In embodiments, each RA is independently selected from:

[1511]

[1512] 91

[1513] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1514]

[1515] In embodiments, each ZA is independently selected from optionally substituted Ci-Cio alkylene, for example optionally substituted C2-C7 alkylene.

[1516] In embodiments, each ZA is optionally substituted Ci alkylene. In embodiments, each ZA is optionally substituted C2 alkylene. In embodiments, each ZA is optionally substituted C3 alkylene. In embodiments, each ZA is optionally substituted C4 alkylene. In embodiments, each ZA is optionally substituted C5 alkylene. In embodiments, each ZA is optionally substituted Ce alkylene. In embodiments, each ZA is optionally substituted C7 alkylene. In embodiments, each ZA is optionally substituted Cs alkylene. In embodiments, each ZA is optionally substituted C9 alkylene. In embodiments, each ZA is optionally substituted C10 alkylene.

[1517] In embodiments, each ZA is independently selected from optionally substituted C2-C10 alkenylene, for example optionally substituted C2-C7 alkenylene.

[1518] In embodiments, each ZA is optionally substituted C2 alkenylene. In embodiments, each ZA is optionally substituted C3 alkenylene. In embodiments, each ZA is optionally substituted C4 alkenylene. In embodiments, each ZA is optionally substituted C5 alkenylene. In embodiments, each ZA is optionally substituted Ce alkenylene. In embodiments, each ZA is optionally substituted C7 alkenylene. In embodiments, each ZA is optionally substituted Cs alkenylene. In embodiments, each ZA is optionally substituted C9 alkenylene. In embodiments, each ZA is optionally substituted C10 alkenylene.

[1519] 92

[1520] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1521] In embodiments, Y if present is -CH2CH2-, each RA is independently selected from optionally substituted C1-C31 alkyl, and each ZA is independently selected from optionally substituted C1-C10 alkylene.

[1522] In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C1 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C2 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C3 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C4 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C5 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C6 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C7 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C8 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C9 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C10 alkylene.

[1523] In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl, and each ZA is independently selected from optionally substituted C2-C7 alkylene.

[1524] In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl and each ZA is C2 alkylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl and each ZA is C3 alkylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl and each ZA is C4 alkylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl and each ZA is C5 alkylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl and each ZA is C6 alkylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl and each ZA is C7 alkylene.

[1525]

[1526] In embodiments, each RA is and each ZA is C7 alkylene.

[1527] In embodiments, each RA is

[1528]

[1529] and each ZA is Ce alkylene.

[1530] In embodiments, each RA is

[1531]

[1532] and each ZA is C2 alkylene.

[1533] 93

[1534] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1535] In embodiments, each RA is

[1536]

[1537] and each ZA is independently selected from C5-C7 alkylene, preferably wherein each ZA is Ce alkylene.

[1538] In embodiments, each RA is

[1539]

[1540] and each ZA is Ce alkylene.

[1541] In embodiments, Y if present is -CH2CH2-, each RA is independently selected from optionally substituted C1-C31 alkyl, and each ZA is independently selected from optionally substituted C2-C10 alkenylene.

[1542] In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C2 alkenylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C3 alkenylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C4 alkenylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C5 alkenylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is Ce alkenylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkyl and each ZA is C7 alkenylene.

[1543] In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl, and each ZA is independently selected from optionally substituted C2-C7 alkenylene.

[1544] In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl and each ZA is C2 alkenylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl and each ZA is C3 alkenylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl and each ZA is C4 alkenylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl and each ZA is C5 alkenylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl and each ZA is Ce alkenylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkyl and each ZA is C7 alkenylene.

[1545] In embodiments, each RA is

[1546]

[1547] and each ZA is C6 alkenylene. In embodiments, Y if present is -CH2CH2-, each RA is independently selected from optionally substituted C1-C31 alkenyl, and each ZA is independently selected from optionally substituted C1-C10 alkylene.

[1548] 94

[1549] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1550] In embodiments, each RA is independently selected from optionally substituted C1-C31 alkenyl, and each ZA is Ci alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkenyl, and each ZA is C2 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkenyl, and each ZA is C3 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkenyl, and each ZA is C4 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkenyl, and each ZA is C5 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkenyl, and each ZA is Ce alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkenyl, and each ZA is C7 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkenyl, and each ZA is Cs alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkenyl, and each ZA is C9 alkylene. In embodiments, each RA is independently selected from optionally substituted C1-C31 alkenyl, and each ZA is C10 alkylene.

[1551] In embodiments, each RA is independently selected from optionally substituted C4-C24 alkenyl, and each ZA is independently selected from optionally substituted C2-C7 alkylene.

[1552] In embodiments, each RA is independently selected from optionally substituted C4-C24 alkenyl, and each ZA is C2 alkylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkenyl, and each ZA is C3 alkylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkenyl, and each ZA is C4 alkylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkenyl, and each ZA is C5 alkylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkenyl, and each ZA is Ce alkylene. In embodiments, each RA is independently selected from optionally substituted C4-C24 alkenyl, and each ZA is C7 alkylene.

[1553] In embodiments, each RA is

[1554]

[1555] and each ZA is Ce alkylene.

[1556] In embodiments, each RA is

[1557]

[1558] and each ZA is C6 alkylene. In embodiments, each R2 is independently selected from

[1559] O

[1560]

[1561] , wherein each RB IS independently selected from optionally substituted C1-C31 alkyl, optionally substituted C1-C31 alkenyl, and optionally substituted Ci-

[1562] 95

[1563] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1564] C31 alkynyl; and wherein each ZB is independently selected from optionally substituted Ci-Cio alkylene and optionally substituted C2-C10 alkenylene.

[1565] In embodiments, each RB is independently selected from optionally substituted C1-C31 alkyl, for example optionally substituted C4-C24 alkyl, for example a branched C4-C24 alkyl.

[1566] In embodiments, each RB is independently selected from:

[1567] (i) ", wherein each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30,

[1568] (ii) I,

[1569] (iii)

[1570] (iv)

[1571] (v)

[1572] (vi),

[1573] (vii),

[1574] (viii)

[1575] (ix)

[1576] (x) or

[1577] (

[1578]

[1579] xi)

[1580] In embodiments, each RB is independently selected from [image formula]n, wherein each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 17, 18, 19,

[1581] 96

[1582] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1583] 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30. In embodiments, each n is 0. In embodiments, each n is 1. In embodiments, each n is 2. In embodiments, each n is 3. In embodiments, each n is 4. In embodiments, each n is 5. In embodiments, each n is 6. In embodiments, each n is 7. In embodiments, each n is 8. In embodiments, each n is 9. In embodiments, each n is 10. In embodiments, each n is 11. In embodiments, each n is 12. In embodiments, each n is 13. In embodiments, each n is 14. In embodiments, each n is 15. In embodiments, each n is 16. In embodiments, each n is 17. In embodiments, each n is 18. In embodiments, each n is 19. In embodiments, each n is 20. In embodiments, each n is 21. In embodiments, each n is 22. In embodiments, each n is 23. In embodiments, each n is 24. In embodiments, each n is 25. In embodiments, each n is 26. In embodiments, each n is 27. In embodiments, each n is 28. In embodiments, each n is 29. In embodiments, each n is 30.

[1584] In embodiments, each RB is independently selected from

[1585]

[1586] , wherein each n is independently selected from 1-29. In embodiments, each RB is independently selected from

[1587]

[1588] wherein each n is independently selected from 3-25. In embodiments, each RB is

[1589] independently selected from

[1590]

[1591] , wherein each n is independently selected from 5-

[1592] 21. In embodiments, each RB is independently selected from

[1593]

[1594] 'n, wherein each n is independently selected from 7-19

[1595]

[1596] 97

[1597] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1598]

[1599] . In embodiments, each RB is. In

[1600] embodiments, each R

[1601]

[1602] B is

[1603] In embodiments, each RB is independently selected from optionally substituted C2-C31 alkenyl, for example optionally substituted C4-C24 alkenyl.

[1604] In embodiments, each RB is independently selected from:

[1605]

[1606] In embodiments, each ZB is independently selected from optionally substituted C1-C10 alkylene, for example optionally substituted C2-C7 alkylene.

[1607] In embodiments, each ZB is optionally substituted Ci alkylene. In embodiments, each ZB is optionally substituted C2 alkylene. In embodiments, each ZB is optionally substituted C3 alkylene. In embodiments, each ZB is optionally substituted C4 alkylene. In embodiments, each ZB is optionally substituted C5 alkylene. In embodiments, each ZB is optionally substituted Ce alkylene. In embodiments, each ZB is optionally substituted C7 alkylene. In embodiments, each ZB is optionally substituted Cs alkylene. In embodiments, each ZB is optionally substituted C9 alkylene. In embodiments, each ZB is optionally substituted C10 alkylene.

[1608] 98

[1609] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1610] In embodiments, each ZB is independently selected from optionally substituted C2-C10 alkenylene, for example optionally substituted C2-C7 alkenylene.

[1611] In embodiments, each ZB is optionally substituted C2 alkenylene. In embodiments, each ZB is optionally substituted C3 alkenylene. In embodiments, each ZB is optionally substituted C4 alkenylene. In embodiments, each ZB is optionally substituted C5 alkenylene. In embodiments, each ZB is optionally substituted Ce alkenylene. In embodiments, each ZB is optionally substituted C7 alkenylene. In embodiments, each ZB is optionally substituted Cs alkenylene. In embodiments, each ZB is optionally substituted C9 alkenylene. In embodiments, each ZB is optionally substituted C10 alkenylene.

[1612] In embodiments, Y if present is -CH2CH2-, each RB is independently selected from optionally substituted C1-C31 alkyl, and each ZB is independently selected from optionally substituted C1-C10 alkylene.

[1613] In embodiments, each RB is independently selected from optionally substituted C1-C31 alkyl and each ZB is Ci alkylene. In embodiments, each RB is independently selected from optionally substituted C1-C31 alkyl and each ZB is C2 alkylene. In embodiments, each RB is independently selected from optionally substituted C1-C31 alkyl and each ZB is C3 alkylene. In embodiments, each RB is independently selected from optionally substituted C1-C31 alkyl and each ZB is C4 alkylene. In embodiments, each RB is independently selected from optionally substituted C1-C31 alkyl and each ZB is C5 alkylene. In embodiments, each RB is independently selected from optionally substituted C1-C31 alkyl and each ZB is Ce alkylene. In embodiments, each RB is independently selected from optionally substituted C1-C31 alkyl and each ZB is C7 alkylene. In embodiments, each RB is independently selected from optionally substituted C1-C31 alkyl and each ZB is Cs alkylene. In embodiments, each RB is independently selected from optionally substituted C1-C31 alkyl and each ZB is C9 alkylene. In embodiments, each RB is independently selected from optionally substituted C1-C31 alkyl and each ZB is C10 alkylene.

[1614] In embodiments, each RB is independently selected from optionally substituted C4-C24 alkyl, and each ZB is independently selected from optionally substituted C2-C7 alkylene.

[1615] In embodiments, each RB is independently selected from optionally substituted C4-C24 alkyl and each ZB is C2 alkylene. In embodiments, each RB is independently selected from optionally substituted C4-C24 alkyl and each ZB is C3 alkylene. In embodiments, each RB is independently selected from optionally substituted C4-C24 alkyl and each ZB is C4 alkylene. In embodiments, each RB is independently selected from optionally substituted C4-C24 alkyl and each ZB is C5 alkylene. In embodiments, each RB is independently selected from optionally 99

[1616] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1617] substituted C4-C24 alkyl and each ZB is Ce alkylene. In embodiments, each RB is independently selected from optionally substituted C4-C24 alkyl and each ZB is C7 alkylene.

[1618] In embodiments, each RB is independently selected from:

[1619] (i)

[1620] (ii) I,

[1621]

[1622] (iii)

[1623] (iv),

[1624] (v)or

[1625] (Vi)

[1626]

[1627] In embodiments, each RB is and each ZB is C5 alkylene.

[1628] In embodiments, each RB is

[1629]

[1630] and each ZB is Ce alkylene. In embodiments, one R2 is optionally substituted C4-C24 alkyl, optionally substituted C4-C24 alkenyl, or optionally substituted C4-C24 alkynyl, and the other R2 is

[1631] O

[1632] Ra\ A \

[1633]

[1634] 0 Za, wherein each RA is independently selected from optionally substituted C1-C31 alkyl, optionally substituted C2-C31 alkenyl, and optionally substituted C2-C31 alkynyl; and wherein each ZA is independently selected from optionally substituted Ci-C10 alkylene and optionally substituted C2-C10 alkenylene.

[1635] In embodiments, one R2 is optionally substituted C4-C24 alkyl, optionally substituted C4-C24 alkenyl, or optionally substituted C4-C24 alkynyl, and the other R2 is

[1636] 100

[1637] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1638]

[1639] RB, wherein each RBIS independently selected from optionally substituted C1-C31 alkyl, optionally substituted C1-C31 alkenyl, and optionally substituted Ci-C31 alkynyl; and wherein each ZB is independently selected from optionally substituted Ci-C10 alkylene and optionally substituted C2-C10 alkenylene.

[1640] In embodiments, each RA, when present, is the same. In embodiments, each RA, when present, is different.

[1641] In embodiments, each ZA, when present, is the same. In embodiments, each ZA, when present, is different.

[1642] In embodiments, each RB, when present, is the same. In embodiments, each RB, when present, is different.

[1643] In embodiments, each ZB, when present, is the same. In embodiments, each ZB, when present, is different.

[1644] In embodiments, each RA, when present, is independently selected from linear C1-C31 alkyl. In embodiments, each RA, when present, is independently selected from branched Ci-C31 alkyl. In embodiments, each RA, when present, is independently selected from linear C4-C24 alkyl. In embodiments, each RA, when present, is independently selected from branched C4-C24 alkyl. In embodiments, one RA is linear C1-C31 alkyl and the other RA is branched Ci-C31 alkyl. In embodiments, one RA is linear C4-C24 alkyl and the other RA is branched C4-C24 alkyl.

[1645] In embodiments, one RA is

[1646]

[1647] and the other RA is C1-C31

[1648] alkyl. In embodiments, one RA is

[1649]

[1650] and the other RA is C4-C24 alkyl.

[1651] In embodiments, one RA is

[1652]

[1653] and the other RA is C8 alkyl.

[1654] In embodiments, each RB, when present, is independently selected from linear C1-C31 alkyl. In embodiments, each RB, when present, is independently selected from branched Ci-C31 alkyl. In embodiments, each RB, when present, is independently selected from linear C4-C24 alkyl. In embodiments, each RB, when present, is independently selected from branched C4-C24 alkyl.

[1655] 101

[1656] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1657] In embodiments, one RA is linear C1-C31 alkyl and the other RA is branched C1-C31 alkyl. In embodiments, one RA is linear C4-C24 alkyl and the other RA is branched C4-C24 alkyl.

[1658] M C I

[1659] In embodiments, the substituents are not optionally substituted. z

[1660] In some embodiments, the lipid of Formula HLP-I has a structure sM Celected from the ZE

[1661] group consisting of: Z

[1662] / ZE°

[1663] O OCL=- \

[1664] 0 00 0

[1665] / ZE°

[1666] OOQ-=- HI-1

[1667] 00 )V FA \

[1668] 0

[1669] 0 0

[1670] \ \o<=

[1671] x F

[1672] y O O - '

[1673] \ / O^

[1674] HI-2 / / 0

[1675] \ / \0°

[1676] )° \=

[1677] \ °

[1678] \0

[1679] \ / ° 0 0

[1680] _ 0

[1681] HI-3

[1682] 0

[1683] HI-400

[1684] H 1 OH

[1685] 0

[1686] HI-5

[1687]

[1688] 102

[1689] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1690] 0 0

[1691] xX^X p X ^ X\X / X Ay ^ / X^Xxxx F\0^ / -X Xx N H2HI-60°XX°

[1692] 0 0 0 1 / ^ / ^ xX^ X^ A x^ / ^ xX^ A x^ X^ P / ^N\ HI-7

[1693] H ° 1

[1694] \ X X / O. Y X^^ X X^ Ao„xyX^-oxX6PxHQ / —X X N. x10 Ox / O

[1695] HI-8

[1696] 101 / A / X^A / X /

[1697] 9 9 I

[1698] x xx xx XX X^X A^xX xX. P^Z\ / N.

[1699] ■^ x x ^oyp 6H° "

[1700] HI-9

[1701] 0

[1702] ii i0H i i

[1703] HI- 10 0 r.

[1704] 0i06H°

[1705] x / v0

[1706] H ° 1 / X / \^Z\ / Oxy xX / \w^ As^ / yX / ^x0x6P^Hox^^xz N. X HI- 11 x^x^xx^A o

[1707] 0

[1708] z^X^XX-Qv0

[1709] HI- 12 \ / \ / X x^\ 1 k / X A H X xX x °Px X-X xN 1.

[1710] OOOd AXXXC^6H

[1711] 0

[1712]

[1713] 103

[1714] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1715] ? ° 1 -p^^^pp - Z — HI- 13 XXxXxXxJ0 XXX°

[1716] \xxxx S 0

[1717] / r° "^XXxX^XX^X^o^Q

[1718] \ OOQ-=- o

[1719] ? ° 1 p ^^^O^p,6HO^ x XXXX / 0 K>

[1720] HI- 14 XXXX^0

[1721] \ o Xx'X^XXX'X. / / o / =0'XX\X\XX^X^0^0

[1722] \ / °

[1723] / °

[1724] HI- 15 ) \ \ ° —

[1725] \ / °

[1726] 'xXX^X / ^x Q o O |

[1727] HI- 16

[1728] X^Xx~XXX^XX^°Xj^XXxX, XXsX^

[1729] X\XXXX^ 0 0

[1730] X^-XX^A / Ox

[1731] Jf N " 1 HI- 17 ^ ^^ o 0 \ Xx^XAo xp\ x\o- zpPx X\ z.

[1732] xXx^xxXx^ "

[1733] 0

[1734] XXx\xX^X\xX0

[1735] HI- 18 1 H? 1

[1736] X \x / XxxXxx / Xx X\XxXxX^A^oX-XyXX-o^6HXO—'X / N. - XxXxXxXXX^°xxXXXXX^°

[1737] 0 0

[1738]

[1739] 104

[1740] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1741]

[1742] 105 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT T HI-24

[1743] z —

[1744] / T°

[1745] \ OOn-=- 0

[1746] 0Vo

[1747] HI-25000

[1748] ( ooo

[1749] (= / \ \

[1750] o 0= / — / \ / 20= / — 0 (

[1751] x° — / \

[1752] x°7\ — / \ o \ / °^

[1753] 7\ o

[1754] \ \ \ / ' 0 — \° —

[1755] \ \ 0

[1756] \°x 0\ /

[1757] ° > 00\ / \ /

[1758] > O >

[1759] HI-2600 \ /

[1760] > 0

[1761] / \ / 0

[1762] 0

[1763] H0q

[1764] q q 0071=- OOTJ q=- 0073=- 0073=- / 0V

[1765] \ 0 0 | z —

[1766] HI-27 z —

[1767] -z — -—.

[1768] z —

[1769] 0 I 0 z T HI-28

[1770] HI-29

[1771]

[1772] 106

[1773] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1774] i HI-30

[1775] +lz. ——- z ——

[1776] z —

[1777] o q

[1778] x x xx,-xvxxvxx 0.Y.. X-. XV. / X A -XTx. P. x- X / / / TxT°°°, XX

[1779] \ OO OO OO0-CLCL===--- HI-31 o o o o o

[1780] ° / — / Yoi'

[1781] x° — / \

[1782] \ \ ° o < y R \ R°°

[1783] oQ=

[1784] ^( / / ^ oo° \===

[1785] o=\ /

[1786] > O

[1787] HI-32 y / / O, \ O \ o - - / — ' A

[1788] \\\ / / Q°O^==- — - o o o o o q

[1789] ' OO-D=- ^o ■

[1790] HI-33

[1791] HI-34

[1792] \ 0 O A

[1793] II H 1 + HI-35 X v^ XX xxX.^ XX 0 \ X / xXAVXXx xXo„ xPv° XX XX x

[1794]

[1795] 0

[1796] or a pharmaceutically acceptable salt thereof.

[1797] In some embodiments, the lipid of Formula HLP-I has a structure selected from the group consisting of:

[1798] 107

[1799] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1800] HI-6

[1801] HI- 12 \ ° 1 H °

[1802] 00 A, N 1.

