Tricine and citric acid lipids

Abstract

Disclosed are cationic lipids which are compounds of Formula A. (A) Cationic lipids provided herein can be useful for delivery and expression of mRNA and encoded protein, e.g., as a component of liposomal delivery vehicle, and accordingly can be useful for treating various diseases, disorders and conditions, such as those associated with deficiency of one or more proteins. X2A X1A X4A X3A X1B n n n X2B O X3BO X4B O R2 R4 R3 R1 O X3A O O X1A X 1B 20 26 20 48 02 22 J un 2 02 6 2 0 2 6 2 0 4 8 0 2 2 2 2 0 2 6 J u n O O O 1 A 1 B

Description

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Serial Number 62 / 864,818, filed on June 21, 2019, the entire disclosure of which is hereby incorporated by reference. BACKGROUND

[0002] Delivery of nucleic acids has been explored extensively as a potential therapeutic option for certain disease states. In particular, messenger RNA (mRNA) therapy has become an increasingly important option for treatment of various diseases, including for those associated with deficiency of one or more proteins. SUMMARY

[0003] The present invention provides, among other things, cationic lipids useful in for delivery of mRNA. Delivery of mRNA provided by cationic lipids described herein can result in targeted delivery, reduce administration frequency, improve patient tolerability, and provide more potent and less toxic mRNA therapy for the treatment of a variety of diseases, including but not limited to cancer, cardiovascular, cystic fibrosis, infectious, and neurological diseases.

[0004] In a first aspect, the present invention provides new cationic lipids.

[0005] In a second aspect, the present invention provides a liposome encapsulating an mRNA encoding a protein wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids, wherein at least one cationic lipid is a cationic lipid as described herein.

[0006] In a third aspect, the present invention provides a nucleic acid encapsulated within a liposome, wherein the liposome comprises a cationic lipid that is a cationic lipid as described herein. 2026204802   22 Jun 2026

[0007] In embodiments, a cationic lipid has a structure according to Formula (A): zx1A X1b I R1 (A), or a pharmaceutically acceptable salt thereof, wherein each n is independently 0 or 1; X1A is independently O or NR1A; R1A is H or Ci-Cg alkyl; X1B is a covalent bond, C(O), CH2CO2, or CH2C(O); one of X2A and X2B is O and the other is a covalent bond; one of X3A and X3B is O and the other is a covalent bond; one of X4A and X4B is O and the other is a covalent bond; R1 is independently L^B1, Cg-Cso alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; R2 is independently L2-B2, Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; R3 is independently L3-B3, Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; R4 is independently L4-B4, Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; L1, L2, L3, and L4 are each independently C1-C30 alkylene; C2-C30 alkenylene; or C2-C30 alkynylene; each of B1, B2, B3, and B4 is independently an ionizable nitrogen-containing group, and wherein the cationic lipid comprises at least one ionizable nitrogen-containing group.

[0008] In embodiments, a cationic lipid has a structure according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein 2026204802   22 Jun 2026 each of R2, R3, and R4 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; and L1 is Ci-Cio alkylene.

[0009] In embodiments, a cationic lipid has a structure according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein B1 is an ionizable nitrogen-containing group; each of R2, R3, and R4 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; and L1 is Ci-Cio alkylene.

[0010] In embodiments, a cationic lipid has a structure according to Formula (II), or a pharmaceutically acceptable salt thereof, wherein each of R2, R3, and R4 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; and L1 is Ci-Cio alkylene.

[0011] In embodiments, a cationic lipid has a structure according to Formula (II), or a pharmaceutically acceptable salt thereof, wherein R1A is H or Ci-Cg alkyl; B1 is an ionizable nitrogen-containing group; each of R2, R3, and R4 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; and 2026204802   22 Jun 2026 L1 is Ci-Cio alkylene.

[0012] In embodiments, a cationic lipid has a structure according to Formula (Al), or a pharmaceutically acceptable salt thereof, wherein L1 is Ci-Cio alkylene; each R6A is independently H or Ci-Cg alkyl; and each R6b is independently H or Ci-Cg alkyl.

[0013] In embodiments, a cationic lipid has a structure according to Formula (All), or a pharmaceutically acceptable salt thereof. 2026204802   22 Jun 2026

[0014] In embodiments, a cationic lipid has a structure according to Formula (AHI), (Alli), or a pharmaceutically acceptable salt thereof, wherein R1A is H.

[0015] In embodiments, a cationic lipid has a structure according to Formula (Ila), or a pharmaceutically acceptable salt thereof, wherein B1 is an ionizable nitrogen-containing group; R1A is H or C(O)-R7; each of R2, R3, R4, and R7 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; and L1 is Ci-Cio alkylene.

[0016] In embodiments, the cationic lipid has a structure according to Formula (lib), 2026204802   22 Jun 2026 or a pharmaceutically acceptable salt thereof, wherein B1 is an ionizable nitrogen-containing group; R1A is H or C(O)-R7; and each of R2, R3, R4, and R7 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

[0017] In embodiments, the cationic lipid has a structure according to Formula (He), (He), or a pharmaceutically acceptable salt thereof, wherein B1 is an ionizable nitrogen-containing group; and each of R2, R3, R4, and R7 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

[0018] In embodiments, a cationic lipid has a structure according to Formula (lid), yR3 or a pharmaceutically acceptable salt thereof, wherein B1 is an ionizable nitrogen-containing group; and each of R2, R3, R4, and R7 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

[0019] In embodiments, R1A is H.

[0020] In embodiments, L1 is unsubstituted C1-C10 alkylene.

[0021] In embodiments, L1 is (CHa)?, (CHa)a, (CH2)4, or (CHa)5. 2026204802   22 Jun 2026

[0022] In embodiments, B1 is independently NH2, guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered nitrogen-containing heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl. N-| zN-|

[0023] In embodiments, B1 is independently H , Me HO Me . Et .     \___.            ,____ ZN—1   ,N-^ HO   N—|    /   N—|

[0024] In embodiments, B1 is independently Me , Et ,    \--- /    , or \— /

[0025] In embodiments, each of R2, R3, R4 and R7 is independently CgHi?, C10H21, C12H25, C14H29, CigHaa, CigHai, C16H29 and C16H32.

[0026] In embodiments, each of R2, R3, R4 and R7 is independently C6-C22 alkyl, C6-C22 alkenyl, or Cg-C22 alkynyl.

[0027] In embodiments, each of R2, R3, R4 and R7 is independently C6-C22 alkyl, or C6-C22 alkenyl.

[0028] In embodiments, each of R2, R3, R4 and R7 is independently unsubstituted linear C6-C22 alkyl, or unsubstituted linear C6-C22 alkenyl.

[0029] In embodiments, R1 is independently CgHi?, C10H21, C12H25, C14H29, C16H33, CigHsi, C16H29 and C16H32.

[0030] In embodiments, R1 is independently unsubstituted linear C6-C22 alkyl, unsubstituted linear C6-C22 alkenyl, or unsubstituted linear C6-C22 alkynyl.

[0031] In embodiments, each of R2, R3, and R4 is independently unsubstituted linear C6-C22 alkyl, unsubstituted linear C6-C22 alkenyl, unsubstituted linear C6-C22 alkynyl, unsubstituted branched C6-C22 alkyl, unsubstituted branched C6-C22 alkenyl, or unsubstituted branched C6-C22 alkynyl.

[0032] In embodiments, each of R2, R3, and R4 is unsubstituted C6-C22 alkyl.