[1803] ( o oo=° \ / / — /

[1804] OOOd JC 20= / —

[1805] x° — / X \

[1806] xXXA

[1807] ° — /

[1808] / \ 06H

[1809] q /

[1810] 0

[1811] 0\ /

[1812] > ° 0 / \ ° > \ / O ' o o \

[1813] HI- 18 1 H? 1

[1814] x^-^ \X^0- Xy-0^0— - q 'XXX / X / Xz°\ / \XXA^ °0x

[1815] 0073= q- q

[1816] 0 0 \ oo OOJ-u==--

[1817] z — z z —— ZE ro HI-24

[1818] ^ 0

[1819] 1

[1820] HI-27

[1821] 0 0

[1822] ' - 'Vzx T -0. - - -, A zx A -x - - r - - - -<r r 0^- - y,-.. zx J 0 Ov,01HI-31

[1823] ^ J

[1824]

[1825] 108

[1826] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1827] > 0 0

[1828] HI-32 II11I

[1829] \ k ^X z\ / \ l +OHz. ——- 0

[1830] S o 0 PT /

[1831] I || OOCL= i-i <

[1832] HI-33

[1833] o o Q X / X / S / ^ oQSO^^ S

[1834] ° / — / 0H

[1835] x° — / \ Ro 0

[1836] \ o

[1837] 2 o4

[1838] ° / \

[1839] HI-34 > O

[1840] y O \ - /

[1841] \ / O=- o o s

[1842] q

[1843] OOm=- ' ^o

[1844] HI-35

[1845]

[1846] or a pharmaceutically acceptable salt thereof.

[1847] In some embodiments, the lipid of Formula HLP-I has a structure selected from the

[1848]

[1849] 109

[1850] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1851] 0

[1852] T

[1853] HI- 18 1 H? 1 z ——

[1854] n 6H°^ Z — "

[1855] O 0 / T°

[1856] OOD_=- o / T \°

[1857] \ o on—=

[1858] o

[1859] HI-24 Ro

[1860] \ R o

[1861] / o4 o <

[1862] 2 o / =

[1863] y O \ / / - ' o —

[1864] o o\Q=\ -o=—

[1865] HI-27 o0 >

[1866] 0 0

[1867] IS

[1868] P-P >*x. XV

[1869] ■" ''VY Iuru6fP 7 HI-31

[1870] VX' ’f!;...\X /

[1871]

[1872] or a pharmaceutically acceptable salt thereof.

[1873] In some embodiments, the lipid of Formula HLP-II has the following structure:

[1874]

[1875] or a pharmaceutically acceptable salt thereof.

[1876] In some embodiments, the lipid of Formula HLP-II has the following structure:

[1877] 110

[1878] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1879]

[1880] or a pharmaceutically acceptable salt thereof.

[1881] In some embodiments, the lipid of Formula HLP-II has the following structure:

[1882]

[1883] or a pharmaceutically acceptable salt thereof.

[1884] In some embodiments, the lipid of Formula HLP-II has the following structure:

[1885]

[1886] (Compound HI-24),

[1887] or a pharmaceutically acceptable salt thereof.

[1888] In some embodiments, the lipid of Formula HLP-II has the following structure:

[1889]

[1890] or a pharmaceutically acceptable salt thereof.

[1891] 111

[1892] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1893] In some embodiments, the lipid of Formula HLP-II has the following structure:

[1894]

[1895] (Compound HI-31),

[1896] or a pharmaceutically acceptable salt thereof.

[1897] In some embodiments, the lipid of Formula HLP-II has the following structure:

[1898]

[1899] or a pharmaceutically acceptable salt thereof.

[1900] In some embodiments, the lipid of Formula HLP-II has the following structure:

[1901]

[1902] or a pharmaceutically acceptable salt thereof.

[1903] In some embodiments, the lipid of Formula HLP-II has the following structure:

[1904]

[1905] or a pharmaceutically acceptable salt thereof.

[1906] In some embodiments, the lipid of Formula HLP-II has the following structure:

[1907] 112

[1908] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1909]

[1910] O (Compound HI-35),

[1911] or a pharmaceutically acceptable salt thereof.

[1912] D. Helper Lipids of Formula (HLP-II)

[1913] In some embodiments, the helper lipid has a structure according to Formula HLP-II:

[1914] R? P O

[1915] / U / -R1A

[1916] R2B'OTON

[1917] J) OH IR

[1918]

[1919] R1C

[1920] (HLP-II),

[1921] or a pharmaceutically acceptable salt thereof, wherein:

[1922] X is -C(i-6)alkylene-, -C(2-6)alkenylene-, -OC(i-6)alkylene-, -OC(2-6)alkenylene-, -OC(O)C(i-6)alkylene-, -OC(O)C(2-6)alkenylene-, -OC(O)OC(i-6)alkylene-, -OC(O)OC(2-6)alkenylene-, -NHC(O)C(i-6)alkylene-, -NHC(O)C(2-6)alkenylene-, or -C(1-6)alkylene-O-C(i-6)alkylene-;

[1923] Y is -C(2-6)alkylene- or -C(2-6)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”;

[1924] R1Aand R1Bare each independently selected from hydrogen and -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; or

[1925] R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group that is optionally substituted with one, two, or three -C(i- 6)alkyl groups;

[1926] R1Cis absent or R1Cis - nitpalkyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, - 113

[1927] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1928] SR” and -SO2R”, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge; or

[1929] RIARIB,anjRicare takentogether with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group that is optionally substituted with one, two, or three -C(i-6)alkyl groups, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge;

[1930] R2A, R2B, and R2Care each independently -OR3, -OC(O)R3, or -C(O)OR3; each R3is independently selected from the group consisting of:

[1931] (i) -C(9-25)alkyl, -C(9-25)alkenyl or -C(9-25)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” or -SO2R”;

[1932] O

[1933] (

[1934]

[1935] ii) R O *, wherein:

[1936] each R3Ais independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-31)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; and

[1937] each ZA is independently -C(6-io)alkylene- or -C(7-io)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; and

[1938] (iii)

[1939]

[1940] 0, wherein:

[1941] each R3Bis independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; and

[1942] each ZB is independently -C(6-10)alkylene- or -C(7-10)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”;

[1943] n is 0 or 1; and

[1944] 114

[1945] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1946] R” is independently for each occurrence -C(i-20)alkyl.

[1947] In some embodiments of the lipid of Formula HLP-II:

[1948] X is -C(i-6)alkylene-, -OC(i-6)alkylene-, -NHC(O)C(i-6)alkylene-, or -C(1-6)alkylene-O-C(i-6)alkylene-;

[1949] Y is -C(2-6)alkylene- or -C(2-6)alkenylene-, each of which is optionally substituted with one -C(O)OH group;

[1950] R1Aand R1Bare each independently selected from hydrogen and -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one -OH group; or

[1951] R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group, that is optionally substituted with one -C(i-6)alkyl group;

[1952] R1Cis absent or -C(1-10)alkyl, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge; or

[1953] R1A, R1B, and R1Care taken together with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group, that is optionally substituted with one -C(i-6)alkyl group, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge;

[1954] R2A, R2B, and R2Care each independently -OR3, -OC(O)R3, or -C(O)OR3; each R3is independently selected from the group consisting of:

[1955] (i) -C(9-25)alkyl, -C(9-25)alkenyl or -C(9-25)alkynyl;

[1956] O

[1957] (

[1958]

[1959] ii) R O *, wherein:

[1960] each R3Ais independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl; and each ZA is independently -C(6-io)alkylene- or -C(7-io)alkenylene-; and

[1961] (iii)

[1962]

[1963] 0, wherein:

[1964] each R3Bis independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl; and each ZB is independently -C(6-io)alkylene- or -C(7-io)alkenylene-; and

[1965] n is 0 or 1.

[1966] In some embodiments of the lipid of Formula HLP-II:

[1967] X is -C(i-6)alkylene- or -OC(2-6)alkylene-;

[1968] Y is -C(2-6)alkylene- that is optionally substituted with one -C(O)OH group;

[1969] R1Aand R1Bare each independently -C(1-5)alkyl that is optionally substituted with one -OH group; or

[1970] 115

[1971] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[1972] R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group;

[1973] R1Cis absent or R1Cis -C(1-5)alkyl, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge; or

[1974] R1A, R1B, and R1Care taken together with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge;

[1975] R2A, R2B, and R2Care each independently -OR3, -OC(O)R3, or -C(O)OR3; each R3is independently selected from the group consisting of:

[1976] (i) -C(9-25)alkyl, -C(9-25)alkenyl or -C(9-25)alkynyl;

[1977] O

[1978] (

[1979]

[1980] ii) R O *, wherein:

[1981] each R3Ais independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl; and each ZA is independently -C(6-io)alkylene- or -C(7-io)alkenylene-; and

[1982] R3B " Y V

[1983] (iii)

[1984]

[1985] O, wherein:

[1986] each R3Bis independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl; and each ZB is independently -C(6-io)alkylene- or -C(7-io)alkenylene-; and

[1987] n is 0 or 1.

[1988] In some embodiments of the lipid of Formula HLP-II:

[1989] X is -CH2-, -O(CH2)3-, or -O(CH2)4-;

[1990] Y

[1991]

[1992] is -CH2CH2- or CT^OH;

[1993] R1Ais -C(1-5)alkyl;

[1994] R1Bis -C(1-5)alkyl that is optionally substituted with one -OH group; or

[1995] R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group;

[1996] R1Cis absent or R1Cis -C(1-5)alkyl, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge; or

[1997] RIARIB,anjRicare takentogether with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge;

[1998] 116

[1999] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2000] R2A, R2B, and R2Care each independently -OR3, -OC(O)R3, or -C(O)OR3; each R3is independently selected from the group consisting of:

[2001] (i) -C(9-25)alkyl or -C(9-25)alkenyl;

[2002] O

[2003] (

[2004]

[2005] ii) R3AOa, wherein:

[2006] each R3Ais -C(i-3i)alkyl; and

[2007] each ZA is -C(6-io)alkylene-; and

[2008] rx || >

[2009] (iii)

[2010]

[2011] 0, wherein:

[2012] each R3Bis -C(i-3i)alkyl; and

[2013] each ZB is -C(6-io)alkylene-; and

[2014] n is 0 or 1.

[2015] In some embodiments of the lipid of Formula HLP-II, the helper lipid has a structure according to Formula (HLP-IF):

[2016] R2A

[2017] R2B

[2018]

[2019] RR22CCA0H

[2020] (HLP-IF),

[2021] or a pharmaceutically acceptable salt thereof, wherein:

[2022] X is -C(i-6)alkylene-, -C(2-6)alkenylene-, -OC(i-6)alkylene-, -OC(2-6)alkenylene-, -OC(O)C(i-6)alkylene-, -OC(O)C(2-6)alkenylene-, -OC(O)OC(i-6)alkylene-, -OC(O)OC(2-6)alkenylene-, -NHC(0)C(i-6)alkylene-, -NHC(O)C(2-6)alkenylene-, or -C(1-6)alkylene-O-C(i-6)alkylene-;

[2023] Y is -C(2-6)alkylene- or -C(2-6)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”;

[2024] R1Aand R1Bare each independently selected from hydrogen and -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; or

[2025] 117

[2026] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2027] R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group that is optionally substituted with one, two, or three -C(i- 6)alkyl groups;

[2028] R1Cis absent or R1Cis - nitpalkyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge; or

[2029] R1A, R1B, and R1Care taken together with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group that is optionally substituted with one, two, or three -C(i-6)alkyl groups, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge;

[2030] R2A, R2B, and R2Care each independently:

[2031]

[2032] each R3is independently selected from the group consisting of:

[2033] (i) -C(4-20)alkenyl or -C(4-20)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” or -SO2R”;

[2034] O

[2035] (

[2036]

[2037] ii) R O *, wherein:

[2038] each R3Ais independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; and

[2039] each ZA is independently -C(1-10)alkylene- or -C(2-io)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; and

[2040] (iii)

[2041]

[2042] O, wherein:

[2043] 118

[2044] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2045] each R3Bis independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; and

[2046] each ZB is independently -C(1-10)alkylene- or -C(2-io)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”;

[2047] n is 0 or 1; and

[2048] R” is independently for each occurrence -C(i-20)alkyl.

[2049] In some embodiments of the lipid of Formula HLP-II, the helper lipid has a structure according to Formula (HLP-IF):

[2050]

[2051] (HLP-IF),

[2052] or a pharmaceutically acceptable salt thereof, wherein:

[2053] X is -C(i-6)alkylene-, -OC(i-6)alkylene-, -NHC(O)C(i-6)alkylene-, or -C(1-6)alkylene-O-C(i-6)alkylene-;

[2054] Y is -C(2-6)alkylene- or -C(2-6)alkenylene-, each of which is optionally substituted with one -C(O)OH group;

[2055] R1Aand R1Bare each independently selected from hydrogen and -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one -OH group; or

[2056] R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group, that is optionally substituted with one -C(i-6)alkyl group;

[2057] R1Cis absent or -C(1-10)alkyl, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge; or

[2058] R1A, R1B, and R1Care taken together with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group, that is optionally substituted with one -C(i-6)alkyl group, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge;

[2059] R2A, R2B, and R2Care each independently:

[2060] 119

[2061] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2062]

[2063] each R3is independently selected from the group consisting of:

[2064] (i) -C(4-20)alkenyl or -C(4-20)alkynyl;

[2065] O

[2066] (

[2067]

[2068] ii) R ® * wherein:

[2069] each R3Ais independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl; and each ZA is independently -C(1-10)alkylene- or -C(2-io)alkenylene-; and

[2070] R3B Y

[2071] (iii) O, wherein:

[2072] each R3Bis independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl; and each ZB is independently -C(1-10)alkylene- or -C(2-io)alkenylene-; and

[2073] n is 0 or 1.

[2074] In some embodiments of the lipid of Formula HLP-II, the helper lipid has a structure according to Formula (HLP-IF):

[2075]

[2076] (HLP-II’),

[2077] or a pharmaceutically acceptable salt thereof, wherein:

[2078] X is -C(i-6)alkylene- or -OC(2-6)alkylene-;

[2079] Y is -C(2-6)alkylene- that is optionally substituted with one -C(O)OH group;

[2080] R1Aand R1Bare each independently -C(1-5)alkyl that is optionally substituted with one -OH group; or

[2081] R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group;

[2082] R1Cis absent or R1Cis -C(1-5)alkyl, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge; or

[2083] RIAIB,anjRicare takentogether with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge;

[2084] 120

[2085] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2086] R2A, R2B, and R2Care each independently:

[2087]

[2088] each R3is independently selected from the group consisting of:

[2089] (i) -C(4-20)alkenyl or -C(4-20)alkynyl;

[2090] O

[2091] J*

[2092] (

[2093]

[2094] ii) R ® r wherein:

[2095] each R3Ais independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl; and each ZA is independently -C(1-10)alkylene- or -C(2-io)alkenylene-; and

[2096] (iii)

[2097]

[2098] O, wherein:

[2099] each R3Bis independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl; and each ZB is independently -C(1-10)alkylene- or -C(2-io)alkenylene-; and

[2100] n is 0 or 1.

[2101] In some embodiments of the lipid of Formula HLP-II, the helper lipid has a structure according to Formula (HLP-IF):

[2102]

[2103] (HLP-II’),

[2104] or a pharmaceutically acceptable salt thereof, wherein:

[2105] X is -CH2-, -O(CH2)3-, or -O(CH2)4-;

[2106] Y

[2107]

[2108] is -CH2CH2- or O^OH;

[2109] R1Ais -C(1-5)alkyl;

[2110] R1Bis -C(1-5)alkyl that is optionally substituted with one -OH group; or

[2111] R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group;

[2112] R1Cis absent or R1Cis -C(1-5)alkyl, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge; or

[2113] 121

[2114] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2115] R1A, R1B, and R1Care taken together with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group that is optionally substituted with one -C(1-6)alkyl group, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge;

[2116] R2A, R2B, and R2Care each independently:

[2117]

[2118] each R3is independently selected from the group consisting of:

[2119] (i) -C(4-20)alkenyl;

[2120] O

[2121] (

[2122]

[2123] ii) R ®, wherein:

[2124] each R3Ais independently -C(i-3i)alkyl; and

[2125] each ZA is independently -C(1-10)alkylene-; and

[2126] (iii)

[2127]

[2128] O, wherein:

[2129] each R3Bis independently -C(i-3i)alkyl; and

[2130] each ZB is independently -C(1-10)alkylene-; and

[2131] n is 0 or 1.

[2132] In some embodiments of the lipid of Formula HLP-II, X is -C(i-6)alkylene-, -C(2-6)alkenylene-, -OC(2-6)alkylene-, -OC(2-6)alkenylene-, -OC(O)C(2-6)alkylene-, -OC(O)C(2-6)alkenylene-, -OC(O)OC(2-6)alkylene-, -OC(O)OC(2-6)alkenylene-, -NHC(O)C(2-6)alkylene-, -NHC(O)C(2-6)alkenylene-, or -C(1-6)alkylene-O-C(2-6)alkylene-.

[2133] In some embodiments of the lipid of Formula HLP-II, X is -C(1-6)alkylene-, -OC(1-6)alkylene-, -NHC(O)C(1-6)alkylene-, or -C(1-6)alkylene-O-C(1-6)alkylene-. In some embodiments of the lipid of Formula HLP-II, X is -C(i-6)alkylene-, -OC(2-6)alkylene-, -NHC(O)C(2-6)alkylene-, or -C(1-6)alkylene-O-C(2-6)alkylene-.

[2134] In some embodiments of the lipid of Formula HLP-II, X is -C(i-6)alkylene- or -OC(2-6)alkylene-.

[2135] In some embodiments of the lipid of Formula HLP-II, X is -C(i-6)alkylene-. In some embodiments of the lipid of Formula HLP-II, X is -CH2-. In some embodiments of the lipid of Formula HLP-II, X is -(CH2)2-. In some embodiments of the lipid of Formula HLP-II, X is -(CH2)3-. In some embodiments of the lipid of Formula HLP-II, X is -(CH2)4-. In some

[2136] 122

[2137] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2138] embodiments of the lipid of Formula HLP-II, X is -(CH2)5-. In some embodiments of the lipid of Formula HLP-II, X is -(CH2)6-.

[2139] In some embodiments of the lipid of Formula HLP-II, X is -C(2-6)alkenylene-.

[2140] In some embodiments of the lipid of Formula HLP-II, X is -OC(i-6)alkylene-. In some embodiments of the lipid of Formula HLP-II, X is -OC(2-6)alkylene-. In some embodiments of the lipid of Formula HLP-II, X is -O(CH2)2-. In some embodiments of the lipid of Formula HLP-II, X is -O(CH2)3-. In some embodiments of the lipid of Formula HLP-II, X is -O(CH2)4-. In some embodiments of the lipid of Formula HLP-II, X is -O(CH2)5-. In some embodiments of the lipid of Formula HLP-II, X is -O(CH2)6-.

[2141] In some embodiments of the lipid of Formula HLP-II, X is -OC(2-6)alkenylene-.

[2142] In some embodiments of the lipid of Formula HLP-II, X is -OC(O)C(i-6)alkylene-. In some embodiments of the lipid of Formula HLP-II, X is -OC(O)C(2-6)alkylene-.

[2143] In some embodiments of the lipid of Formula HLP-II, X is -OC(O)C(2-6)alkenylene-. In some embodiments of the lipid of Formula HLP-II, X is -OC(O)OC(i-6)alkylene-. In some embodiments of the lipid of Formula HLP-II, X is -OC(O)OC(2-6)alkylene-. In some embodiments of the lipid of Formula HLP-II, X is -OC(O)OCH2-. In some embodiments of the lipid of Formula HLP-II, X is -OC(O)O(CH2)2-. In some embodiments of the lipid of Formula HLP-II, X is -OC(O)O(CH2)3-. In some embodiments of the lipid of Formula HLP-II, X is -OC(O)O(CH2)4-. In some embodiments of the lipid of Formula HLP-II, X is -OC(O)O(CH2)5-. In some embodiments of the lipid of Formula HLP-II, X is -OC(O)O(CH2)6-.

[2144] In some embodiments of the lipid of Formula HLP-II, X is -OC(O)OC(2-6)alkenylene-. In some embodiments of the lipid of Formula HLP-II, X is -NHC(O)C(i-6)alkylene-. In some embodiments of the lipid of Formula HLP-II, X is -NHC(O)C(2-6)alkylene-. In some embodiments of the lipid of Formula HLP-II, X is -NHC(O)(CH2)2-. In some embodiments of the lipid of Formula HLP-II, X is -NHC(O)(CH2)3-. In some embodiments of the lipid of Formula HLP-II, X is -NHC(O)(CH2)4-. In some embodiments of the lipid of Formula HLP-II, X is -NHC(O)(CH2)5-. In some embodiments of the lipid of Formula HLP-II, X is -NHC(O)(CH2)6-.

[2145] In some embodiments of the lipid of Formula HLP-II, X is -NHC(O)C(2-6)alkenylene-. In some embodiments of the lipid of Formula HLP-II, X is -C(1-6)alkylene-O-C(i-6)alkylene-. In some embodiments of the lipid of Formula HLP-II, X is -C(1-6)alkylene-O-C(2-6)alkylene-. In some embodiments of the lipid of Formula HLP-II, X is -CH2-O-C(2-6)alkylene-. In some embodiments of the lipid of Formula HLP-II, X is -CH2O(CH2)2-.