[0033] In embodiments, each of R2, R3, and R4 is independently C6-C12 alkyl substituted by -O(CO)R5 or -C(O)OR5, wherein R5 is unsubstituted Cg-Ci4 alkyl.

[0034] In embodiments, each of R2, R3, and R4 is unsubstituted C6-C22 alkenyl. In embodiments, said C6-C22 alkenyl is a monoalkenyl, a dienyl, or a trienyl.

[0035] In embodiments, each of R2, R3, and R4 is 2026204802   22 Jun 2026 2026204802   22 Jun 2026

[0039] In embodiments, a cationic lipid has a structure according to Formula (III), 2026204802   22 Jun 2026 or a pharmaceutically acceptable salt thereof, wherein R1 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

[0040] In embodiments, a cationic lipid has a structure according to Formula (III), or a pharmaceutically acceptable salt thereof, wherein L2, L3, and L4 are each independently C1-C30 alkylene; C2-C30 alkenylene; or C2-C30 alkynylene; each of B2, B3, and B4 is independently an ionizable nitrogen-containing group; and R1 is independently Cg-Cso alkyl, Cg-Cso alkenyl, or Cg-Cso alkynyl.

[0041] In embodiments, a cationic lipid has a structure according to Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R1 is independently Cg-Cso alkyl, Cg-Cso alkenyl, or Cg-Cso alkynyl. 2026204802   22 Jun 2026

[0042] In embodiments, a cationic lipid has a structure according to Formula (IV), or a pharmaceutically acceptable salt thereof, wherein L2, L3, and L4 are each independently C1-C30 alkylene; C2-C30 alkenylene; or C2-C30 alkynylene; each of B2, B3, and B4 is independently an ionizable nitrogen-containing group; R1A is H or Ci-Cg alkyl; and R1 is independently Cg-Cso alkyl, Cg-Cso alkenyl, or Cg-Cso alkynyl.

[0043] In embodiments, R1A is H.

[0044] In embodiments, a cationic lipid has a structure according to Formula (V), or a pharmaceutically acceptable salt thereof, wherein R1 is independently Cg-Cso alkyl, Cg-Cso alkenyl, or Cg-Cso alkynyl.

[0045] In embodiments, a cationic lipid has a structure according to Formula (V), or a pharmaceutically acceptable salt thereof, wherein L2, L3, and L4 are each independently C1-C30 alkylene; C2-C30 alkenylene; or C2-C30 alkynylene; 2026204802   22 Jun 2026 each of B2, B3, and B4 is independently an ionizable nitrogen-containing group; and R1 is independently Cg-Cso alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

[0046] In embodiments, a cationic lipid has a structure according to Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R1 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

[0047] In embodiments, a cationic lipid has a structure according to Formula (VI), or a pharmaceutically acceptable salt thereof, wherein L2, L3, and L4 are each independently C1-C30 alkylene; C2-C30 alkenylene; or C2-C30 alkynylene; each of B2, B3, and B4 is independently an ionizable nitrogen-containing group; R1A is H or Ci-Cg alkyl; and R1 is independently Cg-Cso alkyl, Cg-Cso alkenyl, or Cg-Cso alkynyl.

[0048] In embodiments, R1A is H.

[0049] In embodiments, R1 is independently unsubstituted linear Cg-C22 alkyl, unsubstituted linear Cg-C22 alkenyl, unsubstituted linear Cg-C22 alkynyl, unsubstituted branched Cg-C22 alkyl, unsubstituted branched Cg-C22 alkenyl, or unsubstituted branched Cg-C22 alkynyl.

[0050] In embodiments, R1 is independently unsubstituted Cg-C22 alkyl.

[0051] In embodiments, R1 is independently Cg-Ci2 alkyl substituted by -O(CO)R5 or -C(O)OR5, wherein R5 is unsubstituted Cg-Ci4 alkyl. 2026204802   22 Jun 2026

[0052] In embodiments, R1 is independently unsubstituted C6-C22 alkenyl.

[0053] In embodiments, C6-C22 alkenyl is a monoalkenyl, a dienyl, or a trienyl.

[0054] In embodiments (e.g., of Formula (III) or (IV)), R1 is independently

[0055] In embodiments (e.g., of Formula (III) or (IV)), R1 is independently 2026204802   22 Jun 2026

[0056] In embodiments (e.g., of Formula (V) or (VI)), R1 is independently O 2026204802   22 Jun 2026

[0058] In embodiments, each of L2, L3, and L4 is unsubstituted C1-C10 alkylene.

[0059] In embodiments, each of L2, L3, and L4 is (CHzh, (CFbh, (CFbh, or (CFbh.

[0060] In embodiments, each of B2, B3, and B4 is independently NH2, guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered nitrogen-containing heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl. H . Me . Et . ,n4 znH / H

[0061] In embodiments, each of B2, B3, and B4 is independently H , Me , Et , HC\__       HN^ H HN^ Q-J O^.or O’*. HO Me . Et .      \___. n4 n4 HO \l

[0062] In embodiments, each of B2, B3, and B4 is independently Me , Et ,    \— /

[0063] In embodiments, a cationic lipid is any of Compounds 1-264, la-lh, I lbl-ll b4, I lcl-1 Ic4, 11 la-11 Id, and Va-Vd, or a pharmaceutically acceptable salt thereof.

[0064] In embodiments, a cationic lipid is any of the compounds in any of Tables A-F, or a pharmaceutically acceptable salt thereof.

[0065] In another aspect, the invention features a composition comprising any liposome (e.g., a liposome encapsulating an mRNA encoding a protein) described herein.

[0066] In embodiments, an mRNA encodes for cystic fibrosis transmembrane conductance regulator (CFTR) protein.

[0067] In embodiments, an mRNA encodes for ornithine transcarbamylase (OTC) protein. 2026204802   22 Jun 2026

[0068] In another aspect, the invention features a composition comprising a nucleic acid encapsulated within a liposome as described herein.

[0069] In embodiments, a composition further comprises one more lipids selected from the group consisting of one or more cationic lipids, one or more non-cationic lipids, and one or more PEG-modified lipids.

[0070] In embodiments, a nucleic acid is an mRNA encoding a peptide or polypeptide.

[0071] In embodiments, a mRNA encodes a peptide or polypeptide for use in the delivery to or treatment of the lung of a subject or a lung cell.

[0072] In embodiments, a mRNA encodes a peptide or polypeptide for use in the delivery to or treatment of the lung of a subject or a lung cell.

[0073] In embodiments, an mRNA encodes for cystic fibrosis transmembrane conductance regulator (CFTR) protein.

[0074] In embodiments, a mRNA encodes a peptide or polypeptide for use in the delivery to or treatment of the liver of a subject or a liver cell.

[0075] In embodiments, a mRNA encodes for ornithine transcarbamylase (OTC) protein.

[0076] In embodiments, a mRNA encodes a peptide or polypeptide for use in vaccine.

[0077] In embodiments, a mRNA encodes an antigen.

[0078] In some aspects, the present invention provides methods of treating a disease in a subject comprising administering to the subject a composition as described herein. BRIEF DESCRIPTION OF DRAWINGS

[0079] FIG. 1 depicts in vivo protein (i.e. firefly luciferase (FFL)) production in the lung resulting from the delivery of mRNA (i.e. FFL mRNA) using lipid nanoparticles comprising Compound la, Compound 225, Compound 16, Compound 249, Compound 29, Compound 1, Compound 6, Compound 177, Compound 4, Compound 17, Compound 40, and Compound 10, as described herein. As shown in this Figure, use of these compounds allow high levels of in vivo protein (i.e. FFL ) production 24 hours after administration. 2026204802   22 Jun 2026 DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Definitions

[0080] In order for the present invention to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification. The publications and other reference materials referenced herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference.