[2146] 123

[2147] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2148] In some embodiments of the lipid of Formula HLP-II, X is -CH2-, -O(CH2)3-, -O(CH2)4-, -NHC(O)(CH2)2-, -CH2O(CH2)2-. In some embodiments of the lipid of Formula HLP-II, X is -CH2-, -O(CH2)3-, or -O(CH2)4-. In some embodiments of the lipid of Formula HLP-II, X is -CH2-. In some embodiments of the lipid of Formula HLP-II, X is -O(CH2)3-. In some embodiments of the lipid of Formula HLP-II, X is -O(CH2)4-. In some embodiments of the lipid of Formula HLP-II, X is -NHC(O)(CH2)2-. In some embodiments of the lipid of Formula HLP-II, X is -CH2O(CH2)2-.

[2149] In some embodiments of the lipid of Formula HLP-II, Y is -C(2-6)alkylene- or -C(2-6)alkenylene-, each of which is optionally substituted with one substituent selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2150] In some embodiments of the lipid of Formula HLP-II, Y is -C(2-6)alkylene- or -C(2-6)alkenylene-, each of which is optionally substituted with one -C(O)OH group. In some embodiments of the lipid of Formula HLP-II, Y is -C(2-6)alkylene- or -C(2-6)alkenylene-.

[2151] In some embodiments of the lipid of Formula HLP-II, Y is -C(2-6)alkylene- that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”. In some embodiments of the lipid of Formula HLP-II, Y is -C(2-6)alkylene- that is optionally substituted with one substituent selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2152] In some embodiments of the lipid of Formula HLP-II, Y is -C(2-6)alkylene- that is optionally substituted with one -C(O)OH group. In some embodiments of the lipid of Formula HLP-II, Y is -C(2-6)alkylene-. In some embodiments of the lipid of Formula HLP-II, Y is -(CH2)2-. In some embodiments of the lipid of Formula HLP-II, Y is -(CH2)3-. In some embodiments of the lipid of Formula HLP-II, Y is -(CH2)4-. In some embodiments of the lipid of Formula HLP-II, Y is -(CH2)5-. In some embodiments of the lipid of Formula HLP-II,

[2153] Y is -(CH2)6-. In some embodiments of the lipid of Formula HLP-II, Y is

[2154]

[2155] O OH. In some

[2156] 124

[2157] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2158]

[2159] embodiments of the lipid of Formula HLP-II, Y is

[2160]

[2161] O OH in some embodiments of the

[2162] lipid of Formula H

[2163]

[2164] LP-II, Y is ^O^\)H

[2165] In some embodiments of the lipid of Formula HLP-II, Y is -C(2-6)alkenylene- that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”. In some embodiments of the lipid of Formula HLP-II, Y is -C(2-6)alkenylene- that is optionally substituted with one substituent selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2166] In some embodiments of the lipid of Formula HLP-II, Y is -C(2-6)alkenylene- that is optionally substituted with one -C(O)OH group. In some embodiments of the lipid of Formula HLP-II, Y is -C(2-6)alkenylene-.

[2167]

[2168] In some embodiments of the lipid of Formula HLP-II, Y is -CH2CH2- or O'^'OH In some embodiments of the lipid of Formula HLP-II, Y is -CH2CH2-. In some embodiments

[2169] of the lipid of Formula H

[2170]

[2171] LP-II, Y is O'^'OH

[2172] In some embodiments of the lipid of Formula HLP-II, n is 0. In some embodiments of the lipid of Formula HLP-II, n is 1.

[2173] In some embodiments of the lipid of Formula HLP-II, R2Ais -C(O)OR3. In some embodiments of the lipid of Formula HLP-II, R2Bis -C(O)OR3. In some embodiments of the lipid of Formula HLP-II, R2Cis -C(O)OR3. In some embodiments of the lipid of Formula HLP-II, R2A, R2B, and R2Care each -C(O)OR3. In some embodiments of the lipid of Formula HLP-II, R2A, R2B, and R2Care each -C(O)OR3, and n is 0.

[2174] In some embodiments of the lipid of Formula HLP-II, R2Ais

[2175] O. In some embodiments of the lipid of Formula HLP-II, R2Bis

[2176]

[2177] O. In some embodiments of the lipid of Formula HLP-II, R2Cis

[2178] 125

[2179] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2180] R2.0

[2181] 0. In some embodiments of the lipid of Formula HLP-II, R2A, R2B, R2.0

[2182]

[2183] and R2Care each O. In some embodiments of the lipid of Formula R2.0 HLP-II, R2A, R2B, and R2Care each

[2184]

[2185] O, and n is 0.

[2186] In some embodiments of the lipid of Formula HLP-II’, R2Ais

[2187] O. In some embodiments of the lipid of Formula HLP-II’, R2Bis

[2188] O. In some embodiments of the lipid of Formula HLP-II’, R2Cis

[2189]

[2190] O. In some embodiments of the lipid of Formula HLP-II’, R2A, R2B,

[2191] and R2Care each

[2192]

[2193] In some embodiments of the lipid of Formula

[2194] HLP-II’, R2A, R2B, and R2Care each

[2195]

[2196] O and n is 0.

[2197] In some embodiments of the lipid of Formula HLP-II, the lipid has a structure according to Formula (HLP-IIa):

[2198]

[2199] (HLP-IIa),

[2200] or a pharmaceutically acceptable salt thereof.

[2201] In some embodiments of the lipid of Formula HLP-II, the lipid has a structure according to Formula (HLP-IIa-i):

[2202] 126

[2203] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2204]

[2205] O

[2206] (HLP-IIa-i),

[2207] or a pharmaceutically acceptable salt thereof, wherein:

[2208] XAis -O-, -OC(O)-, -NHC(O)-, or -OC(O)O-;

[2209] m is 1-6; and

[2210] v is 2-6.

[2211] In some embodiments, XA is -O-. In some embodiments, XA is -OC(O)-. In some embodiments, XA is -NHC(O)-. In some embodiments, XA is -OC(O)O-.

[2212] In some embodiments of the lipid of Formula HLP-II, the lipid has a structure according to Formula (HLP-IIa-ii):

[2213] R

[2214] N.

[2215] OH

[2216]

[2217] O

[2218] (HLP-IIa-ii),

[2219] or a pharmaceutically acceptable salt thereof, wherein:

[2220] m is 1-6; and

[2221] v is 2-6.

[2222] In some embodiments, m is 2-6. In some embodiments, m is 2-4. 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.

[2223] In some embodiments, v is 2-4. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4. In some embodiments, v is 5. In some embodiments, v is

[2224] In some embodiments, m is 2-4, and v is 2-4. In some embodiments, m is 2-4, and v is

[2225] 127

[2226] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2227] In some embodiments, R2Ais -OC(O)R3. In some embodiments, R2Bis -OC(O)R3. In some embodiments, R2Cis -OC(O)R3. In some embodiments, R2A, R2B, and R2Care each -OC(O)R3. In some embodiments, R2A, R2B, and R2Care each -OC(O)R3, and n is 1.

[2228] O

[2229] R3

[2230] In some embodiments, R2Ais

[2231]

[2232] O. In some embodiments, O O

[2233] R3R3

[2234]

[2235] R2B’ is O. In some embodiments, R2Cis O'

[2236] O

[2237] R3

[2238] . In some embodiments, R2A, R2B, and R2Care each

[2239]

[2240] O. In some O

[2241] R3embodiments, R2A, R2B, and R2Care each

[2242]

[2243] O, and n is 1.

[2244] O

[2245] R3

[2246] In some embodiments, R2Ais

[2247]

[2248] O. In some embodiments, R2BO O

[2249] R3R3

[2250]

[2251] is O. In some embodiments, R2Cis o v In O

[2252] R3

[2253] some embodiments, R2A, R2B, and R2Care each

[2254]

[2255] O. In some

[2256] O

[2257] R3

[2258] embodiments, R2A, R2B, and R2Care each

[2259]

[2260] O, and n is 1.

[2261] In some embodiments of the lipid of Formula HLP-II, the lipid has a structure according to Formula (HLP-IIb):

[2262]

[2263] (HLP-IIb),

[2264] or a pharmaceutically acceptable salt thereof.

[2265] 128

[2266] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2267] In some embodiments of the lipid of Formula HLP-II, the lipid has a structure according to Formula (HLP-IIb-i):

[2268]

[2269] or a pharmaceutically acceptable salt thereof, wherein:

[2270] XB is absent, -O-, -OC(O)-, -NHC(O)-, -OC(O)O-, or -C(1-6)alkylene-O-;

[2271] p is 1-6; and

[2272] w is 2-6.

[2273] In some embodiments, XB is absent. In some embodiments, XB is -O-. In some embodiments, XB is -OC(O)-. In some embodiments, XB is -NHC(O)-. In some embodiments, XB is -OC(O)O-. In some embodiments, XB is -C(1-6)alkylene-O-. In some embodiments, XB is -CH2O-.

[2274] In some embodiments of the lipid of Formula HLP-II, the lipid has a structure according to Formula (HLP-IIb-ii):

[2275]

[2276] (HLP-IIb-ii),

[2277] or a pharmaceutically acceptable salt thereof, wherein:

[2278] p is 1-6; and

[2279] w is 2-6.

[2280] In some embodiments of the lipid of Formula HLP-II, the lipid has a structure according to Formula (HLP-IIb-iii):

[2281] 129

[2282] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2283]

[2284] (HLP-IIb-iii),

[2285] or a pharmaceutically acceptable salt thereof, wherein:

[2286] p is 1-6; and

[2287] w is 2-6.

[2288] In some embodiments of the lipid of Formula HLP-II, the lipid has a structure according to Formula (HLP-IIb-iv):

[2289]

[2290] or a pharmaceutically acceptable salt thereof, wherein:

[2291] p is 1-6; and

[2292] w is 2-6.

[2293] In some embodiments, p is 1-4. In some embodiments, p is 1-3. In some embodiments, p is 2-4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

[2294] In some embodiments, w is 2-4. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, w is 5. In some embodiments, w is 6.

[2295] In some embodiments, p is 1-4, and w is 2-4. In some embodiments, p is 1-3, and w is 2-4. In some embodiments, p is 2-4, and w is 2-4. In some embodiments, p is 1-4, and w is 2. In some embodiments, p is 1-3, and w is 2. In some embodiments, p is 2-4, and w is 2.

[2296] 130

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[2298] In some embodiments, R2Ais -OR3. In some embodiments, R2Bis -OR3. In some embodiments, R2Cis -OR3. In some embodiments, R2A, R2B, and R2Care each -OR3. In some embodiments, R2A, R2B, and R2Care each -OR3, and n is 1.

[2299] In some embodiments

[2300]

[2301] In some embodiments, R2Bis

[2302]

[2303] R O V In some embodiments, R2Cis R O \ In some embodiments, R2A, R2B, and R2Care each

[2304]

[2305] R' O. In some embodiments, R2A, R2B, and R2Care each R

[2306]

[2307] OA, and n is 1.

[2308] In some embodiments, R2Ais

[2309]

[2310] RO. In some embodiments, R2Bis

[2311]

[2312] R‘ OA. In some embodiments, R2Cis R OA. In some embodiments, R2A, R2B, and R2Care each

[2313]

[2314] R O. In some embodiments, R2A, R2B, and R2Care eachR

[2315]

[2316] O, and n is 1.

[2317] In some embodiments of the lipid of Formula HLP-II, the lipid has a structure according to Formula (HLP-IIc):

[2318] R3

[2319] I

[2320] (X

[2321] > o

[2322]

[2323] (HLP-IIc),

[2324] or a pharmaceutically acceptable salt thereof.

[2325] In some embodiments of the lipid of Formula HLP-II, the lipid has a structure according to Formula (HLP-IIc-i):

[2326]

[2327] (HLP-IIc-i),

[2328] 131

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[2330] or a pharmaceutically acceptable salt thereof, wherein:

[2331] Xc is absent, -O-, -OC(O)-, -NHC(O)-, -OC(O)O-, or -C(1-6)alkylene-O-;

[2332] q is 1-6; and

[2333] z is 2-6.

[2334] In some embodiments, Xc is absent. In some embodiments, Xc is -O-. In some embodiments, Xc is -OC(O)-. In some embodiments, Xc is -NHC(O)-. In some embodiments, Xc is -OC(O)O-. In some embodiments, Xc is -C(1-6)alkylene-O-. In some embodiments, Xc is -CH2O-.

[2335] In some embodiments of the lipid of Formula HLP-II, the lipid has a structure according to Formula (HLP-IIc-ii):

[2336]

[2337] (HLP-IIc-ii),

[2338] or a pharmaceutically acceptable salt thereof, wherein:

[2339] q is 1-6; and

[2340] z is 2-6.

[2341] In some embodiments, q is 1-4. In some embodiments, q is 1-3. In some embodiments, q is 2-4. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6.

[2342] In some embodiments, z is 2-4. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6.

[2343] In some embodiments, q is 1-4, and z is 2-4. In some embodiments, q is 1-3, and z is 2-4. In some embodiments, q is 2-4, and z is 2-4. In some embodiments, q is 1-4, and z is 2. In some embodiments, q is 1-3, and z is 2. In some embodiments, q is 2-4, and z is 2.

[2344] In some embodiments, each R3is the same.

[2345] In some embodiments, each R3is independently -C(9-25)alkyl, -C(9-25)alkenyl or -C(9-25)alkynyl, each of which is optionally substituted with one, two, or three substituents

[2346] 132

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[2348] independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” or -SO2R”.

[2349] In some embodiments, each R3is independently -C(9-25)alkyl, -C(9-25)alkenyl or -C(9-25)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -CN, -OH, -OR”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” or -SO2R”.

[2350] In some embodiments, each R3is -C(9-25)alkyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” or -SO2R”.

[2351] In some embodiments, each R3is -C(9-25)alkenyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” or -SO2R”.

[2352] In some embodiments, each R3is -C(9-25)alkynyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” or -SO2R”.

[2353] In some embodiments, each R3is independently -C(9-25)alkyl, -C(9-25)alkenyl or -C(9-25)alkynyl. In some embodiments, each R3is independently -C(9-25)alkyl or -C(9-25)alkenyl. In some embodiments, each R3is -C(9-25)alkyl. In some embodiments, each R3is -C(9-25)alkenyl. In some embodiments, each R3is -C(9-25)alkynyl.

[2354] In some embodiments, each R3is -C(9)alkyl. In some embodiments, each R3is -C(10)alkyl. In some embodiments, each R3is -C(11)alkyl. In some embodiments, each R3is -C(12)alkyl. In some embodiments, each R3is -C(13)alkyl. In some embodiments, each R3is -C(14)alkyl. In some embodiments, each R3is -C(15)alkyl. In some embodiments, each R3is -C(16)alkyl. In some embodiments, each R3is -C(17)alkyl. In some embodiments, each R3is -C(18)alkyl. In some embodiments, each R3is -C(19)alkyl. In some embodiments, each R3is -C(20)alkyl. In some embodiments, each R3is -C(21)alkyl. In some embodiments, each R3is -C(22)alkyl. In some embodiments, each R3is -C(23)alkyl. In some embodiments, each R3is -C(24)alkyl. In some embodiments, each R3is -C(25)alkyl.

[2355] In some embodiments, each R3is -C(9)alkenyl. In some embodiments, each R3is -C(10)alkenyl. In some embodiments, each R3is -C(11)alkenyl. In some embodiments, each R3is -C(12)alkenyl. In some embodiments, each R3is -C(i3)alkenyl. In some embodiments, each 133

[2356] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2357] R3is -C(14)alkenyl. In some embodiments, each R3is -C(15)alkenyl. In some embodiments, each R3is -C(16)alkenyl. In some embodiments, each R3is -C(17)alkenyl. In some embodiments, each R3is -C(18)alkenyl. In some embodiments, each R3is -C(19)alkenyl. In some embodiments, each R3is -C(20)alkenyl. In some embodiments, each R3is -C(2i)alkenyl. In some embodiments, each R3is -C(22)alkenyl. In some embodiments, each R3is -C(23)alkenyl. In some embodiments, each R3is -C(24)alkenyl. In some embodiments, each R3is -C(25)alkenyl.

[2358] In some embodiments, each R3is -C(9)alkynyl. In some embodiments, each R3is -C(10)alkynyl. In some embodiments, each R3is -C(11)alkynyl. In some embodiments, each R3is -C(12)alkynyl. In some embodiments, each R3is -C(13)alkynyl. In some embodiments, each R3is -C(14)alkynyl. In some embodiments, each R3is -C(15)alkynyl. In some embodiments, each R3is -C(16)alkynyl. In some embodiments, each R3is -C(17)alkynyl. In some embodiments, each R3is -C(18)alkynyl. In some embodiments, each R3is -C(19)alkynyl. In some embodiments, each R3is -C(20)alkynyl. In some embodiments, each R3is -C(2i)alkynyl. In some embodiments, each R3is -C(22)alkynyl. In some embodiments, each R3is -C(23)alkynyl. In some embodiments, each R3is -C(24)alkynyl. In some embodiments, each R3is -C(25)alkynyl.

[2359] In some embodiments, each R3is

[2360]

[2361] .

[2362] In some embodiments, each R3is

[2363]

[2364] In some embodiments, each R3is

[2365]

[2366] In some embodiments, each R3is

[2367]

[2368] In some embodiments, each R3is

[2369]

[2370] In some embodiments, each R3is

[2371]

[2372] In some embodiments, each R3is

[2373]

[2374] O

[2375] In some embodiments, each R3is independently

[2376]

[2377] R u, wherein:

[2378] each R3Ais independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-31)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; and

[2379] each ZA is independently -C(6-io)alkylene- or -C(7-io)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the 134

[2380] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2381] group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2382] O

[2383] A,zA A

[2384] In some embodiments, each R3is independently R 0, wherein each R3Ais independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-31)alkynyl; and each ZA is independently -C(6-10)alkylene- or -C(7-10)alkenylene-.

[2385] O

[2386] In some embodiments, each R3is independently R3A 0

[2387]

[2388] , wherein each R3Ais independently -C(1-31)alkyl or -C(2-31)alkenyl; and each ZA is independently -C(6-10)alkylene- or -C(7-10)alkenylene-.

[2389] O

[2390] A,zA A

[2391] In some embodiments, each R3is independently R O A wherein each R3Ais -C(1-31)alkyl; and each ZA is -C(6-10)alkylene-.

[2392] In some embodiments, each R3Ais -C(1-31)alkyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2393] In some embodiments, each R3Ais -C(2-31)alkenyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2394] In some embodiments, each R3Ais -C(2-31)alkynyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2395] In some embodiments, each R3Ais independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-

[2396] 31)alkynyl. In some embodiments, each R3Ais independently -C(1-31)alkyl or -C(2-31)alkenyl. In some embodiments, each R3Ais -C(1-31)alkyl. In some embodiments, each R3Ais -C(2-

[2397] 31)alkenyl. In some embodiments, each R3Ais -C(2-31)alkynyl.

[2398] In some embodiments, each R3Ais -C(1)alkyl. In some embodiments, each R3Ais -C(2)alkyl. In some embodiments, each R3Ais -C(3)alkyl. In some embodiments, each R3Ais -C(4)alkyl. In some embodiments, each R3Ais -C(5)alkyl. In some embodiments, each R3Ais -

[2399] 135

[2400] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2401] C(6)alkyl. In some embodiments, each R3Ais -C(7)alkyl. In some embodiments, each R3Ais -C(8)alkyl. In some embodiments, each R3Ais -C(9)alkyl. In some embodiments, each R3Ais -C(10)alkyl. In some embodiments, each R3Ais -C(11)alkyl. In some embodiments, each R3Ais -C(12)alkyl. In some embodiments, each R3Ais -C(13)alkyl. In some embodiments, each R3Ais -C(14)alkyl. In some embodiments, each R3Ais -C(15)alkyl. In some embodiments, each R3Ais -C(16)alkyl. In some embodiments, each R3Ais -C(17)alkyl. In some embodiments, each R3Ais -C(18)alkyl. In some embodiments, each R3Ais -C(19)alkyl. In some embodiments, each R3Ais -C(20)alkyl. In some embodiments, each R3Ais -C(21)alkyl. In some embodiments, each R3Ais -C(22)alkyl. In some embodiments, each R3Ais -C(23)alkyl. In some embodiments, each R3Ais -C(24)alkyl. In some embodiments, each R3Ais -C(25)alkyl. In some embodiments, each R3Ais -C(26)alkyl. In some embodiments, each R3Ais -C(27)alkyl. In some embodiments, each R3Ais -C(28)alkyl. In some embodiments, each R3Ais -C(29)alkyl. In some embodiments, each R3Ais -C(30)alkyl. In some embodiments, each R3Ais -C(31)alkyl.