[0081] Amino acid: As used herein, the term "amino acid," in its broadest sense, refers to any compound and / or substance that can be incorporated into a polypeptide chain. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a d-amino acid; in some embodiments, an amino acid is an l-amino acid. "Standard amino acid" refers to any of the twenty standard l-amino acids commonly found in naturally occurring peptides. "Nonstandard amino acid" refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. As used herein, "synthetic amino acid" encompasses chemically modified amino acids, including but not limited to salts, amino acid derivatives (such as amides), and / or substitutions. Amino acids, including carboxy- and / or amino-terminal amino acids in peptides, can be modified by methylation, amidation, acetylation, protecting groups, and / or substitution with other chemical groups that can change the peptide's circulating half-life without adversely affecting their activity. Amino acids may participate in a disulfide bond. Amino acids may comprise one or posttranslational modifications, such as association with one or more chemical entities (e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc.). The term "amino acid" is used interchangeably with "amino acid residue," and may refer to a free amino acid and / or to an amino acid residue of a peptide. It will be apparent from the context in which the term is used whether it refers to a free amino acid or a residue of a peptide.

[0082] Animal: As used herein, the term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans, at any stage of development. In some embodiments, "animal" refers to non-human animals, at any stage of development. In certain 2026204802   22 Jun 2026 embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and / or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, an animal may be a transgenic animal, genetically-engineered animal, and / or a clone.

[0083] Approximately or about: As used herein, the term "approximately" or "about," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0084] Biologically active: As used herein, the term "biologically active" refers to a characteristic of any agent that has activity in a biological system, and particularly in an organism. For instance, an agent that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active.

[0085] Delivery: 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").

[0086] Expression: As used herein, "expression" of a nucleic acid sequence refers to translation of an mRNA into a polypeptide, assemble multiple polypeptides into an intact protein (e.g., enzyme) and / or post-translational modification of a polypeptide or fully assembled protein (e.g., enzyme). In this application, the terms "expression" and "production," and grammatical equivalent, are used inter-changeably.

[0087] Functional: As used herein, a "functional" biological molecule is a biological molecule in a form in which it exhibits a property and / or activity by which it is characterized. 2026204802   22 Jun 2026

[0088] Half-life: 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.

[0089] Improve, increase, or reduce: 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. A "control subject" is a subject afflicted with the same form of disease as the subject being treated, who is about the same age as the subject being treated.

[0090] In Vitro: 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.

[0091] In Vivo: 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).

[0092] Isolated: As used herein, the term "isolated" refers to a substance and / or entity that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature and / or in an experimental setting), and / or (2) produced, prepared, and / or manufactured by the hand of man. isolated substances and / or entities may be separated from about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% of the other components with which they were initially associated. In some embodiments, isolated agents are about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. As used herein, a substance is "pure" if it is substantially free of other components. As used herein, calculation of percent purity of isolated substances and / or entities should not include excipients (e.g., buffer, solvent, water, etc.).

[0093] Liposome: 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 2026204802   22 Jun 2026 lipids or by mixing one or more lipids and polymer(s). In some embodiments, a liposome suitable for the present invention contains a cationic lipids(s) and optionally non-cationic lipid(s), optionally cholesterol-based lipid(s), and / or optionally PEG-modified lipid(s).

[0094] messenger RNA (mRNA): As used herein, the term "messenger RNA (mRNA)" or "mRNA" refers to a polynucleotide that encodes at least one polypeptide. mRNA as used herein encompasses both modified and unmodified RNA. The term "modified mRNA" related to mRNA comprising at least one chemically modified nucleotide. mRNA may contain one or more coding and non-coding regions. mRNA can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, etc. Where appropriate, e.g., in the case of chemically synthesized molecules, mRNA can comprise nucleoside analogs such as analogs having chemically modified bases or sugars, backbone modifications, etc. An mRNA sequence is presented in the 5' to 3' direction unless otherwise indicated. In some embodiments, an mRNA is or comprises natural nucleosides (e.g., adenosine, guanosine, cytidine, uridine); nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine); chemically modified bases; biologically modified bases (e.g., methylated bases); intercalated bases; modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose); and / or modified phosphate groups (e.g., phosphorothioates and 5'- / V-phosphoramidite linkages).

[0095] Nucleic acid: 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. In some embodiments, "nucleic acid" encompasses ribonucleic acids (RNA), including but not limited to any one or more of interference RNAs (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (IncRNA), 2026204802   22 Jun 2026 micro-RNA (miRNA) multimeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA) and CRISPR RNA (crRNA). In some embodiments, "nucleic acid" encompasses deoxyribonucleic acid (DNA), including but not limited to any one or more of single-stranded DNA (ssDNA), double-stranded DNA (dsDNA) and complementary DNA (cDNA). In some embodiments, "nucleic acid" encompasses both RNA and DNA. In embodiments, DNA may be in the form of antisense DNA, plasmid DNA, parts of a plasmid DNA, pre-condensed DNA, a product of a polymerase chain reaction (PCR), vectors (e.g., Pl, PAC, BAC, YAC, artificial chromosomes), expression cassettes, chimeric sequences, chromosomal DNA, or derivatives of these groups. In embodiments, RNA may be in the form of messenger RNA (mRNA), ribosomal RNA (rRNA), signal recognition particle RNA (7 SL RNA or SRP RNA), transfer RNA (tRNA), transfer-messenger RNA (tmRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), SmY RNA, small Cajal body-specific RNA (scaRNA), guide RNA (gRNA), ribonuclease P (RNase P), Y RNA, telomerase RNA component (TERC), spliced leader RNA (SL RNA), antisense RNA (aRNA or asRNA), cis-natural antisense transcript (cis-NAT), CRISPR RNA (crRNA), long noncoding RNA (IncRNA), micro-RNA (miRNA), piwi-interacting RNA (piRNA), small interfering RNA (siRNA), transacting siRNA (tasiRNA), repeat associated siRNA (rasiRNA), 73K RNA, retrotransposons, a viral genome, a viroid, satellite RNA, or derivatives of these groups. In some embodiments, a nucleic acid is a mRNA encoding a protein such as an enzyme.

[0096] Patient: As used herein, the term "patient" or "subject" refers to any organism to which a provided composition may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. A human includes pre- and post-natal forms.

[0097] Pharmaceutically acceptable: 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.

[0098] Pharmaceutically acceptable salt: Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino 2026204802   22 Jun 2026 group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or rnalonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate and aryl sulfonate. Further pharmaceutically acceptable salts include salts formed from the quarternization of an amine using an appropriate electrophile, e.g., an alkyl halide, to form a quarternized alkylated amino salt.

[0099] Systemic distribution or delivery: As used herein, the terms "systemic distribution," "systemic delivery," or grammatical equivalent, refer to a delivery or distribution mechanism or approach that affect the entire body or an entire organism. Typically, systemic distribution or delivery is accomplished via body's circulation system, e.g., blood stream. Compared to the definition of "local distribution or delivery."

[0100] Subject: 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. 2026204802   22 Jun 2026

[0101] Substantially: 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.

[0102] Target tissues: 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.

[0103] Therapeutically effective amount: 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.

[0104] Treating: As used herein, the term "treat," "treatment," or "treating" refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and / or reduce incidence of one or more symptoms or features of a particular disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease and / or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.

[0105] Aliphatic: As used herein, the term aliphatic refers to C1-C40 hydrocarbons and includes both saturated and unsaturated hydrocarbons. An aliphatic may be linear, branched, or cyclic. For example, C1-C20 aliphatics can include C1-C20 alkyls (e.g., linear or branched C1-C20 saturated alkyls), C2-C20 alkenyls (e.g., linear or branched C4-C20 dienyls, linear or branched C6-C20 trienyls, and the like), and C2-C20 alkynyls (e.g., linear or branched C2-C20 alkynyls). C1-C20 aliphatics can include C3-C20 cyclic aliphatics (e.g., C3-C20 cycloalkyls, C4-C20 cycloalkenyls, or C8-C20 cycloalkynyls). In certain embodiments, the aliphatic 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. An aliphatic group is unsubstituted or substituted with one or more substituent groups as described herein. For example, an aliphatic may be substituted with one 2026204802   22 Jun 2026 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 embodiments, the aliphatic is unsubstituted. In embodiments, the aliphatic does not include any heteroatoms.

[0106] Alkyl: As used herein, the term "alkyl" means acyclic linear and branched hydrocarbon groups, e.g. "C1-C20 alkyl" refers to alkyl groups having 1-20 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, Isohexyletc. 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 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 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.

[0107] Alkylene: 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 2026204802   22 Jun 2026 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, alkenylene, 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.

[0108] Alkenyl: 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-C20 alkenyl" refers to an alkenyl group having 2-20 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., 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 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.

[0109] Alkynyl: 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-C20 alkynyl" refers to an alkynyl group having 2-20 carbons. Examples of an alkynyl group include prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, etc. In embodiments, an alkynyl comprises one carbon-carbon triple 2026204802   22 Jun 2026 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, C1-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).

[0110] Aryl: The terms "aryl" and "ar-", used alone or as part of a larger moiety, e.g., "aralkyl", "aralkoxy", or "aryloxyalkyl", refer to an optionally substituted C6-i4aromatic hydrocarbon moiety comprising one to three aromatic rings. For example, the aryl group is a Cg-ioaryl group (i.e., phenyl and naphthyl). Aryl groups include, without limitation, optionally substituted phenyl, naphthyl, or anthracenyl. The terms "aryl" and "ar-", as used herein, also include groups in which an aryl ring is fused to one or more cycloaliphatic rings to form an optionally substituted cyclic structure such as a tetrahydronaphthyl, indenyl, or indanyl ring. The term "aryl" may be used interchangeably with the terms "aryl group", "aryl ring", and "aromatic ring".

[0111] Cycloalkyl: As used herein, the term "cycloalkyl" means a nonaromatic, saturated, cyclic group, e.g. "C3-C10 cycloalkyl." In embodiments, a cycloalkyl is monocyclic. In embodiments, a cycloalkyl is polycyclic (e.g., bicyclic or tricyclic). In polycyclic cycloalkyl groups, individual rings can be fused, bridged, or spirocyclic. Examples of a cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl, bicyclo[3.2.1]octanyl, octahydro-pentalenyl, and spiro[4.5]decanyl, and the like. The term "cycloalkyl" may be used interchangeably with the term "carbocycle". A cycloalkyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, a cycloalkyl 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, C1-C10 alkyl, or C1-C3 alkyl). In embodiments, R' independently is unsubstituted C1-C3 alkyl. In embodiments, the cycloalkyl is unsubstituted. In embodiments, the cycloalkyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). 2026204802   22 Jun 2026

[0112] Halogen: As used herein, the term "halogen" means fluorine, chlorine, bromine, or iodine.

[0113] Heteroalkenyl. The term "heteroalkenyl" is meant a branched or unbranched alkenyl group having from 2 to 14 carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. A heteroalkenyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The heteroalkenyl group may be substituted or unsubstituted.

[0114] Heteroalkynyl. The term "heteroalkynyl" is meant a branched or unbranched alkynyl group having from 2 to 14 carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. A heteroalkynyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The heteroalkynyl group may be substituted or unsubstituted.

[0115] Heteroalkyl. The term "heteroalkyl" is meant a branched or unbranched alkyl group having from 1 to 14 carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls include, without limitation, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. A heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The heteroalkyl group may be substituted or unsubstituted. Examples of heteroalkyls include, without limitation, polyethers, such as methoxymethyl and ethoxyethyl.

[0116] Heteroaryl: The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 n electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. A heteroaryl group may be mono-, bi-, tri-, or polycyclic, for example, mono-, bi-, or tricyclic (e.g., mono- or bicyclic). The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. For example, a nitrogen atom of a heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N-oxide. When a heteroaryl is substituted by a hydroxy group, it also includes its corresponding tautomer. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocycloaliphatic rings. Nonlimiting examples of heteroaryl groups include thienyl, furanyl, 2026204802   22 Jun 2026 pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0117] Heterocyclyl. As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl).

[0118] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. Additionally, a heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings. 2026204802   22 Jun 2026 Cationic Lipids

[0119] Liposomal-based vehicles are considered an attractive carrier for therapeutic agents and remain subject to continued development efforts. While liposomal-based vehicles that comprise a cationic lipid component have shown promising results with regards to encapsulation, stability and site localization, there remains a great need for improvement of liposomal-based delivery systems. For example, a significant drawback of liposomal delivery systems relates to the construction of liposomes that have sufficient cell culture or in vivo stability to reach desired target cells and / or intracellular compartments, and the ability of such liposomal delivery systems to efficiently release their encapsulated materials to such target cells.

[0120] In particular, there remains a need for improved cationic lipids that demonstrate improved pharmacokinetic properties and which are capable of delivering macromolecules, such as nucleic acids to a wide variety cell types and tissues with enhanced efficiency. Importantly, there also remains a particular need for novel cationic lipids that are characterized as having reduced toxicity and are capable of efficiently delivering encapsulated nucleic acids and polynucleotides to targeted cells, tissues and organs.

[0121] Described herein are novel cationic lipids, compositions comprising such lipids, and related methods of their use. In embodiments, the compounds described herein are useful as liposomal compositions or as components of liposomal compositions to facilitate the delivery to, and subsequent transfection of one or more target cells.

[0122] Cationic lipids disclosed herein comprise a basic, ionizable functional group (e.g., an amine or a nitrogen-containing heteroaryl as described herein), which is present in neutral or charged form.

[0123] For example, a basic, ionizable functional group can refer to a nitrogen functional group (e.g., NH2, guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl) that can be converted to a charged group by protonation with an acid or deprotonation with a base. Accordingly, in embodiments, X1 is NH2, guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered heterocycloalkyl, or 5- to 6membered nitrogen-containing heteroaryl. For example, in embodiments, an ionizable nitrogen- 2026204802   22 Jun 2026 containing group is H Et HO Me Et HO HN^ H hn5\h2 j H

[0124] In embodiments, cationic lipids described herein can provide one or more desired characteristics or properties. That is, in certain embodiments, cationic lipids described herein can be characterized as having one or more properties that afford such compounds advantages relative to other similarly classified lipids. For example, cationic lipids disclosed herein can allow for the control and tailoring of the properties of liposomal compositions (e.g., lipid nanoparticles) of which they are a component. In particular, cationic lipids disclosed herein can be characterized by enhanced transfection efficiencies and their ability to provoke specific biological outcomes. Such outcomes can include, for example enhanced cellular uptake, endosomal / lysosomal disruption capabilities and / or promoting the release of encapsulated materials (e.g., polynucleotides) intracellularly.