[2402] In some embodiments, each R3Ais -C(2)alkenyl. In some embodiments, each R3Ais -C(3)alkenyl. In some embodiments, each R3Ais -C(4)alkenyl. In some embodiments, each R3Ais -C(5)alkenyl. In some embodiments, each R3Ais -C(6)alkenyl. In some embodiments, each R3Ais -C(7)alkenyl. In some embodiments, each R3Ais -C(8)alkenyl. In some embodiments, each R3Ais -C(9)alkenyl. In some embodiments, each R3Ais -C(10)alkenyl. In some embodiments, each R3Ais -C(11)alkenyl. In some embodiments, each R3Ais -C(12)alkenyl. In some embodiments, each R3Ais -C(13)alkenyl. In some embodiments, each R3Ais -C(14)alkenyl. In some embodiments, each R3Ais -C(15)alkenyl. In some embodiments, each R3Ais -C(16)alkenyl. In some embodiments, each R3Ais -C(17)alkenyl. In some embodiments, each R3Ais -C(18)alkenyl. In some embodiments, each R3Ais -C(19)alkenyl. In some embodiments, each R3Ais -C(20)alkenyl. In some embodiments, each R3Ais -C(21)alkenyl. In some embodiments, each R3Ais -C(22)alkenyl. In some embodiments, each R3Ais -C(23)alkenyl. In some embodiments, each R3Ais -C(24)alkenyl. In some embodiments, each R3Ais -C(25)alkenyl. In some embodiments, each R3Ais -C(26)alkenyl. In some embodiments, each R3Ais -C(27)alkenyl. In some embodiments, each R3Ais -C(28)alkenyl. In some embodiments, each R3Ais -C(29)alkenyl. In some embodiments, each R3Ais -C(30)alkenyl. In some embodiments, each R3Ais -C(31)alkenyl.

[2403] In some embodiments, each R3Ais -C(2)alkynyl. In some embodiments, each R3Ais -C(3)alkynyl. In some embodiments, each R3Ais -C(4)alkynyl. In some embodiments, each R3Ais -C(5)alkynyl. In some embodiments, each R3Ais -C(6)alkynyl. In some embodiments, each R3Ais -C(7)alkynyl. In some embodiments, each R3Ais -C(8)alkynyl. In some embodiments,

[2404] 136

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[2406] each R3Ais -C(9)alkynyl. In some embodiments, each R3Ais -C(io)alkynyl. In some embodiments, each R3Ais -C(11)alkynyl. In some embodiments, each R3Ais -C(12)alkynyl. In some embodiments, each R3Ais -C(13)alkynyl. In some embodiments, each R3Ais -C(14)alkynyl. In some embodiments, each R3Ais -C(15)alkynyl. In some embodiments, each R3Ais -C(16)alkynyl. In some embodiments, each R3Ais -C(17)alkynyl. In some embodiments, each R3Ais -C(18)alkynyl. In some embodiments, each R3Ais -C(19)alkynyl. In some embodiments, each R3Ais -C(20)alkynyl. In some embodiments, each R3Ais -C(21)alkynyl. In some embodiments, each R3Ais -C(22)alkynyl. In some embodiments, each R3Ais -C(23)alkynyl. In some embodiments, each R3Ais -C(24)alkynyl. In some embodiments, each R3Ais -C(25)alkynyl. In some embodiments, each R3Ais -C(26)alkynyl. In some embodiments, each R3Ais -C(27)alkynyl. In some embodiments, each R3Ais -C(28)alkynyl. In some embodiments, each R3Ais -C(29)alkynyl. In some embodiments, each R3Ais -C(30)alkynyl. In some embodiments, each R3Ais -C(31)alkynyl.

[2407] In some embodiments, each R3Ais

[2408]

[2409] .

[2410] In some embodiments, each R3Ais

[2411]

[2412] .

[2413] In some embodiments, each R3Ais

[2414]

[2415] In some embodiments, each R3Ais

[2416]

[2417] In some embodiments, each ZA is -C(6-io)alkylene- that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2418] In some embodiments, each ZA is -C(7-io)alkenylene- that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2419] In some embodiments, each ZA is independently -C(6-10)alkylene- or -C(7-10)alkenylene-. In some embodiments, each ZA is -C(6-10)alkylene-. In some embodiments, each ZA is -C(7-10)alkenylene-.

[2420] In some embodiments, each ZA is -C(6)alkylene-. In some embodiments, each ZA is -C(7)alkylene-. In some embodiments, each ZA is -C(8)alkylene-. In some embodiments, each ZA is -C(9)alkylene-. In some embodiments, each ZA is -C(10)alkylene-.

[2421] 137

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[2423] In some embodiments, each ZA is -C(7)alkenylene-. In some embodiments, each ZA is -C(8)alkenylene-. In some embodiments, each ZA is -C(9)alkenylene-. In some embodiments, each ZA is -C(10)alkenylene-.

[2424] In some embodiments, each ZA is

[2425]

[2426] In some embodiments, each ZA is

[2427]

[2428] In some embodiments, each ZA is

[2429]

[2430] R3B'°YZB

[2431] In some embodiments, each R3is independently °, wherein:

[2432] each R3Bis independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-31)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; and

[2433] each ZB is independently -C(6-10)alkylene- or -C(7-10)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2434] R3B'°YZB^

[2435] In some embodiments, each R3is independently O, wherein each R3Bis independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-31)alkynyl; and each ZB is independently -C(6-10)alkylene- or -C(7-10)alkenylene-.

[2436] R3B Y

[2437] In some embodiments, each R3is independently0, wherein each R3Bis independently -C(1-31)alkyl or -C(2-31)alkenyl; and each ZB is independently -C(6-10)alkylene- or -C(7-10)alkenylene-.

[2438] R3B V

[2439]

[2440] In some embodiments, each R3is independently0, wherein each R3Bis -C(1-31)alkyl; and each ZB is -C(6-10)alkylene-.

[2441] In some embodiments, each R3Bis -C(1-31)alkyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2442] 138

[2443] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2444] In some embodiments, each R3Bis -C(2-3i)alkenyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2445] In some embodiments, each R3Bis -C(2-31)alkynyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2446] In some embodiments, each R3Bis independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-

[2447] 31)alkynyl. In some embodiments, each R3Bis independently -C(1-31)alkyl or -C(2-31)alkenyl. In some embodiments, each R3Bis -C(1-31)alkyl. In some embodiments, each R3Bis -C(2-

[2448] 31)alkenyl. In some embodiments, each R3Bis -C(2-31)alkynyl.

[2449] In some embodiments, each R3Bis -C(1)alkyl. In some embodiments, each R3Bis -C(2)alkyl. In some embodiments, each R3Bis -C(3)alkyl. In some embodiments, each R3Bis -C(4)alkyl. In some embodiments, each R3Bis -C(5)alkyl. In some embodiments, each R3Bis - C(6)alkyl. In some embodiments, each R3Bis -C(7)alkyl. In some embodiments, each R3Bis - C(8)alkyl. In some embodiments, each R3Bis -C(9)alkyl. In some embodiments, each R3Bis -C(10)alkyl. In some embodiments, each R3Bis -C(11)alkyl. In some embodiments, each R3Bis -C(12)alkyl. In some embodiments, each R3Bis -C(13)alkyl. In some embodiments, each R3Bis -C(14)alkyl. In some embodiments, each R3Bis -C(15)alkyl. In some embodiments, each R3Bis -C(16)alkyl. In some embodiments, each R3Bis -C(17)alkyl. In some embodiments, each R3Bis -C(18)alkyl. In some embodiments, each R3Bis -C(19)alkyl. In some embodiments, each R3Bis -C(20)alkyl. In some embodiments, each R3Bis -C(21)alkyl. In some embodiments, each R3Bis -C(22)alkyl. In some embodiments, each R3Bis -C(23)alkyl. In some embodiments, each R3Bis -C(24)alkyl. In some embodiments, each R3Bis -C(25)alkyl. In some embodiments, each R3Bis -C(26)alkyl. In some embodiments, each R3Bis -C(27)alkyl. In some embodiments, each R3Bis -C(28)alkyl. In some embodiments, each R3Bis -C(29)alkyl. In some embodiments, each R3Bis -C(30)alkyl. In some embodiments, each R3Bis -C(31)alkyl.

[2450] In some embodiments, each R3Bis -C(2)alkenyl. In some embodiments, each R3Bis -C(3)alkenyl. In some embodiments, each R3Bis -C(4)alkenyl. In some embodiments, each R3Bis -C(5)alkenyl. In some embodiments, each R3Bis -C(6)alkenyl. In some embodiments, each R3Bis -C(7)alkenyl. In some embodiments, each R3Bis -C(8)alkenyl. In some embodiments, each R3Bis -C(9)alkenyl. In some embodiments, each R3Bis -C(10)alkenyl. In some embodiments, each R3Bis -C(11)alkenyl. In some embodiments, each R3Bis -C(12)alkenyl. In 139

[2451] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2452] some embodiments, each R3Bis -C(i3)alkenyl. In some embodiments, each R3Bis -C(i4)alkenyl. In some embodiments, each R3Bis -C(i5)alkenyl. In some embodiments, each R3Bis -C(i6)alkenyl. In some embodiments, each R3Bis -C(i7)alkenyl. In some embodiments, each R3Bis -C(18)alkenyl. In some embodiments, each R3Bis -C(19)alkenyl. In some embodiments, each R3Bis -C(20)alkenyl. In some embodiments, each R3Bis -C(2i)alkenyl. In some embodiments, each R3Bis -C(22)alkenyl. In some embodiments, each R3Bis -C(23)alkenyl. In some embodiments, each R3Bis -C(24)alkenyl. In some embodiments, each R3Bis -C(25)alkenyl. In some embodiments, each R3Bis -C(26)alkenyl. In some embodiments, each R3Bis -C(27)alkenyl. In some embodiments, each R3Bis -C(28)alkenyl. In some embodiments, each R3Bis -C(29)alkenyl. In some embodiments, each R3Bis -C(30)alkenyl. In some embodiments, each R3Bis -C(3i)alkenyl.

[2453] In some embodiments, each R3Bis -C(2)alkynyl. In some embodiments, each R3Bis -C(3)alkynyl. In some embodiments, each R3Bis -C(4)alkynyl. In some embodiments, each R3Bis -C(5)alkynyl. In some embodiments, each R3Bis -C(6)alkynyl. In some embodiments, each R3Bis -C(7)alkynyl. In some embodiments, each R3Bis -C(8)alkynyl. In some embodiments, each R3Bis -C(9)alkynyl. In some embodiments, each R3Bis -C(io)alkynyl. In some embodiments, each R3Bis -C(ii)alkynyl. In some embodiments, each R3Bis -C(i2)alkynyl. In some embodiments, each R3Bis -C(i3)alkynyl. In some embodiments, each R3Bis -C(i4)alkynyl. In some embodiments, each R3Bis -C(i5)alkynyl. In some embodiments, each R3Bis -C(i6)alkynyl. In some embodiments, each R3Bis -C(i7)alkynyl. In some embodiments, each R3Bis -C(i8)alkynyl. In some embodiments, each R3Bis -C(i9)alkynyl. In some embodiments, each R3Bis -C(20)alkynyl. In some embodiments, each R3Bis -C(2i)alkynyl. In some embodiments, each R3Bis -C(22)alkynyl. In some embodiments, each R3Bis -C(23)alkynyl. In some embodiments, each R3Bis -C(24)alkynyl. In some embodiments, each R3Bis -C(25)alkynyl. In some embodiments, each R3Bis -C(26)alkynyl. In some embodiments, each R3Bis -C(27)alkynyl. In some embodiments, each R3Bis -C(28)alkynyl. In some embodiments, each R3Bis -C(29)alkynyl. In some embodiments, each R3Bis -C(30)alkynyl. In some embodiments, each R3Bis -C(3i)alkynyl.

[2454] In some embodiments, each R3Bis

[2455]

[2456] In some embodiments, each R3Bis

[2457]

[2458] In some embodiments, each R3Bis

[2459]

[2460] In some embodiments, each R3Bis

[2461]

[2462] 140

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[2464] In some embodiments, each ZB is -C(6-io)alkylene- that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2465] In some embodiments, each ZB is -C(7-io)alkenylene- that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2466] In some embodiments, each ZB is independently -C(6-io)alkylene- or -C(7-io)alkenylene-. In some embodiments, each ZB is -C(6-io)alkylene-. In some embodiments, each ZB is -C(7-io)alkenylene-.

[2467] In some embodiments, each ZB is -C(6)alkylene-. In some embodiments, each ZB is -C(7)alkylene-. In some embodiments, each ZB is -C(8)alkylene-. In some embodiments, each ZB is -C(9)alkylene-. In some embodiments, each ZB is -C(io)alkylene-.

[2468] In some embodiments, each ZB is -C(7)alkenylene-. In some embodiments, each ZB is -C(8)alkenylene-. In some embodiments, each ZB is -C(9)alkenylene-. In some embodiments, each ZB is -C(io)alkenylene-.

[2469] In some embodiments, each ZB is

[2470]

[2471] In some embodiments, each ZB is

[2472]

[2473] In some embodiments, each ZB is

[2474]

[2475] O

[2476] In some embodiments, each R3is

[2477]

[2478] ' °

[2479]

[2480] In some embodiments, each R3is0

[2481]

[2482] In some embodiments, each R3is0

[2483]

[2484] In some embodiments, each R3is O

[2485] O

[2486] In some embodiments, each R3is

[2487]

[2488]

[2489] In some embodiments, each R3is O

[2490] 141

[2491] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2492]

[2493] In some embodiments, each R3is independently selected from the group consisting O

[2494] of: (i) -C(9-25)alkyl, -C(9-25)alkenyl or -C(9-25)alkynyl; (ii)

[2495]

[2496] r3AO, wherein each R3Ais independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-31)alkynyl; and each ZA is independently -C(6-10)alkylene- or -C(7-10)alkenylene-; and (iii) O, wherein each R3Bis independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-31)alkynyl; and each ZB is independently -C(6-10)alkylene- or -C(7-10)alkenylene-.

[2497] In some embodiments, each R3is independently selected from the group consisting O

[2498] of: (i) -C(9-25)alkyl or -C(9-25)alkenyl; (ii)

[2499]

[2500] r3AO, wherein each R3Ais independently -C(1-31)alkyl or -C(2-31)alkenyl; and each ZA is independently -C(6-10)alkylene- or -C(7-10)alkenylene-; and (iii) O, wherein each R3Bis independently -C(1-31)alkyl or -C(2-31)alkenyl; and each ZB is independently -C(6-10)alkylene- or -C(7-10)alkenylene-.

[2501] In some embodiments, each R3is independently selected from the group consisting O

[2502] of: (i) -C(9-25)alkyl or -C(9-25)alkenyl; (ii)

[2503]

[2504] r3AO, wherein each R3Ais -C(1-31)alkyl,

[2505]

[2506] and each ZA is -C(6-10)alkylene-; and (iii) O, wherein each R3Bis -C(1-31)alkyl, and each ZB is -C(6-10)alkylene-.

[2507] In some embodiments, R2A, R2B, and R2Care each independently selected from the group consisting of:

[2508] O

[2509]

[2510] 142

[2511] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2512]

[2513] 143

[2514] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2515] In some embodiments, each R3is the same.

[2516] In some embodiments, each R3is independently -C(4-20)alkenyl or -C(4-20)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2517] In some embodiments, each R3is independently -C(4-20)alkenyl or -C(4-20)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -CN, -OH, -OR”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2518] In some embodiments, each R3is -C(4-20)alkenyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2519] In some embodiments, each R3is -C(4-20)alkynyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2520] In some embodiments, each R3is independently -C(4-20)alkenyl or -C(4-20)alkynyl. In some embodiments, each R3is -C(4-20)alkenyl. In some embodiments, each R3is independently -C(4-20)alkynyl.

[2521] In some embodiments, each R3is -C(4)alkenyl. In some embodiments, each R3is -C(5)alkenyl. In some embodiments, each R3is -C(6)alkenyl. In some embodiments, each R3is -C(7)alkenyl. In some embodiments, each R3is -C(8)alkenyl. In some embodiments, each R3is -C(9)alkenyl. In some embodiments, each R3is -C(io)alkenyl. In some embodiments, each R3is -C(ii)alkenyl. In some embodiments, each R3is -C(i2)alkenyl. In some embodiments, each R3is -C(i3)alkenyl. In some embodiments, each R3is -C(14)alkenyl. In some embodiments, each R3is -C(15)alkenyl. In some embodiments, each R3is -C(16)alkenyl. In some embodiments, each R3is -C(17)alkenyl. In some embodiments, each R3is -C(18)alkenyl. In some embodiments, each R3is -C(19)alkenyl. In some embodiments, each R3is -C(20)alkenyl.

[2522] In some embodiments, each R3is -C(4)alkynyl. In some embodiments, each R3is -C(5)alkynyl. In some embodiments, each R3is -C(6)alkynyl. In some embodiments, each R3is -C(7)alkynyl. In some embodiments, each R3is -C(8)alkynyl. In some embodiments, each R3is -C(9)alkynyl. In some embodiments, each R3is -C(io)alkynyl. In some embodiments, each R3is -C(ii)alkynyl. In some embodiments, each R3is -C(i2)alkynyl. In some embodiments, each 144

[2523] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2524] R3is -C(i3)alkynyl. In some embodiments, each R3is -C(i4)alkynyl. In some embodiments, each R3is -C(i5)alkynyl. In some embodiments, each R3is -C(i6)alkynyl. In some embodiments, each R3is -C(i7)alkynyl. In some embodiments, each R3is -C(i8)alkynyl. In some embodiments, each R3is -C(i9)alkynyl. In some embodiments, each R3is -C(20)alkynyl.

[2525] In some embodiments, each R3is

[2526]

[2527] In some embodiments, each R3is

[2528]

[2529] O

[2530] In some embodiments, each R3is independently

[2531]

[2532] r3AA0*, wherein:

[2533] each R3Ais independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-31)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; and

[2534] each ZA is independently -C(1-10)alkylene- or -C(2-io)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2535] OMA

[2536] In some embodiments, each R3is independently

[2537]

[2538] R 0A wherein each R3Ais independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl; and each ZA is independently -C(1-10)alkylene- or -C(2-10)alkenylene-.

[2539] O

[2540] In some embodiments, each R3is independently

[2541]

[2542] R 0 / A A wherein each R3Ais independently -C(i-3i)alkyl or -C(2-3i)alkenyl; and each ZA is independently -C(1-10)alkylene- or -C(2-10)alkenylene-.

[2543] O

[2544] In some embodiments, each R3is independently

[2545]

[2546] RA0,zAA. wherein each R3Ais -C(1-31)alkyl; and each ZA is -C(1-10)alkylene-.

[2547] In some embodiments, each R3Ais -C(1-31)alkyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2548] 145

[2549] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2550] In some embodiments, each R3Ais -C(2-3i)alkenyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2551] In some embodiments, each R3Ais -C(2-31)alkynyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2552] In some embodiments, each R3Ais independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-

[2553] 31)alkynyl. In some embodiments, each R3Ais independently -C(1-31)alkyl or -C(2-31)alkenyl. In some embodiments, each R3Ais -C(1-31)alkyl. In some embodiments, each R3Ais -C(2-

[2554] 31)alkenyl. In some embodiments, each R3Ais -C(2-31)alkynyl.

[2555] In some embodiments, each R3Ais - palkyl. In some embodiments, each R3Ais -C(2)alkyl. In some embodiments, each R3Ais -C(3)alkyl. In some embodiments, each R3Ais - C(4)alkyl. In some embodiments, each R3Ais -C(5)alkyl. In some embodiments, each R3Ais - C(6)alkyl. In some embodiments, each R3Ais -C(7)alkyl. In some embodiments, each R3Ais - C(8)alkyl. In some embodiments, each R3Ais -C(9)alkyl. In some embodiments, each R3Ais - C(io)alkyl. In some embodiments, each R3Ais -C(11)alkyl. In some embodiments, each R3Ais -C(12)alkyl. In some embodiments, each R3Ais -C(i3)alkyl. In some embodiments, each R3Ais -C(i4)alkyl. In some embodiments, each R3Ais -C(i5)alkyl. In some embodiments, each R3Ais -C(i6)alkyl. In some embodiments, each R3Ais -C(i7)alkyl. In some embodiments, each R3Ais -C(i8)alkyl. In some embodiments, each R3Ais -C(i9)alkyl. In some embodiments, each R3Ais -C(20)alkyl. In some embodiments, each R3Ais -C(21)alkyl. In some embodiments, each R3Ais -C(22)alkyl. In some embodiments, each R3Ais -C(23)alkyl. In some embodiments, each R3Ais -C(24)alkyl. In some embodiments, each R3Ais -C(25)alkyl. In some embodiments, each R3Ais -C(26)alkyl. In some embodiments, each R3Ais -C(27)alkyl. In some embodiments, each R3Ais -C(28)alkyl. In some embodiments, each R3Ais -C(29)alkyl. In some embodiments, each R3Ais -C(30)alkyl. In some embodiments, each R3Ais -C(3i)alkyl.