[0125] In embodiments, a cationic lipid has a structure according to Formula (A): X3A zX1A X1B I R1 (A), or a pharmaceutically acceptable salt thereof, wherein each n is independently 0 or 1; X1A is independently O or NR1A; R1A is H or Ci-Cg alkyl; X1B is a covalent bond, C(O), CH2CO2, or CH2C(O); one of X2A and X2B is O and the other is a covalent bond; one of X3A and X3B is O and the other is a covalent bond; one of X4A and X4B is O and the other is a covalent bond; R1 is independently L^B1, Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; R2 is independently L2-B2, Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; 2026204802   22 Jun 2026 R3 is independently L3-B3, Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; R4 is independently L4-B4, Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; L1, L2, L3, and L4 are each independently C1-C30 alkylene; C2-C30 alkenylene; or C2-C30 alkynylene; each of B1, B2, B3, and B4 is independently an ionizable nitrogen-containing group, and wherein the cationic lipid comprises at least one ionizable nitrogen-containing group.

[0126] In embodiments, each n is 1. In embodiments, two n are 2, and one n is 1.

[0127] In embodiments, X1A is O. In embodiments, X1A is NR1A. In embodiments, X1A is NH.

[0128] In embodiments, X1B is a covalent bond. In embodiments, X1B is C(O). In embodiments, X1B is CH2CO2. In embodiments, X1B is CH2C(O).

[0129] In embodiments, X2A is a covalent bond, and X2B is O. In embodiments, X3A is a covalent bond, and X3B is O. In embodiments, X4A is a covalent bond, and X4B is O.

[0130] In embodiments, X2A is O, and X2B is a covalent bond. In embodiments, X3A is O, and X3B is a covalent bond. In embodiments, X4A is O, and X4B is a covalent bond.

[0131] In embodiments, each of X2A, X3A, and X4A is a covalent bond, and each of X2B, X3B, and X4B is 0.

[0132] In embodiments, each of X2A, X3A, and X4A is O, and each of X2B, X3B, and X4B is a covalent bond.

[0133] In embodiments, the cationic lipid comprises one ionizable nitrogen-containing group.

[0134] In embodiments, the cationic lipid comprises two ionizable nitrogen-containing groups.

[0135] In embodiments, the cationic lipid comprises three ionizable nitrogen-containing groups.

[0136] In embodiments, the cationic lipid comprises four ionizable nitrogen-containing groups.

[0137] In embodiments, a cationic lipid has a structure according to Formula (I), L1 B1                    (I), or a pharmaceutically acceptable salt thereof, wherein each of R2, R3, and R4 is independently Cg-Cso alkyl, Cg-Cso alkenyl, or Cg-Cso alkynyl; and L1 is C1-C10 alkylene. 2026204802   22 Jun 2026

[0138] In embodiments, a cationic lipid has a structure according to Formula (I), L1 B1                    (I), or a pharmaceutically acceptable salt thereof, wherein B1 is an ionizable nitrogen-containing group; each of R2, R3, and R4 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; and L1 is Ci-Cio alkylene.

[0139] In embodiments, a cationic lipid has a structure according to Formula (Al), X1A X1B R6A / L1 N r6B                       (Al), or a pharmaceutically acceptable salt thereof, wherein L1 is Ci-Cio alkylene; each R6A is independently H or Ci-Cg alkyl; and each R6b is independently H or Ci-Cg alkyl.

[0140] In embodiments, a cationic lipid has a structure according to Formula (All), X1A X1B I '"N \                               (All), or a pharmaceutically acceptable salt thereof. 2026204802   22 Jun 2026

[0141] In embodiments, a cationic lipid has a structure according to Formula (AHI), (Alli), or a pharmaceutically acceptable salt thereof, wherein R1A is H.

[0142] In embodiments, a cationic lipid has a structure according to Formula (II), or a pharmaceutically acceptable salt thereof, wherein each of R2, R3, and R4 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; and L1 is Ci-Cio alkylene.

[0143] In embodiments, a cationic lipid has a structure according to Formula (II), or a pharmaceutically acceptable salt thereof, wherein B1 is an ionizable nitrogen-containing group; R1A is H or Ci-Cg alkyl; 2026204802   22 Jun 2026 each of R2, R3, and R4 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; and L1 is Ci-Cio alkylene.

[0144] In embodiments, R1A is H.

[0145] In embodiments, L1 is unsubstituted Ci-Cio alkylene.

[0146] In embodiments, L1 is (CHah, (CHa)a, (CHah, or (CHa)5.

[0147] In embodiments, L1 is (CH2), (CH2)g, (CH2)7, (CH2)8, (CH2)9, or (CH2)i0.

[0148] In embodiments, B1 is independently NH2, guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered nitrogen-containing heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl. HO          uki^

[0149] In embodiments, B1 is independently H

[0150] In embodiments, B1 is independently

[0151] In embodiments, B1 is independently

[0152] In embodiments, B1 is independently

[0153] In embodiments, B1 is independently

[0154] In embodiments, B1 is independently

[0155] In embodiments, each of R2, R3, and R4 is independently C8Hi7, CioHai, CiaHas, CuHag, CigHaa, CigHai, CigHas and CigHaa.

[0156] In embodiments, each of R2, R3, and R4 is independently Cg-Caa alkyl, Cg-Caa alkenyl, or Cg-Caa alkynyl.

[0157] In embodiments, each of R2, R3, and R4 is independently Cg-Caa alkyl, or Cg-Caa alkenyl.

[0158] In embodiments, each of R2, R3,and R4 is independently unsubstituted linear Cg-Caa alkyl, or unsubstituted linear Cg-Caa alkenyl. 2026204802   22 Jun 2026

[0159] In embodiments, each of R2, R3, and R4 is independently unsubstituted linear C6-C22 alkyl, unsubstituted linear C6-C22 alkenyl, unsubstituted linear C6-C22 alkynyl, unsubstituted branched C6-C22 alkyl, unsubstituted branched C6-C22 alkenyl, or unsubstituted branched C6-C22 alkynyl.

[0160] In embodiments, each of R2, R3, and R4 is unsubstituted C6-C22 alkyl.

[0161] In embodiments, each of R2, R3, and R4 is -CgHn, -C7H15, -C8Hi7, -C9H19, -C10H21, -C11H23, -C12H25, -C13H27, -C14H29, -C15H31, -C16H33, -C17H35, -C18H37, -C19H39, -C20H41, -C21H43, -C22H45, -C23H47, -C24H49, or -C25H51.

[0162] In embodiments, each of R2, R3, and R4 is independently Cg-Ci2 alkyl substituted by -O(CO)R5 or -C(O)OR5, wherein R5 is unsubstituted Cg-Ci4 alkyl.

[0163] In embodiments, each of R2, R3, and R4 is unsubstituted C6-C22 alkenyl. In embodiments, said C6-C22 alkenyl is a monoalkenyl, a dienyl, or a trienyl.