[2556] In some embodiments, each R3Ais -C(2)alkenyl. In some embodiments, each R3Ais -C(3)alkenyl. In some embodiments, each R3Ais -C(4)alkenyl. In some embodiments, each R3Ais -C(5)alkenyl. In some embodiments, each R3Ais -C(6)alkenyl. In some embodiments, each R3Ais -C(7)alkenyl. In some embodiments, each R3Ais -C(8)alkenyl. In some embodiments, each R3Ais -C(9)alkenyl. In some embodiments, each R3Ais -C(io)alkenyl. In some embodiments, each R3Ais -C(11)alkenyl. In some embodiments, each R3Ais -C(12)alkenyl. In 146

[2557] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2558] some embodiments, each R3Ais -C(i3)alkenyl. In some embodiments, each R3Ais -C(i4)alkenyl. In some embodiments, each R3Ais -C(i5)alkenyl. In some embodiments, each R3Ais -C(i6)alkenyl. In some embodiments, each R3Ais -C(i7)alkenyl. In some embodiments, each R3Ais -C(i8)alkenyl. In some embodiments, each R3Ais -C(i9)alkenyl. In some embodiments, each R3Ais -C(20)alkenyl. In some embodiments, each R3Ais -C(21)alkenyl. In some embodiments, each R3Ais -C(22)alkenyl. In some embodiments, each R3Ais -C(23)alkenyl. In some embodiments, each R3Ais -C(24)alkenyl. In some embodiments, each R3Ais -C(25)alkenyl. In some embodiments, each R3Ais -C(26)alkenyl. In some embodiments, each R3Ais -C(27)alkenyl. In some embodiments, each R3Ais -C(28)alkenyl. In some embodiments, each R3Ais -C(29)alkenyl. In some embodiments, each R3Ais -C(30)alkenyl. In some embodiments, each R3Ais -C(31)alkenyl.

[2559] In some embodiments, each R3Ais -C(2)alkynyl. In some embodiments, each R3Ais -C(3)alkynyl. In some embodiments, each R3Ais -C(4)alkynyl. In some embodiments, each R3Ais -C(5)alkynyl. In some embodiments, each R3Ais -C(6)alkynyl. In some embodiments, each R3Ais -C(7)alkynyl. In some embodiments, each R3Ais -C(8)alkynyl. In some embodiments, each R3Ais -C(9)alkynyl. In some embodiments, each R3Ais -C(io)alkynyl. In some embodiments, each R3Ais -C(ii)alkynyl. In some embodiments, each R3Ais -C(i2)alkynyl. In some embodiments, each R3Ais -C(i3)alkynyl. In some embodiments, each R3Ais -C(i4)alkynyl. In some embodiments, each R3Ais -C(i5)alkynyl. In some embodiments, each R3Ais -C(i6)alkynyl. In some embodiments, each R3Ais -C(i7)alkynyl. In some embodiments, each R3Ais -C(i8)alkynyl. In some embodiments, each R3Ais -C(i9)alkynyl. In some embodiments, each R3Ais -C(20)alkynyl. In some embodiments, each R3Ais -C(2i)alkynyl. In some embodiments, each R3Ais -C(22)alkynyl. In some embodiments, each R3Ais -C(23)alkynyl. In some embodiments, each R3Ais -C(24)alkynyl. In some embodiments, each R3Ais -C(25)alkynyl. In some embodiments, each R3Ais -C(26)alkynyl. In some embodiments, each R3Ais -C(27)alkynyl. In some embodiments, each R3Ais -C(28)alkynyl. In some embodiments, each R3Ais -C(29)alkynyl. In some embodiments, each R3Ais -C(30)alkynyl. In some embodiments, each R3Ais -C(3i)alkynyl.

[2560] In some embodiments, each R3Ais

[2561]

[2562] .

[2563] In some embodiments, each R3Ais

[2564]

[2565] In some embodiments, each R3Ais

[2566]

[2567] In some embodiments, each R3Ais

[2568]

[2569] 147

[2570] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2571] In some embodiments, each ZA is -C(1-10)alkylene- that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2572] In some embodiments, each ZA is -C(2-10)alkenylene- that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2573] In some embodiments, each ZA is independently -C(1-10)alkylene- or -C(2-10)alkenylene-. In some embodiments, each ZA is -C(1-10)alkylene-. In some embodiments, each ZA is -C(2-10)alkenylene-.

[2574] In some embodiments, each ZA is -C(i)alkylene-. In some embodiments, each ZA is -C(2)alkylene-. In some embodiments, each ZA is -C(3)alkylene-. In some embodiments, each ZA is -C(4)alkylene-. In some embodiments, each ZA is -C(5)alkylene-. In some embodiments, each ZA is -C(6)alkylene-. In some embodiments, each ZA is -C(7)alkylene-. In some embodiments, each ZA is -C(8)alkylene-. In some embodiments, each ZA is -C(9)alkylene-. In some embodiments, each ZA is -C(10)alkylene-.

[2575] In some embodiments, each ZA is -C(2)alkenylene-. In some embodiments, each ZA is -C(3)alkenylene-. In some embodiments, each ZA is -C(4)alkenylene-. In some embodiments, each ZA is -C(5)alkenylene-. In some embodiments, each ZA is -C(6)alkenylene-. In some embodiments, each ZA is -C(7)alkenylene-. In some embodiments, each ZA is -C(8)alkenylene-. In some embodiments, each ZA is -C(9)alkenylene-. In some embodiments, each ZA is -C(10)alkenylene-.

[2576] In some embodiments, each ZA is

[2577]

[2578] In some embodiments, each ZA is

[2579]

[2580] In some embodiments, each ZA is

[2581]

[2582]

[2583] In some embodiments, each R3is independently °, wherein:

[2584] each R3Bis independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-31)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; and

[2585] 148

[2586] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2587] each ZB is independently -C(1-10)alkylene- or -C(2-10)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2588]

[2589] In some embodiments, each R3is independently O, wherein each R3Bis independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-31)alkynyl; and each ZB is independently -C(1-10)alkylene- or -C(2-10)alkenylene-.

[2590] R3B V

[2591]

[2592] In some embodiments, each R3is independently O, wherein each R3Bis independently -C(1-31)alkyl or -C(2-31)alkenyl; and each ZB is independently -C(1-10)alkylene- or -C(2-10)alkenylene-.

[2593] R3B'°YZB^

[2594] In some embodiments, each R3is independently O, wherein each R3Bis -C(1-31)alkyl; and each ZB is -C(1-10)alkylene-.

[2595] In some embodiments, each R3Bis -C(1-31)alkyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2596] In some embodiments, each R3Bis -C(2-31)alkenyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2597] In some embodiments, each R3Bis -C(2-31)alkynyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2598] In some embodiments, each R3Bis independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-

[2599] 31)alkynyl. In some embodiments, each R3Bis independently -C(1-31)alkyl or -C(2-31)alkenyl. In some embodiments, each R3Bis -C(1-31)alkyl. In some embodiments, each R3Bis -C(2-

[2600] 31)alkenyl. In some embodiments, each R3Bis -C(2-31)alkynyl.

[2601] In some embodiments, each R3Bis -C(1)alkyl. In some embodiments, each R3Bis -C(2)alkyl. In some embodiments, each R3Bis -C(3)alkyl. In some embodiments, each R3Bis - 149

[2602] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2603] C(4)alkyl. In some embodiments, each R3Bis -C(5)alkyl. In some embodiments, each R3Bis - C(6)alkyl. In some embodiments, each R3Bis -C(7)alkyl. In some embodiments, each R3Bis - C(8)alkyl. In some embodiments, each R3Bis -C(9)alkyl. In some embodiments, each R3Bis - C(io)alkyl. In some embodiments, each R3Bis -C(ii)alkyl. In some embodiments, each R3Bis - C(i2)alkyl. In some embodiments, each R3Bis -C(i3)alkyl. In some embodiments, each R3Bis - C(i4)alkyl. In some embodiments, each R3Bis -C(i5)alkyl. In some embodiments, each R3Bis - C(i6)alkyl. In some embodiments, each R3Bis -C(i7)alkyl. In some embodiments, each R3Bis - C(i8)alkyl. In some embodiments, each R3Bis -C(i9)alkyl. In some embodiments, each R3Bis - C(20)alkyl. In some embodiments, each R3Bis -C(2i)alkyl. In some embodiments, each R3Bis - C(22)alkyl. In some embodiments, each R3Bis -C(23)alkyl. In some embodiments, each R3Bis - C(24)alkyl. In some embodiments, each R3Bis -C(25)alkyl. In some embodiments, each R3Bis - C(26)alkyl. In some embodiments, each R3Bis -C(27)alkyl. In some embodiments, each R3Bis - C(28)alkyl. In some embodiments, each R3Bis -C(29)alkyl. In some embodiments, each R3Bis - C(30)alkyl. In some embodiments, each R3Bis -C(3i)alkyl.

[2604] In some embodiments, each R3Bis -C(2)alkenyl. In some embodiments, each R3Bis -C(3)alkenyl. In some embodiments, each R3Bis -C(4)alkenyl. In some embodiments, each R3Bis -C(5)alkenyl. In some embodiments, each R3Bis -C(6)alkenyl. In some embodiments, each R3Bis -C(7)alkenyl. In some embodiments, each R3Bis -C(8)alkenyl. In some embodiments, each R3Bis -C(9)alkenyl. In some embodiments, each R3Bis -C(io)alkenyl. In some embodiments, each R3Bis -C(ii)alkenyl. In some embodiments, each R3Bis -C(i2)alkenyl. In some embodiments, each R3Bis -C(i3)alkenyl. In some embodiments, each R3Bis -C(i4)alkenyl. In some embodiments, each R3Bis -C(i5)alkenyl. In some embodiments, each R3Bis -C(i6)alkenyl. In some embodiments, each R3Bis -C(i7)alkenyl. In some embodiments, each R3Bis -C(i8)alkenyl. In some embodiments, each R3Bis -C(i9)alkenyl. In some embodiments, each R3Bis -C(20)alkenyl. In some embodiments, each R3Bis -C(2i)alkenyl. In some embodiments, each R3Bis -C(22)alkenyl. In some embodiments, each R3Bis -C(23)alkenyl. In some embodiments, each R3Bis -C(24)alkenyl. In some embodiments, each R3Bis -C(25)alkenyl. In some embodiments, each R3Bis -C(26)alkenyl. In some embodiments, each R3Bis -C(27)alkenyl. In some embodiments, each R3Bis -C(28)alkenyl. In some embodiments, each R3Bis -C(29)alkenyl. In some embodiments, each R3Bis -C(30)alkenyl. In some embodiments, each R3Bis -C(3i)alkenyl.

[2605] In some embodiments, each R3Bis -C(2)alkynyl. In some embodiments, each R3Bis -C(3)alkynyl. In some embodiments, each R3Bis -C(4)alkynyl. In some embodiments, each R3Bis -C(5)alkynyl. In some embodiments, each R3Bis -C(6)alkynyl. In some embodiments, each 150

[2606] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2607] R3Bis -C(7)alkynyl. In some embodiments, each R3Bis -C(8)alkynyl. In some embodiments, each R3Bis -C(9)alkynyl. In some embodiments, each R3Bis -C(io)alkynyl. In some embodiments, each R3Bis -C(ii)alkynyl. In some embodiments, each R3Bis -C(i2)alkynyl. In some embodiments, each R3Bis -C(i3)alkynyl. In some embodiments, each R3Bis -C(i4)alkynyl. In some embodiments, each R3Bis -C(i5)alkynyl. In some embodiments, each R3Bis -C(i6)alkynyl. In some embodiments, each R3Bis -C(i7)alkynyl. In some embodiments, each R3Bis -C(i8)alkynyl. In some embodiments, each R3Bis -C(i9)alkynyl. In some embodiments, each R3Bis -C(20)alkynyl. In some embodiments, each R3Bis -C(2i)alkynyl. In some embodiments, each R3Bis -C(22)alkynyl. In some embodiments, each R3Bis -C(23)alkynyl. In some embodiments, each R3Bis -C(24)alkynyl. In some embodiments, each R3Bis -C(25)alkynyl. In some embodiments, each R3Bis -C(26)alkynyl. In some embodiments, each R3Bis -C(27)alkynyl. In some embodiments, each R3Bis -C(28)alkynyl. In some embodiments, each R3Bis -C(29)alkynyl. In some embodiments, each R3Bis -C(30)alkynyl. In some embodiments, each R3Bis -C(3i)alkynyl.

[2608] In some embodiments, each R3Bis

[2609]

[2610] .

[2611] In some embodiments, each R3Bis

[2612]

[2613] .

[2614] In some embodiments, each R3Bis

[2615]

[2616] In some embodiments, each R3Bis

[2617]

[2618] .

[2619] In some embodiments, each ZB is -C(1-10)alkylene- that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2620] In some embodiments, each ZB is -C(2-io)alkenylene- that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2621] In some embodiments, each ZB is independently -C(1-10)alkylene- or -C(2-io)alkenylene-. In some embodiments, each ZB is -C(1-10)alkylene-. In some embodiments, each ZB is -C(2-io)alkenylene-.

[2622] In some embodiments, each ZB is -C(i)alkylene-. In some embodiments, each ZB is -C(2)alkylene-. In some embodiments, each ZB is -C(3)alkylene-. In some embodiments, each ZB is -C(4)alkylene-. In some embodiments, each ZB is -C(5)alkylene-. In some embodiments,

[2623] 151

[2624] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2625] each ZB IS -C(6)alkylene-. In some embodiments, each ZB IS -C(7)alkylene-. In some embodiments, each ZB is -C(8)alkylene-. In some embodiments, each ZB is -C(9)alkylene-. In some embodiments, each ZB is -C(io)alkylene-.

[2626] In some embodiments, each ZB is -C(2)alkenylene-. In some embodiments, each ZB is -C(3)alkenylene-. In some embodiments, each ZB is -C(4)alkenylene-. In some embodiments, each ZB is -C(5)alkenylene-. In some embodiments, each ZB is -C(6)alkenylene-. In some embodiments, each ZB is -C(7)alkenylene-. In some embodiments, each ZB is -C(8)alkenylene-. In some embodiments, each ZB is -C(9)alkenylene-. In some embodiments, each ZB is - C(io)alkenylene-.

[2627] In some embodiments, each

[2628]

[2629] In some embodiments, each

[2630]

[2631] In some embodiments, each

[2632]

[2633] In some embodiments, each

[2634]

[2635] In some embodiments, each

[2636]

[2637] In some embodiments, each

[2638]

[2639] In some embodiments, each

[2640]

[2641] In some embodiments, each

[2642]

[2643] In some embodiments, each

[2644]

[2645] In some embodiments, each

[2646]

[2647] In some embodiments, each

[2648]

[2649] 152

[2650] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2651] In some embodiments, each R3is independently selected from the group consisting O

[2652] of: (i) -C(4-20)alkenyl or -C(4-20)alkynyl; (ii) R3A

[2653]

[2654] , wherein each R3Ais independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl; and each ZA is independently -R»'°YZB /

[2655] C(i-io)alkylene- or -C(2-io)alkenylene-; and (iii)0, wherein each R3Bis independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl; and each ZB is independently -C(1-10)alkylene- or -C(2-io)alkenylene-.

[2656] In some embodiments, each R3is independently selected from the group consisting O

[2657] of: (i) -C(4-20)alkenyl; (ii)

[2658]

[2659] R3A° *, wherein each R3Ais independently -C(i-3i)alkyl or -C(2-3i)alkenyl; and each ZA is independently -C(1-10)alkylene- or -C(2-io)alkenylene-; and (iii)

[2660]

[2661] 0, wherein each R3Bis independently -C(i-3i)alkyl or -C(2-3i)alkenyl; and each ZB is independently -C(1-10)alkylene- or -C(2-io)alkenylene-.

[2662] In some embodiments, each R3is independently selected from the group consisting O

[2663] of: (i) -C(4-20)alkenyl; (ii)

[2664]

[2665] R3A°, wherein each R3Ais -C(i-3i)alkyl, and each ZA is -

[2666] R3B'°YZB^

[2667] C(i-io)alkylene-; and (iii) °, wherein each R3Bis -C(i-3i)alkyl, and each ZB is - C(i-io)alkylene-.

[2668] In some embodiments, R2A, R2B, and R2Care each independently selected from the group consisting of:

[2669]

[2670] 153

[2671] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2672]

[2673] In some embodiments, R1Ais hydrogen or -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2674] In some embodiments, R1Ais hydrogen or -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one -OH group.

[2675] In some embodiments, R1Ais hydrogen.

[2676] In some embodiments, R1Ais -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2677] In some embodiments, R1Ais -C(1-10)alkyl that is optionally substituted with one -OH group. In some embodiments, R1Ais -C(1-10)alkyl that is substituted with one -OH group. In some embodiments, R1Ais -C(1-5)alkyl that is optionally substituted with one -OH group. In some embodiments, R1Ais -C(1-5)alkyl that is substituted with one -OH group.

[2678] 154

[2679] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2680] In some embodiments, R1Ais -C(1-10)alkyl. In some embodiments, R1Ais -C(1-5)alkyl. In some embodiments, R1Ais selected from the group consisting of hydrogen, -CH3, -CH2CH2OH, -(CH2)3OH, and -(CH2)4OH.

[2681] In some embodiments, R1Ais selected from the group consisting of -CH3, -CH2CH2OH, -(CH2)3OH, and -(CH2)4OH. In some embodiments, R1Ais -CH3. In some embodiments, R1Ais -CH2CH2OH. In some embodiments, R1Ais -(CH2)3OH. In some embodiments, R1Ais -(CH2)4OH.

[2682] In some embodiments, R1Bis hydrogen or -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2683] In some embodiments, R1Bis hydrogen or -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one -OH group.

[2684] In some embodiments, R1Bis hydrogen.

[2685] In some embodiments, R1Bis -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”.

[2686] In some embodiments, R1Bis -C(1-10)alkyl that is optionally substituted with one -OH group. In some embodiments, R1Bis -C(1-10)alkyl that is substituted with one -OH group. In some embodiments, R1Bis -C(1-5)alkyl that is optionally substituted with one -OH group. In some embodiments, R1Bis -C(1-5)alkyl that is substituted with one -OH group.

[2687] In some embodiments, R1Bis -C(1-10)alkyl. In some embodiments, R1Bis -C(1-5)alkyl. In some embodiments, R1Bis selected from the group consisting of hydrogen, -CH3, -CH2CH2OH, -(CH2)3OH, and -(CH2)4OH.

[2688] In some embodiments, R1Bis selected from the group consisting of -CH3, -CH2CH2OH, -(CH2)3OH, and -(CH2)4OH. In some embodiments, R1Bis -CH3. In some embodiments, R1Bis -CH2CH2OH. In some embodiments, R1Bis -(CH2)3OH. In some embodiments, R1Bis -(CH2)4OH.

[2689] In some embodiments, R1Aand R1Bare each independently selected from hydrogen and -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one -OH group.

[2690] In some embodiments, R1Aand R1Bare each -C(1-10)alkyl that is optionally substituted with one -OH group. In some embodiments, R1Aand R1Bare each -C(1-5)alkyl that is optionally substituted with one -OH group.

[2691] 155

[2692] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2693] In some embodiments, R1Aand R1Bare each independently selected from the group consisting of hydrogen, -CH3, -CH2CH2OH, -(CH2)3OH, and -(CH2)4OH.

[2694] In some embodiments, R1Aand R1Bare each independently selected from the group consisting of -CH3, -CH2CH2OH, -(CH2)3OH, and -(CH2)4OH.

[2695] In some embodiments, R1Ais -C(1-5)alkyl, and R1Bis -C(1-5)alkyl that is optionally substituted with one -OH group.

[2696] In some embodiments, R1Ais -CH3, and R1Bis -CH3, -CH2CH2OH, -(CH2)3OH, or -(CH2)4OH.

[2697] In some embodiments, R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group that is optionally substituted with one, two, or three -C(i-6)alkyl groups. In some embodiments, R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group.

[2698] In some embodiments, R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-6-membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group.

[2699] In some embodiments, R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group. In some embodiments, R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-6-membered heterocyclic group.

[2700] In some embodiments, R1Cis absent or R1Cis -C(1-10)alkyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge.

[2701] In some embodiments, R1Cis absent or R1Cis -C(1-10)alkyl, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge. In some embodiments, R1Cis absent or R1Cis -C(1-5)alkyl, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge. In some embodiments, R1Cis absent or R1Cis -CH3, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge.

[2702] In some embodiments, R1Cis absent. When R1Cis absent, the nitrogen to which R1Aand R1Bare attached can interconvert between a protonated and unprotonated state:

[2703] 156

[2704] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2705] H N

[2706] I

[2707]

[2708] R1BH

[2709] It is to be understood that when R1Cis absent, both the protonated and unprotonated form of the nitrogen atom are encompassed.

[2710] When R1Cis present and the nitrogen to which it is attached bears a positive charge, it is to be understood that the positive charge on the nitrogen atom can be balanced by the presence of a counterion (i.e., a counteranion).

[2711] In some embodiments, R1Cis -C(1-10)alkyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”, wherein the nitrogen to which R1Cis bonded bears a positive charge.

[2712] In some embodiments, R1Cis -C(1-10)alkyl, wherein the nitrogen to which R1Cis bonded bears a positive charge. In some embodiments, R1Cis -C(1-5)alkyl, wherein the nitrogen to which R1Cis bonded bears a positive charge. In some embodiments, R1Cis -CH3, wherein the nitrogen to which R1Cis bonded bears a positive charge.