[0164] In embodiments, each of R2, R3, and R4 is -(CH2)4CH=CH2, -(CH2)5CH=CH2, -(CH2)6CH=CH2, -(CH2)7CH=CH2, -(CH2)8CH=CH2, -(CH2)9CH=CH2, -(CH2)ioCH=CH2, -(CH2)iiCH=CH2, -(CH2)i2CH=CH2, -(CH2)i3CH=CH2, -(CH2)i4CH=CH2, -(CH2)i5CH=CH2, -(CH2)i6CH=CH2, -(CH2)i7CH=CH2, -(CH2)18CH=CH2, -(CH2)7CH=CH(CH2)3CH3, -(CH2)7CH=CH(CH2)5CH3, -(CH2)4CH=CH(CH2)8CH3, -(CH2)7CH=CH(CH2)7CH3, -(CH2)6CH=CHCH2CH=CH(CH2)4CH3, -(CH2)7CH=CHCH2CH=CH(CH2)4CH3, -(CH2)7CH=CHCH2CH=CHCH2CH=CHCH2CH3, -(CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)4CH3, -(CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH3, -(CH2)hCH=CH(CH2)7CH3, or -(CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH3.

[0165] In embodiments, each of R2, R3, and R4 is 2026204802   22 Jun 2026

[0166] In embodiments, each of R2, R3, and R4 is

[0167] In embodiments, (e.g., of Formula (Al), (All), (AHI), or (11)) each of R2, R3, and R4 is 2026204802   22 Jun 2026

[0168] In embodiments, (e.g., of Formula (Al), (All), (Alli), or (11)) each of R2, R3, and R4 is O

[0169] In embodiments, each of R2, R3, and R4 is

[0170] In embodiments, each of R2, R3, and R4 is

[0171] In embodiments, each of R2, R3, and R4 is

[0172] In embodiments, each of R2, R3, and R4 is

[0173] In embodiments, each of R2, R3, and R4 is

[0174] In embodiments, each of R2, R3, and R4 is

[0175] In embodiments, each of R2, R3, and R4 is 2026204802   22 Jun 2026

[0176] In embodiments, each of R2, R3, and R4 is

[0177] In embodiments, each of R2, R3, and R4 is

[0178]

[0179]

[0180] In embodiments, each of R2, R3, and R4 is In embodiments, each of R2, R3, and R4 is In embodiments, each of R2, R3, and R4 is O

[0181] In embodiments, (e.g., of Formula (Al), (All), (Alli), or (11)) each of R2, R3, and R4 is

[0182] In embodiments, (e.g., of Formula (Al), (All), (Alli), or (11)) each of R2, R3, and R4 is

[0183] In embodiments, (e.g., of Formula (Al), (All), (Alli), or (11)) each of R2, R3, and R4 is

[0184] In embodiments, (e.g., of Formula (Al), (All), (Alli), or (11)) each of R2, R3, and R4 is

[0185] In embodiments, (e.g., of Formula (Al), (All), (Alli), or (11)) each of R2, R3, and R4 is

[0186] In embodiments, (e.g., of Formula (Al), (All), (Alli), or (11)) each of R2, R3, and R4 is

[0187] In embodiments, (e.g., of Formula (Al), (All), (Alli), or (11)) each of R2, R3, and R4 is 2026204802   22 Jun 2026

[0188] In embodiments, (e.g., of Formula (Al), (All), (Alli), or (11)) each of R2, R3, and R4 is

[0189] In embodiments, (e.g., of Formula (Al), (All), (Alli), or (11)) each of R2, R3, and R4 is

[0190] In embodiments, (e.g., of Formula (Al), (All), (Alli), or (11)) each of R2, R3, and R4 is O

[0191] In embodiments, (e.g., of Formula (Al), (All), (Alli), or (11)) each of R2, R3, and R4 is

[0192] In embodiments, (e.g., of Formula (Al), (All), (AHI), or (11)) each of R2, R3, and R4 is O

[0193] In embodiments, a cationic lipid has a structure according to Formula (Ila), or a pharmaceutically acceptable salt thereof, wherein B1 is an ionizable nitrogen-containing group; R1A is H or C(O)-R7; each of R2, R3, R4, and R7 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; and L1 is Ci-Cio alkylene.

[0194] In embodiments of Formula (Ila), R1A is H.

[0195] In embodiments of Formula (Ila), R1A is C(O)-R7.ln embodiments of Formula (Ila), L1 is unsubstituted Ci-Cio alkylene. 2026204802   22 Jun 2026

[0196] In embodiments of Formula (Ila), L1 is (CHzh, (CFbh, (CFbh, or (Cl-bh-

[0197] In embodiments of Formula (Ila), L1 is (CH2), (CFbJs, (CFb)?, (CFbJg, (CH2)9, or (CFbho-

[0198] In embodiments of Formula (Ila), L1 is (CFbh-

[0199] In embodiments of Formula (Ila), B1 is independently NH2, guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered nitrogen-containing heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl. H . Me . Et . ,N * zN-i ,N i

[0200] In embodiments of Formula (Ila), B1 is independently H , Me , Et , HC\__       HN^ H hoQn4 NO^,0r O4 HO Me . Et .     \____ n4 n-J ho I

[0201] In embodiments of Formula (Ila), B1 is independently Me , Et ,    X— /    , or

[0202] In embodiments of Formula (Ila), B1 is independently Et

[0203] In embodiments of Formula (Ila), B1 is independently

[0204] In embodiments of Formula (Ila), B1 is independently Et

[0205] In embodiments of Formula (Ila), B1 is independently

[0206] In embodiments, each of R2, R3, R4, and R7 is independently C8Hi7, C10H21, C12H25, C14H29, CigHaa, CigHai, C16H29 and C16H32.

[0207] In embodiments, each of R2, R3, R4, and R7 is independently C6-C22 alkyl, C6-C22 alkenyl, or Cg-C22 alkynyl.

[0208] In embodiments, each of R2, R3, R4, and R7 is independently C6-C22 alkyl, or C6-C22 alkenyl.

[0209] In embodiments, each of R2, R3, R4, and R7 is independently unsubstituted linear C6-C22 alkyl, or unsubstituted linear C6-C22 alkenyl. 2026204802   22 Jun 2026

[0210] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is independently unsubstituted linear C6-C22 alkyl, unsubstituted linear C6-C22 alkenyl, unsubstituted linear C6-C22 alkynyl, unsubstituted branched C6-C22 alkyl, unsubstituted branched C6-C22 alkenyl, or unsubstituted branched C6-C22 alkynyl.

[0211] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is unsubstituted C6-C22 alkyl.

[0212] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is -CgHn, -C7H15, -C8Hi7, -C9H19, -C10H21, -C11H23, -C12H25, -C13H27, -C14H29, -C15H31, -C16H33, -C17H35, -C18H37, -C19H39, -C20H41, -C21H43, - C22H45, -C23H47, -C24H49, or -C25H51.

[0213] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is independently C6-C12 alkyl substituted by -O(CO)R5 or -C(O)OR5, wherein R5 is unsubstituted Cg-Ci4 alkyl.

[0214] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is unsubstituted C6-C22 alkenyl. In embodiments, said C6-C22 alkenyl is a monoalkenyl, a dienyl, or a trienyl.

[0215] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is -(CH2)4CH=CH2, -(CH2)sCH=CH2, -(CH2)6CH=CH2, -(CH2)7CH=CH2, -(CH2)8CH=CH2, -(CH2)9CH=CH2, -(CH2)ioCH=CH2, -(CH2)iiCH=CH2, -(CH2)i2CH=CH2, -(CH2)i3CH=CH2, -(CH2)i4CH=CH2, -(CH2)i5CH=CH2, -(CH2)i6CH=CH2, -(CH2)i7CH=CH2, -(CH2)18CH=CH2, -(CH2)7CH=CH(CH2)3CH3, -(CH2)7CH=CH(CH2)5CH3, -(CH2)4CH=CH(CH2)8CH3, -(CH2)7CH=CH(CH2)7CH3, -(CH2)6CH=CHCH2CH=CH(CH2)4CH3, -(CH2)7CH=CHCH2CH=CH(CH2)4CH3, -(CH2)7CH=CHCH2CH=CHCH2CH=CHCH2CH3, -(CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)4CH3, -(CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH3, -(CH2)hCH=CH(CH2)7CH3, or -(CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH3.