[2713] In some embodiments, R1A, R1B, and R1Care taken together with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group that is optionally substituted with one, two, or three -C(i-6)alkyl groups, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge. In some embodiments, R1A, R1B, and R1Care taken together with the nitrogen to which they are attached to form a 5-11 -membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge.

[2714] In some embodiments, R1A, R1B, and R1Care taken together with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge.

[2715] In some embodiments, R1Aand R1Bare each independently selected from hydrogen and -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one -OH group; or R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group, that is optionally substituted with one -C(i-6)alkyl group; and

[2716] R1Cis absent or -C(1-10)alkyl, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge; or

[2717] 157

[2718] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2719] R1A, R1B, and R1Care taken together with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group, that is optionally substituted with one -C(i-6)alkyl group, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge.

[2720] In some embodiments, R1Aand R1Bare each independently -C(1-5)alkyl that is optionally substituted with one -OH group; or

[2721] R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group; and

[2722] R1Cis absent or R1Cis -C(1-5)alkyl, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge; or

[2723] R1A, R1B, and R1Care taken together with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge;

[2724] In some embodiments, R1Ais -C(1-5)alkyl;

[2725] R1Bis -C(1-5)alkyl that is optionally substituted with one -OH group; or

[2726] R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group; and

[2727] R1Cis absent or R1Cis -C(1-5)alkyl, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge; or

[2728] R1A, R1B, and R1Care taken together with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group that is optionally substituted with one -C(i-6)alkyl group, wherein the nitrogen to which R1A, R1B, and R1Care bonded bears a positive charge;

[2729] In some embodiments:

[2730] (i) R1Ais hydrogen, R1Bis hydrogen, and R1Cis absent;

[2731] (ii) R1Ais -C(1-5)alkyl, R1Bis -C(1-5)alkyl, and R1Cis absent;

[2732] (iii) R1Ais -C(1-5)alkyl, R1Bis -C(1-5)alkyl, and R1Cis -C(1-5)alkyl;

[2733] (iv) R1Ais -C(1-5)alkyl, R1Bis -C(1-5)alkyl substituted with one -OH group, and R1Cis absent;

[2734] (v) R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group, and R1Cis absent;

[2735] (vi) R1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group, and R1Cis -C(1-5)alkyl; or

[2736] 158

[2737] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2738] (vii) R1A, R1B, and R1Care taken together with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group.

[2739] In some embodiments:

[2740] (i) R1Ais hydrogen, R1Bis hydrogen, and R1Cis absent;

[2741] (ii) R1Ais -CH3, R1Bis -CH3, and R1Cis absent;

[2742] (iii) R1Ais -CH3, R1Bis -CH3, and R1Cis -CH3;

[2743] (iv) R1Ais -CH3, R1Bis -CH2CH2OH, and R1Cis absent;

[2744] (v) R1Ais -CH3, R1Bis -(CH2)3OH, and R1Cis absent; or

[2745] (vi) R1Ais -CH3, R1Bis -(CH2)4OH, and R1Cis absent.

[2746] In some embodiments:

[2747] (i) R1Ais -CH3, R1Bis -CH3, and R1Cis absent;

[2748] (ii) R1Ais -CH3, R1Bis -CH3, and R1Cis -CH3;

[2749] (iii) R1Ais -CH3, R1Bis -CH2CH2OH, and R1Cis absent;

[2750] (iv) R1Ais -CH3, R1Bis -(CH2)3OH, and R1Cis absent; or

[2751] (v) R1Ais -CH3, R1Bis -(CH2)4OH, and R1Cis absent.

[2752] In some embodiments, R1A, R1B, and R1Ctogether with the nitrogen to which they are attached form a group selected from:

[2753]

[2754] wherein RNis hydrogen or -C(i-6)alkyl.

[2755] In some embodiments, R1A, R1B, and R1Ctogether with the nitrogen to which they are attached form a group selected from:

[2756]

[2757] wherein RNis hydrogen or -C(i-6)alkyl.

[2758] 159

[2759] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2760] In some embodiments, R1A, R1B, and R1Ctogether with the nitrogen to which they are attached form a group selected from:

[2761]

[2762] wherein RNis hydrogen or -C(i-6)alkyl.

[2763] In some embodiments, R1A, R1B, and R1Ctogether with the nitrogen to which they are attached form a group selected from:

[2764]

[2765] In some embodiments, R1A, R1B, and R1Ctogether with the nitrogen to which they are NH2

[2766] attached form the following group:

[2767] In some embodiments, R1A, R1B, and R1Ctogether with the nitrogen to which they are

[2768] attached form the following group:

[2769]

[2770] “

[2771] In some embodiments, R1A, R1B, and R1Ctogether with the nitrogen to which they are

[2772] attached form the following group:

[2773]

[2774] In some embodiments, R1A, R1B, and R1Ctogether with the nitrogen to which they are

[2775] attached form the following group:

[2776]

[2777] In some embodiments, R1A, R1B, and R1Ctogether with the nitrogen to which they are

[2778] attached form the following group:

[2779]

[2780] OH

[2781] In some embodiments, R1A, R1B, and R1Ctogether with the nitrogen to which they are

[2782] attached form the following group:

[2783]

[2784] 160

[2785] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2786] In some embodiments, R” is independently for each occurrence -C(1-10)alkyl. In some embodiments, R” is independently for each occurrence -C(1-5)alkyl. In some embodimen®zt z —s —, R” is independently for each occurrence -C(1-3)alkyl.

[2787] In some embodiments, the lipid of Formula HLP-II has a structure sele / x°

[2788] OOQ-=c-ted from the \

[2789] group consisting of: o o

[2790] Cpd Structure

[2791] o

[2792] Y^^xx^-^^ o0

[2793] HII-. o o X o X o

[2794] 1 / 00 \ / 00 \^^

[2795] jj ( ( < <

[2796] HII-2

[2797] (' °°< y O O x o

[2798] (' °° YAA o^\X QO^X

[2799] o

[2800] >( <

[2801] q

[2802] HII-3 f o OOTJ= OOTJ-=- / TOOm=c-TO

[2803] z—

[2804] _ 0 z —

[2805] ®z-01

[2806] HII-4 o I

[2807] I

[2808] 5

[2809] HII-5

[2810] HII-6

[2811]

[2812] 161

[2813] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2814] I Iz- ^ z O Z — Z — HII-7

[2815] \ T \° °

[2816] / OOCL=- / T

[2817] OO° oCL o5o==<°

[2818] / \T- o OOCL o=- o

[2819] o o o o

[2820] \ / ° —

[2821] H / cor \ P z' P-. o o. X o o X

[2822] II-8 / o o \ / OO \^^

[2823] —

[2824] \ o o < o o

[2825] Y O o

[2826] HII-9

[2827] >( < >( <

[2828] o

[2829] 0073=- HU- 10

[2830] z —.

[2831] HII-11

[2832] 0

[2833] o-^C P

[2834] 0 0^ 0 I \ 0— < / — 0 >11 1HII-12

[2835] 0

[2836]

[2837] 162

[2838] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2839]

[2840] 163 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2841]

[2842] 164 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2843] HU-24

[2844] z —

[2845] Z —

[2846] HII-25 / T°

[2847] OOQ-=- ° / ° \ / / / \

[2848] ° ° / \ \ / / T° b

[2849] VV \ )°o o r \ OOQ-=- / 7V o c o o> — y (o o / —^ n / ?^ o~

[2850] \ / °

[2851] ( / \o=V oo

[2852] \ / °

[2853] HII-26 ^ / \o=° \ / /

[2854] ° / \

[2855] Z —

[2856] D

[2857] 0 oxO

[2858] HII-27 0 1 0 V OH 1 o'' O^OH D 5

[2859] °b ° 1 HII-28 / \zoo

[2860] oOHXXx^XX^ / =xx^x^x^-vV^Q

[2861] 5 )

[2862] 9 I HII-29 OH

[2863] ) 5

[2864]

[2865] 165

[2866] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2867]

[2868] 166 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2869]

[2870] In some embodiments, the lipid of Formula HLP-II has a structure selected from the

[2871]

[2872] In some embodiments, the lipid of Formula HLP-II has the following structure:

[2873]

[2874] 167

[2875] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2876] (Compound HII-13),

[2877] or a pharmaceutically acceptable salt thereof.

[2878] In some embodiments, the lipid of Formula HLP-II has the following structure:

[2879] .0

[2880]

[2881] (Compound HII-14),

[2882] or a pharmaceutically acceptable salt thereof.

[2883] In some embodiments, the lipid of Formula HLP-II has the following structure:

[2884]

[2885] or a pharmaceutically acceptable salt thereof.

[2886] E. Further Helper Lipids

[2887] In some embodiments, the LNP comprises a helper lipid such as 1,2-dioleoyl-SN-glycero-3 -phosphoethanolamine (DOPE); l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); l,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS); l,2-dielaidoyl-sn-glycero-3-phosphoethanolamine (DEPE); and l,2-dioleoyl-sn-glycero-3 -phosphocholine (DPOC), dipalmitoylphosphatidylcholine (DPPC), l,2-dilauroyl-sn-glycero-3 -phosphocholine (DLPC), 1,2-Distearoylphosphatidylethanolamine (DSPE), or l,2-dilauroyl-sn-glycero-3-phosphoethanolamine (DLPE). Helper lipids enhance 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

[2888] 168

[2889] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2890] Further exemplary helper lipids include 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-phosphatidyethanolamine (SOPE), or a combination thereof.

[2891] In some embodiments, the helper lipid is DOPE. In some embodiments, the helper lipid is DSPC.

[2892] In some embodiments, the helper lipid comprises a lipid of Formula HLP-I and DOPE. In some embodiments, the helper lipid comprises a lipid of Formula HLP-II and DOPE.

[2893] F. Structural Lipids

[2894] A structural lipid component provides stability to the lipid bilayer structure within the lipid nanoparticle. 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), l,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), P-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 (5a-cholest-7-en-3B-ol), diosgenin ((3p,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.

[2895] In some embodiments, the structural lipid is selected from the group consisting of cholesterol, a-amyrin, P-amyrin, a-boswellic acid, P-boswellic acid, 11-keto-P-boswellic acid, 3 -O-acetyl-11-keto-P-boswellic acid, taraxasterol, senegenin, arjungenin, cycloastrogenol, P-elemonic acid, ganoderic acid A, ganoderic acid B, ganoderic acid D, ganoderic acid F, ganoderic acid H, yamogenin, steviol, brusatol, y-oryzanol,

[2896] 169

[2897] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2898] phytolaccagenin, hecogenin, pristimerin, erythrodiol, guggulsterone Z, corosolic acid, soyasapogenol B, and combinations thereof.

[2899] In some embodiments, the structural lipid is selected from the group consisting of cholesterol, P-amyrin, and a combination thereof. In some embodiments, the structural lipid is cholesterol. In some embodiments, the structural lipid is P-amyrin. In some embodiments, the structural lipid comprises cholesterol and P-amyrin.

[2900] G. Stealth Lipids

[2901] 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 lipidnucleic 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.

[2902] 5,885,613).

[2903] 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(methoxypolyethylene glycol)] (C8 PEG ceramide)). In some embodiments, the PEGylated lipid is l,2-dimyristoyl-rac-glycero-3-methoxypoly ethylene glycol (DMG-PEG); l,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol (DSPE- PEG); l,2-dilauroyl-sn-glycero-3-phosphoethanolamine-poly ethylene glycol (DLPE-PEG); or 1,2-distearoyl-rac-glycero-polyethelene glycol (DSG-PEG).

[2904] 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).

[2905] In some embodiments, the stealth lipid is a polyoxazoline polymer-conjugated lipid. Polyoxazoline polymer-conjugated lipids suitable for the LNP compositions of the present disclosure are described, for example, in WO2022 / 173667 and WO2023 / 031394.

[2906] In some embodiments, the stealth lipid is a polysarcosine-conjugated (pSar) lipid. In some embodiment, the polysarcosine comprises 25-45 sarcosine units. In some embodiment,

[2907] 170

[2908] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2909] the polysarcosine comprises 25 sarcosine units. In some embodiment, the polysarcosine comprises 35 sarcosine units. In some embodiment, the polysarcosine comprises 45 sarcosine units. Nonlimiting examples of pSar lipids include N-tetradecyl-pSar25, N-hexadecyl-pSar25, N-octadecyl-pSar25, N-dodecyl-pSar25, 1,2-dimyristoyl-sn-glycero-3-succinyl-N-polysarcosine-25 (DMG-pSar25), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-polysarcosine-25 (18:1 PE (DOPE) pSar25), N, N-ditetradecylamine-N-succinyl[methyl(polysarcosine)45], N, N-ditetradecylamine-N-succinyl[methyl(polysarcosine)35], and N, N-ditetradecyl-polysarcosine-25. Further examples of pSar lipids suitable for the LNP compositions of the present disclosure are described in W02020 / 070040.

[2910] H. Combinations of Lipid Components and Molar Ratios

[2911] In some embodiments, the ionizable or cationic lipid constitutes from about 35 mol% to about 40 mol% of the total lipid content of the LNP. In some embodiments, the ionizable or cationic lipid constitutes from about 37 mol% to about 43 mol% of the total lipid content of the LNP. In some embodiments, the ionizable or cationic lipid constitutes from about 42 mol% to about 48 mol% of the total lipid content of the LNP. In some embodiments, the ionizable or cationic lipid constitutes from about 45 mol% to about 50 mol% of the total lipid content of the LNP. In some embodiments, the ionizable or cationic lipid constitutes about 38.5 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the ionizable or cationic lipid constitutes about 40 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the ionizable or cationic lipid constitutes about 45 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the ionizable or cationic lipid constitutes about 47.5 mol% of the total lipid content of the lipid nanoparticle.

[2912] In some embodiments, the helper lipid constitutes from about 10 mol% to about 15 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the helper lipid constitutes from about 13 mol% to about 16 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the helper lipid constitutes from about 12 mol% to about 18 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the helper lipid constitutes about 13.5 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the helper lipid constitutes about 15 mol% of the total lipid content of the lipid nanoparticle.

[2913] In some embodiments, the structural lipid constitutes from about 35 mol% to about 40 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the structural 171

[2914] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2915] lipid constitutes from about 42 mol% to about 48 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the structural lipid constitutes about 36 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the structural lipid constitutes about 38.5 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the structural lipid constitutes about 44.8 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the structural lipid constitutes about 45 mol% of the total lipid content of the lipid nanoparticle.

[2916] In some embodiments, In some embodiments, the stealth lipid constitutes from about 1 mol% to about 1.7 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the stealth lipid constitutes from about 1.3 mol% to about 1.7 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the stealth lipid constitutes from about 1 mol% to about 1.8 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the stealth lipid constitutes about 1.5 mol% of the total lipid content of the lipid nanoparticle. In some embodiments, the stealth lipid constitutes about 1.7 mol% of the total lipid content of the lipid nanoparticle.

[2917] In some embodiments, the ionizable or cationic lipid constitutes from about 35 mol% to about 40 mol% of the total lipid content of the LNP; the helper lipid constitutes from about 12 mol% to about 18 mol% of the total lipid content of the LNP; the structural lipid constitutes from about 42 mol% to about 48 mol% of the total lipid content of the lipid LNP; and the stealth lipid constitutes from about 1 mol% to about 1.8 mol% of the total lipid content of the LNP. In some embodiments, the ionizable or cationic lipid constitutes about 38.5 mol% of the total lipid content of the LNP; the helper lipid constitutes about 15 mol% of the total lipid content of the LNP; the structural lipid constitutes about 45 mol% of the total lipid content of the lipid LNP; and the stealth lipid constitutes about 1.5 mol% of the total lipid content of the LNP.

[2918] In some embodiments, the ionizable or cationic lipid constitutes from about 42 mol% to about 48 mol% of the total lipid content of the LNP; the helper lipid constitutes from about 12 mol% to about 18 mol% of the total lipid content of the LNP; the structural lipid constitutes from about 35 mol% to about 40 mol% of the total lipid content of the lipid LNP; and the stealth lipid constitutes from about 1 mol% to about 1.8 mol% of the total lipid content of the LNP. In some embodiments, the ionizable or cationic lipid constitutes about 45 mol% of the total lipid content of the LNP; the helper lipid constitutes about 15 mol% of the total lipid content of the LNP; the structural lipid constitutes about 38.5 mol% of the total

[2919] 172

[2920] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2921] lipid content of the LNP; and the stealth lipid constitutes about 1.5 mol% of the total lipid content of the LNP.

[2922] In some embodiments, the ionizable or cationic lipid constitutes from about 45 mol% to about 50 mol% of the total lipid content of the LNP; the helper lipid constitutes from about 12 mol% to about 18 mol% of the total lipid content of the LNP; the structural lipid constitutes from about 35 mol% to about 40 mol% of the total lipid content of the lipid LNP; and the stealth lipid constitutes from about 1 mol% to about 1.8 mol% of the total lipid content of the LNP. In some embodiments, the ionizable or cationic lipid constitutes about 47.5 mol% of the total lipid content of the LNP; the helper lipid constitutes about 15 mol% of the total lipid content of the LNP; the structural lipid constitutes about 36 mol% of the total lipid content of the LNP; and the stealth lipid constitutes about 1.5 mol% of the total lipid content of the LNP.

[2923] In some embodiments, the ionizable or cationic lipid constitutes from about 37 mol% to about 43 mol% of the total lipid content of the LNP; the helper lipid constitutes from about 10 mol% to about 15 mol% of the total lipid content of the LNP; the structural lipid constitutes from about 42 mol% to about 48 mol% of the total lipid content of the lipid LNP; and the stealth lipid constitutes from about 1 mol% to about 1.8 mol% of the total lipid content of the LNP. In some embodiments, the ionizable or cationic lipid constitutes about 40 mol% of the total lipid content of the LNP; the helper lipid constitutes about 13.5 mol% of the total lipid content of the LNP; the structural lipid constitutes about 44.8 mol% of the total lipid content of the LNP; and the stealth lipid constitutes about 1.7 mol% of the total lipid content of the LNP.

[2924] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-I or Formula CAT -II; and the helper lipid is DOPE, a lipid of Formula HLP-I, a lipid of Formula HLP-II, or a combination thereof. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-I or Formula CAT-II; the helper lipid is DOPE, a lipid of Formula HLP-I, a lipid of Formula HLP-II, or a combination thereof; the structural lipid is cholesterol, P-amyrin, or a combination thereof; and the stealth lipid is DMG-PEG2000.

[2925] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-I, and the helper lipid is DOPE, a lipid of Formula HLP-I, a lipid of Formula HLP-II, or a combination thereof. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-I, and the helper lipid is a lipid of Formula HLP-I. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-I, and the helper lipid is a lipid of Formula HLP-II. In some embodiments, the ionizable or cationic lipid is a lipid of Formula 173

[2926] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2927] CAT-I, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-I. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-I, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-II.

[2928] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-II, and the helper lipid is DOPE, a lipid of Formula HLP-I, a lipid of Formula HLP-II, or a combination thereof. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-II, and the helper lipid is a lipid of Formula HLP-I. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-II, and the helper lipid is a lipid of Formula HLP-II. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-II, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-I. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-II, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-II.

[2929] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-I; the helper lipid is DOPE, a lipid of Formula HLP-I, a lipid of Formula HLP-II, or a combination thereof; the structural lipid is cholesterol, P-amyrin, or a combination thereof; and the stealth lipid is DMG-PEG2000.

[2930] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-II; the helper lipid is DOPE, a lipid of Formula HLP-I, a lipid of Formula HLP-II, or a combination thereof; the structural lipid is cholesterol, P-amyrin, or a combination thereof; and the stealth lipid is DMG-PEG2000.

[2931] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a lipid of Formula HLP-Ia-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ia-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a lipid of Formula HLP-Id-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Id-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a lipid of Formula HLP-Ib. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ib. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a lipid of Formula HLP-Ia-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ia-iv. In some embodiments, the ionizable or cationic lipid is a lipid of 174

[2932] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2933] Formula CAT-Ia, and the helper lipid is a lipid of Formula HLP-Id-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Id-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a lipid of Formula HLP-Ie-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-ii.

[2934] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a lipid of Formula HLP-Ie-iii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-iii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a lipid of Formula HLP-Ie-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-iv.

[2935] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a lipid of Formula HLP-IIb-i. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-IIb-i. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a lipid of Formula HLP-IIb-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ia, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-IIb-ii.

[2936] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a lipid of Formula HLP-Ia-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ia-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a lipid of Formula HLP-Id-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Id-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a lipid of Formula HLP-Ib. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ib. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a lipid of Formula HLP-Ia-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ia-iv. In some embodiments, the ionizable or cationic lipid is a lipid of 175

[2937] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2938] Formula CAT-Ic, and the helper lipid is a lipid of Formula HLP-Id-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Id-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a lipid of Formula HLP-Ie-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-ii.

[2939] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a lipid of Formula HLP-Ie-iii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-iii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a lipid of Formula HLP-Ie-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-iv.

[2940] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a lipid of Formula HLP-IIb-i. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-IIb-i. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a lipid of Formula HLP-IIb-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-IIb-ii.

[2941] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a lipid of Formula HLP-Ia-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ia-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a lipid of Formula HLP-Id-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Id-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a lipid of Formula HLP-Ib. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ib. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a lipid of Formula HLP-Ia-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ia-iv. In some embodiments, the ionizable or cationic lipid is a lipid of 176

[2942] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2943] Formula CAT-IIb-i, and the helper lipid is a lipid of Formula HLP-Id-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Id-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a lipid of Formula HLP-Ie-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-ii.

[2944] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a lipid of Formula HLP-Ie-iii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-iii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a lipid of Formula HLP-Ie-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-iv.

[2945] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a lipid of Formula HLP-IIb-i. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-IIb-i. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a lipid of Formula HLP-IIb-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIb-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-IIb-ii.

[2946] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a lipid of Formula HLP-Ia-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ia-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a lipid of Formula HLP-Id-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Id-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a lipid of Formula HLP-Ib. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ib. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a lipid of Formula HLP-Ia-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ia-iv. In some embodiments, the ionizable or cationic lipid is a lipid of 177

[2947] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2948] Formula CAT-IIc-i, and the helper lipid is a lipid of Formula HLP-Id-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Id-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a lipid of Formula HLP-Ie-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-ii.

[2949] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a lipid of Formula HLP-Ie-iii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-iii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a lipid of Formula HLP-Ie-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-iv.

[2950] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a lipid of Formula HLP-IIb-i. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-IIb-i. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a lipid of Formula HLP-IIb-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIc-i, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-IIb-ii.

[2951] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a lipid of Formula HLP-Ia-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ia-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a lipid of Formula HLP-Id-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Id-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a lipid of Formula HLP-Ib. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ib. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a lipid of Formula HLP-Ia-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ia-iv. In some embodiments, the ionizable or cationic lipid is a lipid of 178

[2952] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2953] Formula CAT-IIe, and the helper lipid is a lipid of Formula HLP-Id-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Id-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a lipid of Formula HLP-Ie-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-ii.

[2954] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a lipid of Formula HLP-Ie-iii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-iii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a lipid of Formula HLP-Ie-iv. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-Ie-iv.

[2955] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a lipid of Formula HLP-IIb-i. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-IIb-i. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a lipid of Formula HLP-IIb-ii. In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-IIe, and the helper lipid is a combination of DOPE and a lipid of Formula HLP-IIb-ii.

[2956] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic, CAT-IIc-I, or CAT-IIe; the helper lipid is DOPE, a lipid of Formula HLP-Id-ii, a lipid of Formula HLP-Ib, a lipid of Formula HLP-Id-iv, a lipid of Formula HLP-Ie-ii, a lipid of Formula HLP-Ie-iii, a lipid of Formula HLP-Ie-iv, or a combination thereof; the structural lipid is cholesterol, P-amyrin, or a combination thereof; and the stealth lipid is DMG-PEG2000.

[2957] In some embodiments, the ionizable or cationic lipid is a lipid of Formula CAT-Ic or CAT-IIc-I; the helper lipid is DOPE, a lipid of Formula HLP-Id-ii, a lipid of Formula HLP-Ib, a lipid of Formula HLP-Id-iv, a lipid of Formula HLP-Ie-ii, or a combination thereof; the structural lipid is cholesterol, P-amyrin, or a combination thereof; and the stealth lipid is DMG-PEG2000.

[2958] In some embodiments, the ionizable or cationic lipid is selected from the group consisting of GL-HEPES-E3-E12-DS-4-E10, Compound CII-3, and Compound CII-24, and the helper lipid is selected from the group consisting of Compounds HI-6, HI-12, HI-18, HI- 179

[2959] 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT

[2960] 24, HI-27, HI-31, HI-32, HI-33, HI-34, HI-35, HII-13, HII-14, and HII-23. In some embodiments, the ionizable or cationic lipid is selected from the group consisting of GL-HEPES-E3-E12-DS-4-E10, Compound CII-3, and Compound CII-24, and the helper lipid is a combination of DOPE and a lipid selected from the group consisting of Compounds HI-6, HI-12, HI-18, HI-24, HI-27, HI-31, HI-32, HI-33, HI-34, HI-35, HII-13, HII-14, and HII-23. In some embodiments, the ionizable or cationic lipid is selected from the group co...

Claims

1. 772787: SA9-887PC / / PAT24318-WO-PCTCLAIMS1. A lipid nanoparticle (LNP) comprising:(1) an ionizable or cationic lipid that constitutes from about 35 mol% to about 50 mol% of the total lipid content of the lipid nanoparticle, wherein the ionizable or cationic lipid has a structure according to Formula (CAT-I):(CAT-I),or a pharmaceutically acceptable salt thereof,wherein:A1is selected fromwherein the left hand side of each depicted structure is bound to the -(CH2)a-;Z1is selected from, wherein the right hand side of each depicted structure is bound to the -(CH2)a-;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, and25981659747v1772787: SA9-887PC / / PAT24318-WO-PCT-(*C=O)-O-optionally substituted alkenyl, wherein the atom marked with a * is connected to X1;b is 1, 2, 3, 4, or 5; andeach a is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;preferably wherein the ionizable or cationic lipid is selected from the group consistingOH26081659747v1772787: SA9-887PC / / PAT24318-WO-PCTor a pharmaceutically acceptable salt thereof;more preferably wherein the ionizable or cationic lipid isor a pharmaceutically acceptable salt thereof;(2) a helper lipid that constitutes from about 10 mol% to about 18 mol% of the total lipid content of the lipid nanoparticle;(3) a structural lipid that constitutes from about 35 mol% to about 50 mol% of the total lipid content of the lipid nanoparticle; and(4) a stealth lipid that constitutes from about 1 mol% to about 3 mol% of the total lipid content of the lipid nanoparticle.

2. A lipid nanoparticle (LNP) comprising:(1) an ionizable or cationic lipid that constitutes from about 35 mol% to about 50 mol% of the total lipid content of the lipid nanoparticle, wherein the ionizable or cationic lipid has a structure according to Formula (CAT-II):26181659747v1772787: SA9-887PC / / PAT24318-WO-PCT(CAT-II)or a pharmaceutically acceptable salt thereof wherein: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:O(i) / b, wherein each R1is independently selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl;(ii)0H, 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, andeach 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;26281659747v1772787: SA9-887PC / / PAT24318-WO-PCT, wherein each R3is independently selected fromoptionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and(iv), wherein each R4is independently selected from optionallysubstituted cycloalkyl or optionally substituted heterocycloalkyl;wherein at least three R are independently selected from(i)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; andeach c is independently selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10;preferably wherein the ionizable or cationic lipid is selected from the group consisting26381659747v1772787: SA9-887PC / / PAT24318-WO-PCTOHxx xx xx. T1 Y H Ox o YxZXzXxXx'Xx' CII-3 \ \ / : O "~~O H 1THOOH- x\ xx / x x-- z\ y / OH o / / ( () } j A -HCII-4 <) \ f~ 90HO < H \ o~\ — / °Y-.,.2 J\ z\ / Zx. / 'z,z-z x ) >g X oZ —“ \- H i 1S O Z— °Y^\ / \Z'NX0r YoYA O^^°Y oCYHT^,'■ o o^ y° Yo4oxY~- oCII-5 \( T \o I \ \ / oO Z —~xf Y Y< s( (cn-6< <> / / < (. / > <OH / X / XY oN xx JYr o HX _z zx '.z XX.,z z~x xz XX xz Z'. X / XX ". X z~x -X -x 'OH / X-> r Oxcn-7 \ X / OHOX '\ 1H b P'^' --Z---XX 'xX x.x'xz-xx- xz-,1 z. NO'"' '■'''!HO" ''-■' '■•' '•' "'■' ''Z xz X' ZX26481659747v1772787: SA9-887PC / / PAT24318-WO-PCTOHor^— ^oI I Hcn-8 <' y-o OHu <0 A / \ / X^X / X / H i \C..^.x / 'x..zN..i j; 0 A / X. x-x / X / < A °--'A > 0° / OH / '• V0' ■* x / Xx,.. 1 o $ Vo r LI \ / v^z\ / '0A / \^\0 HM’HOHO-A OHcn-9 { < A,x l l ° 1o r >cr - As / V / V / xx.... '....■.. ■.•...,. ■.■....,,. ■.....-. ■ xQ. A........ < (... J...?o —~ / \, / \ / 0-rH7O s:—cn-io ' LO I _V H O XA.•Nx ^-x A? r A «cn-n Xl<(VAX 1 / OH 0 r '•'• ''' ° AA 1HO 1 ''x.•>A ( 7 A. JI / / K'xuA'\zy'ZAxA'''xZ / ^\. / 'X: / A''^^ / ’XvAz'’A;?VL° \. „ x. CII-12" ^x^ ’yVzW ’ AxVzXZXXXZy j.xXxxxxxx^. X.xA., VACII-13 / AN 026581659747v1772787: SA9-887PC / / PAT24318-WO-PCTOH O0 HO.. J \ Hr r- °,x-x ^, O.XY'x / s... J \ J / OH CII-14 'vo If ' H0A ~.X x-x xNx0- " J. _x _ _ _HO ~AXA / AA^A / -°VAXAAA<OHli T H, Oy OH° W X o A ™CII-15 o A HQA^ rO OH HQAYAX-AXASYAZ''OH 0'XAY-X / '^AH H, Oy O r" 'O' ' - •" "'' ' cn-16 0 < N ^.- A -< H1 S'- \, A O - JN, "] OO "0 H X0 OHcn-17. X YQ, A. r 7Azj T VA 'P^xx^Y-0X AzX...x. 1^xxxxx-A.xxxxxf Aycn-18nr C" yKz A-xx A / O " Af xA AA ° AA A / ^A -Xx-- A- " “ L x. X x~x x_.x x'Xx..x X°x y xL V x-X~xX, XXx xx x XHOX X^YAX-'AX-AX'A AA / AXA O OH AAA / V AAAAAAOAAXAA> AO H,. U.> H k xAAxA^AAA cn-19 Z-NAAA0^A0OHe AXxAQ26681659747v1772787: SA9-887PC / / PAT24318-WO-PCT / ) \ \ cn-20O x— / 7X / / x{ r o4-~oX X— / Q < — i- —CII-21XOZ —?15^ o=p 9\!■ 'xxzx ° OHO ° °y x _ 1 _ x \ / ''T H, O—, ooCII-22 oyoo= \= xe □° ^-0ZH \ 1' x _ 1OH 6X \\ _ O z- ft \ X / XH 0-. 0 HO^ OHCII-23 U J,}? O z— \OH L J L J 'u °J'OH0~0 H) >CII-24 X \ J1 _ 1 _r0HCII-25HU '-’OHH 0-. OCD-26 / NSAA^VOSX J I J°0 HOH26781659747v1772787: SA9-887PC / / PAT24318-WO-PCTOH- xx, x, x, OH i1 1.oH-,°. i j\ \ ■-. - CII-27 y.. r v K!VA- / )0“-d H X \ \; < I HO'OH I 1) >CI - 8pJ / / A L I 2 °””O z—°\= <1 / << o— - / X‘ O Z —9 / / ^ACD-29 / ( o~ -. X"“"r^E■ Z o—p ^■°o o— x / \ OH^x.^xx xx.xxxvz-'x x 'x.zOH ■ o1 O^ H,o JP ok z-., Okx J'' V x~~... O r' • 'Xxx'x,x x^' 'xx'X z \ / X / x,z'1 ii J,cn-30 r f cX / x[0'-o H / oX— A °oxH0- 1. x..- - V. X.OH \ J'' x__OH dr.h oHO O Z-.CD-31 < J O _ ) )ZP° — / / X\ \ 0 iLX ''0- rN\ 0.OH n ° H 1O Z-~xOH OH„.-v,? ) „0.,-xx,\ JDH!- - '■■■•' ~ - Y ■" TH, p-y 0> >CD-320??,o„,,-xx x,-.vJ d ^0';'H Jr K [HO- '■x,--' '^..- x^x-x^,.x--x^x-x„,-xx^,!0 OHOH O > > \ \ ^'■-^^- ■-_. / -■ ^■''■■~XOH \r:: j¥ ' T H. p- oCD-330. xA o,xx-x.. / X. _, O,X.xx....xxx x^ ^ OL-0 H!I 0 5 HO" ‘' ’O'' 'xx-'x^.xx^.,. x..,.' -.v / / x.zx^xsp O OHCD-34x, X ^.x x. X==x.ZO^ZX_, ZX, XX., OH 9H90 - (OAPP OCD-35 N If T f M■n-H° '■ ■" J?6 OHHO'■'" ° " '26881659747v1772787: SA9-887PC / / PAT24318-WO-PCT\X 'X ^X V-X XZ Qj A -H\ (CII-36 f 7“O OHOH O- / A Azz'xz\^^^H i | i 3OyOv / \ / Nx < o> >oo oXX >"* i ( 3 A XX x-x Xx x*x X HOQ r. ’ZX X -X XX X zX Xv xxY-OHoI X Ji < o / AJ <o1='N 'O' '0 p-x,xC " Z - z X -x X •T-3 7 v,-,x y ) ’ A. y o7=H__0HX / -C°:OH _ I \ Jxx0 ° °-X )' A x-v xx x-v x XX x < o o= H i ro °vzO^X\z>N\oo 0 HO' >x z -"■'■■■..zv.. Xv ". X X / IOH \ ° / A / ^zZ'XxX^zXx^XXx'^ QnzXL xz v v.. xx y A v.Qx ° I J H\X^ZzX^ _ / / X ) o,z-v^xX0H\ f~QCII-38\ / / H0^ xv x~x / \ x~xx~x H i [OvxOXX'\X~vA / \ {0 L\z / 'xx'vzz''xX'''X-'''\ / / *7OH1 _ 1 _CII-39cn-4026981659747v1772787: SA9-887PC / / PAT24318-WO-PCT J> \ I OH1| H H O'-, oCII-41 > )> 0 H H |OHH° / / X\ \ °oz, J 4\ o z X ozV„ X-. ’—x \ I1<CII-42 ( O \ — / . \ X / “T / o z X 0 o1^o c O= W;\ r.^^xv r °x°~4 \x _ x 1x °'co _ I \ J _ \ Js'' °OH w<n IZ0 < x x3:H Hp-~, oCII-43 OVU. X X JJ - J1 $) 0 K 'NcA^^-^-^OH X\ * os O _ Z.— °L°H HyQ X __ / / OHx r °2-~'^ ( o-Xz7\ X\ O z: — \cn-44)r ri _ 1 _ <> CII-45CD-46OH I H, p-y 0rz1'',., Z\,.z-'X / -x / -., / ' CD-47 N 3;!.0ZH iOH27081659747v1772787: SA9-887PC / / PAT24318-WO-PCT ^ jCn-48- —- CII-51fp A x^^ CII-52- xxx x x x J Ax x xx x - -CII-53CII-54 X I A xx J ™ xJ Y A L -CII-5527181659747v1772787: SA9-887PC / / PAT24318-WO-PCTCII-56?H9CT-57^TO z ° X H0XI ) ) O — \—1v iXxX' o z—\XXX^^X010H.CII-58oXXX^ o ^.oX°7< sO OH A ° 0ZC H O-" NZ°T / \'v° o OH o0 \ / ' T _ XXXCC r\5 < Vo / N. JA \ / ' T _1 11 J I H oCII-59 °zOH I i n TOy-^X. 0X O Z^.0) / o ) O -— / / I) ' > o 0 —— / / IOH0 OHrN^^oy>~|cn-600HOX^V^X^ / cn-6iZXX^^X'OH o0HT _ _ X Hz0^ 1CD-62 i A X / \ ^\ / NXT H n0H0 H0 / W W \ / 27281659747v1772787: SA9-887PC / / PAT24318-WO-PCTOH XXxX\ / XxXZXX / \ O OHCII-63 V?)0HQAXXXXXX / \ / OH XXXX CD-64? ° O °° / o OZH HO O(O=\X < < O— — / W1b\ i( ( o—, -Z'1o zCD-65' Jo\=oo( — I / CD-66 v°0\ / *'- x0 _\ / '5' < ZE _5 <CD-67 j o^ o / )O ) -—J (1( -- °HO ozH^\b / ) o —— )oO 0H / / = ZEo \H, 0^ o HO / / zO ) / / / / / CD-68° °H 0yx / \zyOH 0| OH OHzo XXX^^X^^QXY-^X^^^X^ / X^ / ^ o 22CD-69 N'^-ZY Yv K- '0AzNx \0 XQ |-|HO'^XX^^Q'^XXXXXXX O OHz / xx^xxxz <^f^°OH OT / cn-701=1NHHOx^\X\X\x\o< Jxx"\x\NOH27381659747v1772787: SA9-887PC / / PAT24318-WO-PCT / Z—” v™( 0 O / ::::::o o Q bcn-7i \ X Xo— / / z< ()T > -- ( < / 6-.{( o= QX■•••' '\ X / 7( ( O—, -Cyo ■o\ ZEbcn-72 r^\V x.. J'* / O OH j Z 3Zo W / ZNX / ] 9 NHHx 1cn- x Z r 73 ' izOT / JL JH fjHA I K or / ZE.0 ) ) OHxOO== O„QH f!O O H H, P“- 0 ' ( ( O -— X. Z >xo.z x—z / 'x / X^ Xx..

1. ' 'cn-74 x •.. •fiJ Ji.... \ \ ZE7 h i;<VN- q o™ -O. 0 x-o H H J pHO' 'xz' -X... Z x.„.z XQZ Xx__,z- Xxz-Xx,, Z- \ 0 c > H )cn-750...... A%°'i? r — ''-xcAcn-767 - f ryV'-'". A o• ■■0■■ 'O H H I XX zx X. X. x...Q, x.0cn-77yO27481659747v1772787: SA9-887PC / / PAT24318-WO-PCTCD-78I 77\ \ / ° —o zo \> >°( oCD-791o -- I( < O— / —'L^ O ■Z o c / VT ( —oVo>° xjV'rzV° oO CZ () ZIcn-80TT"" —' \ / \ — I — \L1 <V °o oA 1( / X'' ° x z= _ _o IZ CD / JOHY OH\ / V * °7 / ° —cn-8i TO I A^0 H P O z^OH 1 V ) / o — / HO / / TOH / \ / V^^^Xx / OH11 H,0CD-82 ■[X?-'SA-^N'I / X^XxXxXxxJ °Uo H 1IH0 / X / -'-'^^^ o < OHCD-83Ooo<N--^SANH1 II 1 J HCD-84 pxo0°XKPH i \ T 1 HNYS^^NJ Oo27581659747v1772787: SA9-887PC / / PAT24318-WO-PCT(Compound CII-3),or a pharmaceutically acceptable salt thereof;(2) a helper lipid that constitutes from about 10 mol% to about 18 mol% of the totallipid content of the lipid nanoparticle;(3) a structural lipid that constitutes from about 35 mol% to about 50 mol% of thetotal lipid content of the lipid nanoparticle; and(4) a stealth lipid that constitutes from about 1 mol% to about 3 mol% of the totallipid content of the lipid nanoparticle.