[0216] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is 2026204802   22 Jun 2026

[0217]

[0218]

[0219] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is

[0220] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is

[0221] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is

[0222] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is

[0223] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is

[0224] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is

[0225] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is

[0226] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is

[0227] In embodiments of Formula (Ila), each of R2, R3, R4, and R7 is 2026204802   22 Jun 2026

[0228] In embodiments of Formula (Ila), each of R2, R3, R4 and R7 is

[0229] In embodiments, the cationic lipid has a structure according to Formula (lib), or a pharmaceutically acceptable salt thereof, wherein B1 is an ionizable nitrogen-containing group; R1A is H or C(O)-R7; and each of R2, R3, R4, and R7 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

[0230] In embodiments of Formula (lib), R1A is H.

[0231] In embodiments of Formula (lib), R1A is C(O)-R7.

[0232] In embodiments of Formula (lib), B1 is independently NH2, guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered nitrogen-containing heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl. H . Me . Et . ,N? / H ,N“5

[0233] In embodiments of Formula (lib), B1 is independently H , Me , Et , H<\__ HN^ H nq^N-i        CH or CH HO Me . Et .     \____ N-|       ho

[0234] In embodiments of Formula (lib), B1 is independently Me , Et ,    \— /    , or CH Me

[0235] In embodiments of Formula (lib), B1 is independently Me 2026204802   22 Jun 2026

[0236]

[0237]

[0238] In embodiments of Formula (lib), B1 is independently In embodiments of Formula (lib), B1 is independently In embodiments of Formula (lib), B1 is independently

[0239] In embodiments, each of R2, R3, R4, and R7 is independently C8Hi7, C10H21, C12H25, C14H29, CigHaa, CigHai, C16H29 and C16H32.

[0240] In embodiments, each of R2, R3, R4, and R7 is independently C6-C22 alkyl, C6-C22 alkenyl, or Cg-C22 alkynyl.

[0241] In embodiments, each of R2, R3, R4, and R7 is independently C6-C22 alkyl, or C6-C22 alkenyl.

[0242] In embodiments, each of R2, R3, R4, and R7 is independently unsubstituted linear C6-C22 alkyl, or unsubstituted linear C6-C22 alkenyl.

[0243] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is independently unsubstituted linear C6-C22 alkyl, unsubstituted linear C6-C22 alkenyl, unsubstituted linear C6-C22 alkynyl, unsubstituted branched C6-C22 alkyl, unsubstituted branched C6-C22 alkenyl, or unsubstituted branched C6-C22 alkynyl.

[0244] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is unsubstituted C6-C22 alkyl.

[0245] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is -CgHn, -C7H15, -C8Hi7, -C9H19, -C10H21, -C11H23, -C12H25, -C13H27, -C14H29, -C15H31, -C16H33, -C17H35, -C18H37, -C19H39, -C20H41, -C21H43, -C22H45, -C23H47, -C24H49, or -C25H51.

[0246] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is independently Cg-Ci2 alkyl substituted by -O(CO)R5 or -C(O)OR5, wherein R5 is unsubstituted Cg-Ci4 alkyl.

[0247] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is unsubstituted C6-C22 alkenyl. In embodiments, said C6-C22 alkenyl is a monoalkenyl, a dienyl, or a trienyl.

[0248] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is -(CH2)4CH=CH2, -(CH2)sCH=CH2, -(CH2)6CH=CH2, -(CH2)7CH=CH2, -(CH2)8CH=CH2, -(CH2)9CH=CH2, -(CH2)ioCH=CH2, -(CH2)iiCH=CH2, -(CH2)i2CH=CH2, -(CH2)i3CH=CH2, -(CH2)i4CH=CH2, -(CH2)i5CH=CH2, -(CH2)i6CH=CH2, -(CH2)i7CH=CH2, -(CH2)18CH=CH2, -(CH2)7CH=CH(CH2)3CH3, -(CH2)7CH=CH(CH2)5CH3, -(CH2)4CH=CH(CH2)8CH3, -(CH2)7CH=CH(CH2)7CH3, -(CH2)6CH=CHCH2CH=CH(CH2)4CH3, 2026204802   22 Jun 2026 -(CH2)7CH=CHCH2CH=CH(CH2)4CH3, -(ch2)7ch=chch2ch=chch2ch=chch2ch3, -(CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)4CH3, -(CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH3, -(CH2)hCH=CH(CH2)7CH3, or -(CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH3.

[0249] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is

[0250] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is

[0251] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is

[0252] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is

[0253] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is

[0254] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is

[0255] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is 2026204802   22 Jun 2026

[0256] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is

[0257] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is

[0258] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is

[0259] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is

[0260] In embodiments of Formula (lib), each of R2, R3, R4, and R7 is

[0261] In embodiments of Formula (lib), each of R2, R3, R4 and R7 is O

[0262] In embodiments, the cationic lipid has a structure according to Formula (lie), (He), or a pharmaceutically acceptable salt thereof, wherein B1 is an ionizable nitrogen-containing group; and each of R2, R3, R4, and R7 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

[0263] In embodiments of Formula (He), B1 is independently NH2, guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered nitrogen-containing heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl. 2026204802   22 Jun 2026 H . Me . Et . N-|             N-|

[0264] In embodiments of Formula (He), B1 is independently H , Me , Et , __      HN^ H Ho^N-| hn^ nQ-| O-1. HO Me . Et .     \____ N-|   N-| HO

[0265] In embodiments of Formula (He), B1 is independently Me , Et ,    \— /    , or O*

[0266] In embodiments of Formula (He), B1 is independently Me I Me

[0267] In embodiments of Formula (He), B1 is independently Et

[0268] In embodiments of Formula (He), B1 is independently

[0269] In embodiments of Formula (He), B1 is independently

[0270] In embodiments, each of R2, R3, R4, and R7 is independently C8Hi7, C10H21, C12H25, C14H29, CigHaa, CigHai, C16H29 and C16H32.

[0271] In embodiments, each of R2, R3, R4, and R7 is independently C6-C22 alkyl, C6-C22 alkenyl, or Cg-C22 alkynyl.

[0272] In embodiments, each of R2, R3, R4, and R7 is independently C6-C22 alkyl, or C6-C22 alkenyl.

[0273] In embodiments, each of R2, R3, R4, and R7 is independently unsubstituted linear C6-C22 alkyl, or unsubstituted linear C6-C22 alkenyl.

[0274] In embodiments of Formula (He), each of R2, R3, R4, and R7 is independently unsubstituted linear C6-C22 alkyl, unsubstituted linear C6-C22 alkenyl, unsubstituted linear C6-C22 alkynyl, unsubstituted branched C6-C22 alkyl, unsubstituted branched C6-C22 alkenyl, or unsubstituted branched C6-C22 alkynyl.

[0275] In embodiments of Formula (lie), each of R2, R3, R4, and R7 is unsubstituted C6-C22 alkyl.

[0276] In embodiments of Formula (lie), each of R2, R3, R4, and R7 is -CgHis, -C7H15, -C8Hi7, -C9H19, - C10H21, -C11H23, -C12H25, -C13H27, -C14H29, -C15H31, -C16H33, -C17H35, -C18H37, -C19H39, -C20H41, -C21H43, - 2026204802   22 Jun 2026 C22H45, -C23H47, -C24H49, or -C25H51.