3. The LNP of claim 1 or claim 2, wherein the helper lipid has a structure according to Formula (HLP-I):27681659747v1772787: SA9-887PC / / PAT24318-WO-PCTO OO (HLP-I)or a pharmaceutically acceptable salt thereof, wherein:Y is selected from optionally substituted C2-C6 alkylene or optionally substituted C4-C6 alkenylene;Rais absent, or Ra is optionally substituted C1-C10 alkyl, wherein, when Ra is present, the nitrogen to which Ra is bonded bears a positive charge;each Ri is independently selected from hydrogen or optionally substituted C1-C10 alkyl; each R2 is independently selected from:(x) optionally substituted C4-C24 alkyl, optionally substituted C4-C24 alkenyl, and optionally substituted C4-C24 alkynyl;ORA\(xi)0 Za, wherein each RA is independently selected from optionally substituted C1-C31 alkyl, optionally substituted C2-C31 alkenyl, and optionally substituted C2-C31 alkynyl; andwherein each ZA is independently selected from optionally substituted C1-C10 alkylene and optionally substituted C2-C10 alkenylene;O(xii)B 5, wherein each RB is independently selected from optionally substituted C1-C31 alkyl, optionally substituted C2-C31 alkenyl, and optionally substituted C2-C31 alkynyl; andwherein each ZB is independently selected from optionally substituted C1-C10 alkylene and optionally substituted C2-C10 alkenylene;preferably wherein the helper lipid is selected from the group consisting of:27781659747v1772787: SA9-887PC / / PAT24318-WO-PCT0 0oM C HI-1 ZE M C Z ZEZ0 0 / ^°\ OOQ-=- o / ZE°\ OOCL=- HI-2 o\ O O - 'K F\ O O( / - 'xoF!=0II 2 °f<= 0II HI-3 / \G=AC^H°2\ ° \= °\ °2 )° (=\ / °_ oHI-4 0 L / ^^P^ / \ / NH29 T / °0OH00O.0II / \ / N H2HI-500HI-60 0 0 1 HI-727881659747v1772787: SA9-887PC / / PAT24318-WO-PCT 9 9 1 p^ p po 6p- -10 0^.0 Z. — - HI-81 ° 1 / T°\ OOQ-=- o9 " 1HI-96HO^ - P>°\ °2 °f^\ \ P —ii i H i HI- 10 \° oX< / x^P^,xx, N.° I ° OH° / \ / °09 ° 1 Z^X^ N / p^ -^ pp0 6 HO—. HI- 11 / °0I? 9 1 HI- 12 \ ^S. k / -\ Jk / \ ^Px / l\k cooci A.xxx.r6h0HI- 13H ° 16O-— - HI- 14'XxX"'x-xXXx / ^^27981659747v1772787: SA9-887PC / / PAT24318-WO-PCTz — HI- 15 / x°OOCL=- \x-^x^\x^x o O \ 0 | oHI- 160 \ o O / o4X / VX^ / x A Ao o0? ° 1 HI- 17 ^^^^ 0 20= k / — / x A x^x x6Px ^ x^X\x xN. x \ / ° / °x° — / \) \ \ ° —\ / °0° \ / > oHI- 18X x^x / \ / x 1 \x-^xA H.^x-X x-X^x °Px^Z-x / N 1.nAq°6qHO-'- - ^X / ^X / A^O^ / X^X^X^O oo-u=- 0 0z — HI- 191 o O I II II 1 HI-20 \ \X x-X^X 'XX / - \ \x xX^\0\ X^x X^ xX-A xQ / x-~X X X / \ XQ / xP|X XQ / X^X x^x XNX X,II | OH\ \x X--\ ^X A ''o^ X-A V xXX ^X X^xX / X X / xO028081659747v1772787: SA9-887PC / / PAT24318-WO-PCT281 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT T T+l HI-27 z ——Z — z — / T° / '^x''xx'X^x°yO OOn-=- O o / X / T \°°\ OOn-O=D--=- o o] 9 9 1HI-28YO R"0000- AOOO z \ R \0^\ O °( / oo= 6H / ( / o / "= 0o=O O III II 1 x. x\ XX XX / Ck / X / X xX X x\ xxZPXxx „I\L xx x xX XX XX Xx xX XX XX XX^Q O Xp ^ OH O, \ — 'II ZXXx O / \ / ( —o=— AOHHI-29 ^XZ °^ o / / o — ' ZX / \ / 0(0 ■ / o=—\ °= — \X\ / XxX 0 O o0 ■HI-300 0.0..---x XX A XX zx p- ••-••.z, v y J - - Q. yOyyvy HI-31A 00'l S. f Xz- xz -.. X, X -QZ XX Xz-HI-3228281659747v1772787: SA9-887PC / / PAT24318-WO-PCTmore preferably wherein the helper lipid is selected from the group consisting of Compounds HI-6, HI- 12, HI- 18, HI-24, HI-27, and HI-31.

4. The LNP of claim 1 or claim 2, wherein the helper lipid has a structure according to Formula (HLP-II):R2A’II^R1AN;R2B'OHR1CR2C "(HLP-II),or a pharmaceutically acceptable salt thereof, wherein:X is -C(i-6)alkylene-, -C(2-6)alkenylene-, -OC(i-6)alkylene-, -OC(2-6)alkenylene-, -OC(O)C(i-6)alkylene-, -OC(O)C(2-6)alkenylene-, -OC(O)OC(i-6)alkylene-, -OC(O)OC(2-6)alkenylene-, -NHC(O)C(i-6)alkylene-, -NHC(O)C(2-6)alkenylene-, or -C(1-6)alkylene-O-C(i-6)alkylene-;Y is -C(2-6)alkylene- or -C(2-6)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -28381659747v1772787: SA9-887PC / / PAT24318-WO-PCTC(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”;R1Aand R1Bare each independently selected from hydrogen and -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; orR1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group that is optionally substituted with one, two, or three -C(i-6)alkyl groups;R1Cis absent or R1Cis -C(1-10)alkyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge; orR 1 A, R IB, and R 1C are taken together with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group that is optionally substituted with one, two, or three -C(i-6)alkyl groups, wherein the nitrogen to which R1A, R1B, and R1Cis bonded bears a positive charge;R2A, R2B, and R2Care each independently -OR3, -OC(O)R3, or -C(O)OR3; each R3is independently selected from the group consisting of:(i) -C(9-25)alkyl, -C(9-25)alkenyl or -C(9-25)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” or -SO2R”;O(ii) R ®, wherein:each R3Ais independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; andeach ZA is independently -C(6-io)alkylene- or -C(7-io)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; and28481659747v1772787: SA9-887PC / / PAT24318-WO-PCT T O© zV — — ^ Z —(iii) O, wherein: z / rx°°\ OO OOn-n—==- each R3Bis independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl, / T e o o°ach of000—=which is optionally substituted with one, two, or three substituents independe ontly selectedfrom the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, - o oOC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; andeach ZB is independently -C(6-io)alkylene- or -C(7-io)alkeyyny o X o o X oX O / 00 / 00 \ \^^lene-, each of which is optionally substituted with one, two, or three substituents ind X O O / 00 \^ependently selected from thegroup consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”;n is 0 or 1; andR” is independently for each occurrence -C(i-20)alkyl;preferably wherein the helper lipid is selected from the group consisting of:>( < >( <>( <HII-1HII-2HII-30° iHII-4° )0H528581659747v1772787: SA9-887PC / / PAT24318-WO-PCTCM I IZ. — z —© O z Z — 00 1 \ °HII-5 / / / TIT°°°jH0 06H° OO OO OOQ-Q- / Q-===T---°OO \ \CL=- o o oo5 oo o oHII-6. o o X o X o o O X / y\a~~ / / 00 / oo / OO \ \ \( / ^^^ ° °^ —< o o / \ \ °HII-7>( <HII-8o\ OHHII-9 T0 / 015 HII-1028681659747v1772787: SA9-887PC / / PAT24318-WO-PCT© z —HII-11 / T°\ OOQ-=- oy { ooV-— \ / / \ / / \ / \ / \ \ / / \ / ° / \ / ( \(o o!==HII-12L ° °^4^3 < o 00^,\ o o) ( ) / ( ) / ( / ) / ( \ / ( \ 9 I HII-13 — o'Vo^N- OH° \ / / ° \ / 00 \ / V.^' O QV 500<o o^ )4^^^ o o 5 ^x—<' / o^oo ooV oo=- HII-14OO OOTI-D==-- z —o z z — — I HII-15X\ / X ^x Z\ _O 0. O |HII-16 J OH0^528781659747v1772787: SA9-887PC / / PAT24318-WO-PCT288 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT289 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT290 81659747v1772787: SA9-887PC / / PAT24318-WO-PCTZ —HII-35 / T°\ OOQ-=- 0 / o—\ / 0HD-36( ) oo / ==° \ / / 0)00\ / or a pharmaceutically acceptable salt thereof; ) (\ °\ / ( )°0° r=more preferably wherein the helper lipid is selected from the group consisting of Compounds HII-13, HII-14, and HII-23.

5. A lipid nanoparticle (LNP) comprising:(1) an ionizable or cationic lipid that constitutes from about ^ / >00— 35 mol% to about 50 / \ / mol% of the total lipid content of the lipid nanoparticle;(2) a helper lipids that constitutes from about 10 mol% to about 18 m 0ol% of the total OOm=-lipid content of the lipid nanoparticle, wherein the helper lipid has a structure according to Formula (HLP-I):O O z— tsO(HLP-I)or a pharmaceutically acceptable salt thereof, wherein:Y is selected from optionally substituted C2-C6 alkylene or optionally substituted C4-C6 alkenylene;Rais absent, or Ra is optionally substituted C1-C10 alkyl, wherein, when Ra is present, the nitrogen to which Ra is bonded bears a positive charge;29181659747v1772787: SA9-887PC / / PAT24318-WO-PCTeach Ri is independently selected from hydrogen or optionally substituted C1-C10 alkyl; each R2 is independently selected from:(xiii) optionally substituted C4-C24 alkyl, optionally substituted C4-C24 alkenyl, and optionally substituted C4-C24 alkynyl;ORA\(xiv)0 Za, wherein each RA is independently selected from optionally substituted C1-C31 alkyl, optionally substituted C2-C31 alkenyl, and optionally substituted C2-C31 alkynyl; andwherein each ZA is independently selected from optionally substituted C1-C10 alkylene and optionally substituted C2-C10 alkenylene;O(xv)BJ, wherein each RB is independently selected from optionally substituted C1-C31 alkyl, optionally substituted C2-C31 alkenyl, and optionally substituted C2-C31 alkynyl; andwherein each ZB is independently selected from optionally substituted C1-C10 alkylene and optionally substituted C2-C10 alkenylene;preferably wherein the helper lipid is selected from the group consisting of:29281659747v1772787: SA9-887PC / / PAT24318-WO-PCT0HI-4 0 L9 T0OH000 0 / ^X^x^" X^X / O\ px^_^^w^X^Ay ^x-px / x^,x ^ fA / XX' x x N H2HI-5 ^X^X / 0° y0A ° / \z\o= / o< oHI-6 \o= \° \ / ° ° ' \ o o\ —K0 0 > OO-D=- 0 1 x^ ^ x^ x^ A x^ / ^ x^ A / ^ x^ P / X^N^ HI-7^ AAAxA^'^^04^x°°?^ ( q0'^0z / — OOT=- A ■9 1 \ / -\ / x^Oxxx_ / 'X / ^^p^ / \ / N\ Z1o Ox / O ZE I 80HH - ro 101X-AX^XX^Q'A^XAHI-90ii i0ii 1 i HI- 10 o A^^X P^ / \ / N.0i06H°o29381659747v1772787: SA9-887PC / / PAT24318-WO-PCTZ. — - HI- 11 / T°\ OOQ-=- / VX / XX / Ox3' oX o 0 I II II 1 HI- 12 \ xx \ / x A x^X x\ „Px X. N.\ ° oood ( / o= 6h° ° / 0({o O==\ / \O / A ( \\ / ° \ c>HI- 13 / °) \ \ ° — \ ' O — \\ / °° ° / / \ / < > P o OH ° 16 HoXx ° qHI- 14 XX^ / X / Xx^0, XXxAX / O q\ OOJ= oo--u=- Xx^Xx^XX\ / J0— z — HI- 15\ / 'Xxxx^^ 0 O 1 xxxx^oA^ ^ Ao^o, J HI- 16z^V^XX / X / O^ / X / X / XXyO x^xxx^x^ O o'XXX^x A xO.? 9 1 HI- 170k / x A / X XX xPx x'X xNv AA°6h° / ^Xx^Xx^xx^'29481659747v1772787: SA9-887PC / / PAT24318-WO-PCT295 81659747v1772787: SA9-887PC / / PAT24318-WO-PCTHI-24HI-2500((o= o= / \ \ / o o°z\ / —z\ / o ox° — / \\ \ ' ' 0 O — - \ VHI-2600\ / \ / ° > 0 \ / > O00q0 q\ 0 0 \ OOJ= q- 0073=- |HI-27 0073=- V0H0 z — z — z — — I HI-28 I? 9 I T 0000- OOOOO06h0 0 III II I X H J n02 I 0. ^ ^ xI A 0 / OOi ^ 9H0 OH x / - x^^x^ / x^ / -^ J O"x^^x / ^x / ^X^-Q^Q29681659747v1772787: SA9-887PC / / PAT24318-WO-PCTHI-30> >X X'-, X X. xxX,.x x, O. x. Xxx- -x X X. JL x.0Xx XY-X. A x,,, x. „ x A A xX'x J O O x OHI-31 x-' x / x / x / Xy-'o o o o o oxX -.. X X... ° / — o / ° ox / — / X.. Q. 1 XX XX f°x° — / — / / 0 2= \° / —x— / \x° — / ° \ — / \HI-32 ° \ / ° / \o°=\ > / ° / O / > \ o / O"s A q q OO" U=- o OOm=- oo-u=- S o 0 OOm=z- 'o / HI-33 II11[°Hz —0 z — —+z l — -— I HI-34HI-35or a pharmaceutically acceptable salt thereof;more preferably wherein the helper lipid is selected from the group consisting of Compounds HI-6, HI-12, HI-18, HI-24, HI-27, and HI-31;29781659747v1772787: SA9-887PC / / PAT24318-WO-PCT(3) a structural lipid that constitutes from about 35 mol% to about 50 mol% of the total lipid content of the lipid nanoparticle; and(4) a stealth lipid that constitutes from about 1 mol% to about 3 mol% of the total lipid content of the lipid nanoparticle.

6. A lipid nanoparticle (LNP) comprising:(1) an ionizable or cationic lipid that constitutes from about 35 mol% to about 50 mol% of the total lipid content of the lipid nanoparticle;(2) a helper lipid that constitutes from about 10 mol% to about 18 mol% of the total lipid content of the lipid nanoparticle, wherein the helper lipid has a structure according to Formula (HLP-II):R2AO / -R1AR2B OT° NJ) OH IRR1C(HLP-II),or a pharmaceutically acceptable salt thereof, wherein:X is -C(i-6)alkylene-, -C(2-6)alkenylene-, -OC(i-6)alkylene-, -OC(2-6)alkenylene-, -OC(O)C(i-6)alkylene-, -OC(O)C(2-6)alkenylene-, -OC(O)OC(i-6)alkylene-, -OC(O)OC(2-6)alkenylene-, -NHC(O)C(i-6)alkylene-, -NHC(O)C(2-6)alkenylene-, or -C(1-6)alkylene-O-C(i-6)alkylene-;Y is -C(2-6)alkylene- or -C(2-6)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”;R1Aand R1Bare each independently selected from hydrogen and -C(1-10)alkyl, wherein the -C(1-10)alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; orR1Aand R1Bare taken together with the nitrogen to which they are attached to form a 4-10-membered heterocyclic group that is optionally substituted with one, two, or three -C(i-6)alkyl groups;R1Cis absent or R1Cis -C(1-10)alkyl that is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -29881659747v1772787: SA9-887PC / / PAT24318-WO-PCTSR” and -SO2R”, wherein when R1Cis present, the nitrogen to which R1Cis bonded bears a positive charge; orR 1 A, R IB, and R 1C are taken together with the nitrogen to which they are attached to form a 5-11-membered heterocyclic group that is optionally substituted with one, two, or three -C(i-6)alkyl groups, wherein the nitrogen to which R1A, R1B, and R1Cis bonded bears a positive charge;R2A, R2B, and R2Care each independently -OR3, -OC(O)R3, or -C(O)OR3; each R3is independently selected from the group consisting of:(i) -C(9-25)alkyl, -C(9-25)alkenyl or -C(9-25)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” or -SO2R”;O(ii) R3AO C, wherein:each R3Ais independently -C(1-31)alkyl, -C(2-31)alkenyl, or -C(2-31)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; andeach ZA is independently -C(6-io)alkylene- or -C(7-io)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; andR-°YZB / (iii)O, wherein:each R3Bis independently -C(i-3i)alkyl, -C(2-3i)alkenyl, or -C(2-3i)alkynyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”; andeach ZB is independently -C(6-10)alkylene- or -C(7-10)alkenylene-, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -C(O)R”, -C(O)OH, -C(O)OR”, -CN, -OH, -OR”, -OC(O)R”, -OC(O)OR”, -NH2, -NHR”, -N(R”)2, -SR” and -SO2R”;n is 0 or 1; andR” is independently for each occurrence -C(i-20)alkyl;29981659747v1T 772787: SA9-887PC / / PAT24318-WO ^-PCT O ©© z Z zV — — — —ZZZpreferably wherein the helper lipid is selected from the group consisting of:z —Z / / / x°OO 00n-=IIx0—=- °°°\ \ 00 000—0—==o o o oHII-1 / T°000—=oo o o oX o o o X o / 0 / 00 \ / 00 \^^.. o X o o X Oyy£-- OO0 / 00 \ \^^HII-2. o o X / 00 \^HII-3>( < >( < / \ o o^^ 00>( < MA 0OO° iHII-4 W —0H° ) q0HOO" U=- 5z —HII-5THII-6HII-730081659747v1772787: SA9-887PC / / PAT24318-WO-PCT CM I I O Z z z. — — z. — ^ \".- z — \ ° / / TT°°\ / T OO OOCLCL==--° / \ o oT OO \D-°=- o OOn-=- oHII-8 bo o o o^^y^ y (\ / \ / \ / Q °°>o~y^ \x / / X<x°^° °° / —f\ \ / Q,>. o- o o o °—~. o X X / 00 \ / \ \ / ox \ o X^o!=( O OO\ OHHII-9 / \ \ ° I'0 > 01 / X / X / X / X / Q\ ) / ( o oOX 0, O0 5 V^ r °°1 O o / ( \) HHII-10HII-11HII-12HII-1330181659747v1772787: SA9-887PC / / PAT24318-WO-PCT302 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT303 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT304 81659747v1772787: SA9-887PC / / PAT24318-WO-PCT305 81659747v1772787: SA9-887PC / / PAT24318-WO-PCTmore preferably wherein the helper lipid is selected from the group consisting of Compounds HII-13, HII-14, and HII-23;(3) a structural lipid that constitutes from about 35 mol% to about 50 mol% of the total lipid content of the lipid nanoparticle; and(4) a stealth lipid that constitutes from about 1 mol% to about 3 mol% of the total lipid content of the lipid nanoparticle.

7. The LNP of any one of claims 1-6, wherein the helper lipid further comprises DOPE.

8. The LNP of any one of claims 1-7, wherein:the structural lipid is selected from the group consisting of cholesterol, P-amyrin, and a combination thereof, preferably wherein the structural lipid is cholesterol; and / orthe stealth lipid is DMG-PEG2000.

9. The LNP of any one of claims 1-8, wherein:the ionizable or cationic lipid constitutes from about 35 mol% to about 40 mol% of the total lipid content of the LNP, preferably about 38.5 mol% of the total lipid content of the LNP;the helper lipid constitutes from about 12 mol% to about 18 mol% of the total lipid content of the LNP, preferably about 15 mol% of the total lipid content of the LNP;the structural lipid constitutes from about 42 mol% to about 48 mol% of the total lipid content of the LNP, preferably about 45 mol% of the total lipid content of the LNP; and the stealth lipid constitutes from about 1 mol% to about 1.8 mol% of the total lipid content of the LNP, preferably about 1.5 mol% of the total lipid content of the LNP.

10. The LNP of any one of claims 1-8, wherein:the ionizable or cationic lipid constitutes from about 42 mol% to about 48 mol% of the total lipid content of the LNP, preferably about 45 mol% of the total lipid content of the LNP;the helper lipid constitutes from about 12 mol% to about 18 mol% of the total lipid content of the LNP, preferably about 15 mol% of the total lipid content of the LNP;the structural lipid constitutes from about 35 mol% to about 40 mol% of the total lipid content of the LNP, preferably about 38.5 mol% of the total lipid content of the LNP; and30681659747v1772787: SA9-887PC / / PAT24318-WO-PCTthe stealth lipid constitutes from about 1 mol% to about 1.8 mol% of the total lipid content of the LNP, preferably about 1.5 mol% of the total lipid content of the LNP.

11. The LNP of any one of claims 1-8, wherein:the ionizable or cationic lipid constitutes from about 45 mol% to about 50 mol% of the total lipid content of the LNP, preferably about 47.5 mol% of the total lipid content of the LNP;the helper lipid constitutes from about 12 mol% to about 18 mol% of the total lipid content of the LNP, preferably about 15 mol% of the total lipid content of the LNP;the structural lipid constitutes from about 35 mol% to about 40 mol% of the total lipid content of the LNP, preferably about 36 mol% of the total lipid content of the LNP; and the stealth lipid constitutes from about 1 mol% to about 1.8 mol% of the total lipid content of the LNP, preferably about 1.5 mol% of the total lipid content of the LNP.

12. The LNP of any one of claims 1-8, wherein:the ionizable or cationic lipid constitutes from about 37 mol% to about 43 mol% of the total lipid content of the LNP, preferably about 40 mol% of the total lipid content of the LNP;the helper lipid constitutes from about 10 mol% to about 15 mol% of the total lipid content of the LNP, preferably about 13.5 mol% of the total lipid content of the LNP;the structural lipid constitutes from about 42 mol% to about 48 mol% of the total lipid content of the LNP, preferably about 44.8 mol% of the total lipid content of the LNP; and the stealth lipid constitutes from about 1 mol% to about 1.8 mol% of the total lipid content of the LNP, preferably about 1.7 mol% of the total lipid content of the LNP.

13. A pharmaceutical composition comprising the LNP of any one of claims 1-12 and a pharmaceutically acceptable excipient, diluent, or carrier, wherein the LNP encapsulates an mRNA encoding a peptide or protein.

14. The pharmaceutical composition of claim 13 for use in therapy.

15. The pharmaceutical composition of claim 13 for use in a method of treating or preventing a disease amenable to treatment or prevention by the peptide or protein encoded by the mRNA, optionally wherein the mRNA encodes an antigen and / or the disease is (a) a 30781659747v1772787: SA9-887PC / / PAT24318-WO-PCTprotein deficiency, optionally wherein the protein deficiency affects the liver, lung, brain or muscle, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer.30881659747v1

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