[0277] In embodiments of Formula (He), each of R2, R3, R4, and R7 is independently Cg-Ci2 alkyl substituted by -O(CO)R5 or -C(O)OR5, wherein R5 is unsubstituted Cg-Ci4 alkyl.

[0278] In embodiments of Formula (He), each of R2, R3, R4, and R7 is unsubstituted C6-C22 alkenyl. In embodiments, said C6-C22 alkenyl is a monoalkenyl, a dienyl, or a trienyl.

[0279] In embodiments of Formula (lie), each of R2, R3, R4, and R7 is -(CH2)4CH=CH2, -(CH2)sCH=CH2, -(CH2)6CH=CH2, -(CH2)7CH=CH2, -(CH2)8CH=CH2, -(CH2)9CH=CH2, -(CH2)ioCH=CH2, -(CH2)iiCH=CH2, -(CH2)i2CH=CH2, -(CH2)i3CH=CH2, -(CH2)i4CH=CH2, -(CH2)i5CH=CH2, -(CH2)i6CH=CH2, -(CH2)i7CH=CH2, -(CH2)18CH=CH2, -(CH2)7CH=CH(CH2)3CH3, -(CH2)7CH=CH(CH2)5CH3, -(CH2)4CH=CH(CH2)8CH3, -(CH2)7CH=CH(CH2)7CH3, -(CH2)6CH=CHCH2CH=CH(CH2)4CH3, -(CH2)7CH=CHCH2CH=CH(CH2)4CH3, -(CH2)7CH=CHCH2CH=CHCH2CH=CHCH2CH3, -(CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)4CH3, -(CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH3, -(CH2)hCH=CH(CH2)7CH3, or -(CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH3.

[0280] In embodiments of Formula (lie), each of R2, R3, R4, and R7 is 2026204802   22 Jun 2026

[0281] In embodiments of Formula (He), each of R2, R3, R4, and R7 is

[0282] In embodiments of Formula (He), each of R2, R3, R4, and R7 is

[0283] In embodiments of Formula (lie), each of R2, R3, R4, and R7 is

[0284] In embodiments of Formula (lie), each of R2, R3, R4, and R7 is

[0285] In embodiments of Formula (lie), each of R2, R3, R4, and R7 is

[0286] In embodiments of Formula (lie), each of R2, R3, R4, and R7 is

[0287] In embodiments of Formula (lie), each of R2, R3, R4, and R7 is

[0288] In embodiments of Formula (lie), each of R2, R3, R4, and R7 is

[0289] In embodiments of Formula (lie), each of R2, R3, R4, and R7 is

[0290] In embodiments of Formula (lie), each of R2, R3, R4, and R7 is O

[0291] In embodiments of Formula (lie), each of R2, R3, R4, and R7 is

[0292] In embodiments of Formula (lie), each of R2, R3, R4 and R7 is O 2026204802   22 Jun 2026

[0293] In embodiments, a cationic lipid has a structure according to Formula (lid), °^R3 O or a pharmaceutically acceptable salt thereof, wherein B1 is an ionizable nitrogen-containing group; and each of R2, R3, R4, and R7 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

[0294] In embodiments of Formula (lid), B1 is independently NH2, guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered nitrogen-containing heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl. H . Me . Et . M / N—| N-f

[0295] In embodiments of Formula (lid), B1 is independently H , Me , Et , H<\__ HN^ H O^,or HO Me . Et .     \____ N-|   N-| HO

[0296] In embodiments of Formula (lid), B1 is independently Me , Et ;    \— /    , or Me . ,N^

[0297] In embodiments of Formula (lid), B1 is independently Me Etx .

[0298] In embodiments of Formula (lid), B1 is independently . HO HO   N—|

[0299] In embodiments of Formula (lid), B1 is independently \.

[0300] In embodiments of Formula (lid), B1 is independently '—. 2026204802   22 Jun 2026

[0301] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is independently unsubstituted linear C6-C22 alkyl, unsubstituted linear C6-C22 alkenyl, unsubstituted linear C6-C22 alkynyl, unsubstituted branched C6-C22 alkyl, unsubstituted branched C6-C22 alkenyl, or unsubstituted branched C6-C22 alkynyl.

[0302] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is unsubstituted C6-C22 alkyl.

[0303] In embodiments, each of R2, R3, R4, and R7 is independently C8Hi7, C10H21, C12H25, C14H29, CigHaa, CigHai, C16H29 and C16H32.

[0304] In embodiments, each of R2, R3, R4, and R7 is independently C6-C22 alkyl, C6-C22 alkenyl, or Cg-C22 alkynyl.

[0305] In embodiments, each of R2, R3, R4, and R7 is independently C6-C22 alkyl, or C6-C22 alkenyl.

[0306] In embodiments, each of R2, R3, R4, and R7 is independently unsubstituted linear C6-C22 alkyl, or unsubstituted linear C6-C22 alkenyl.

[0307] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is -CgHn, -C7H15, -C8Hi7, -C9H19, -C10H21, -C11H23, -C12H25, -C13H27, -C14H29, -C15H31, -C16H33, -C17H35, -C18H37, -C19H39, -C20H41, -C21H43, -C22H45, -C23H47, -C24H49, or -C25H51.

[0308] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is independently C6-C12 alkyl substituted by -O(CO)R5 or -C(O)OR5, wherein R5 is unsubstituted Cg-Ci4 alkyl.

[0309] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is unsubstituted C6-C22 alkenyl. In embodiments, said C6-C22 alkenyl is a monoalkenyl, a dienyl, or a trienyl.

[0310] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is -(CH2)4CH=CH2, -(CH2)sCH=CH2, -(CH2)6CH=CH2, -(CH2)7CH=CH2, -(CH2)8CH=CH2, -(CH2)9CH=CH2, -(CH2)ioCH=CH2, -(CH2)iiCH=CH2, -(CH2)i2CH=CH2, -(CH2)i3CH=CH2, -(CH2)i4CH=CH2, -(CH2)i5CH=CH2, -(CH2)i6CH=CH2, -(CH2)i7CH=CH2, -(CH2)18CH=CH2, -(CH2)7CH=CH(CH2)3CH3, -(CH2)7CH=CH(CH2)5CH3, -(CH2)4CH=CH(CH2)8CH3, -(CH2)7CH=CH(CH2)7CH3, -(CH2)6CH=CHCH2CH=CH(CH2)4CH3, -(CH2)7CH=CHCH2CH=CH(CH2)4CH3, -(CH2)7CH=CHCH2CH=CHCH2CH=CHCH2CH3, -(CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)4CH3, -(CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH3, -(CH2)hCH=CH(CH2)7CH3, or -(CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH3. 2026204802   22 Jun 2026

[0311] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is

[0312] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is

[0313] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is

[0314] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is

[0315] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is

[0316] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is

[0317] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is

[0318] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is 2026204802   22 Jun 2026

[0319] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is

[0320] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is

[0321] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is O

[0322] In embodiments of Formula (lid), each of R2, R3, R4, and R7 is

[0323] In embodiments of Formula (lid), each of R2, R3, R4 and R7 is O

[0324] In embodiments, a cationic lipid has a structure according to Formula (III), or a pharmaceutically acceptable salt thereof, wherein R1 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

[0325] In embodiments, a cationic lipid has a structure according to Formula (III), or a pharmaceutically acceptable salt thereof, wherein L2, L3, and L4 are each independently C1-C30 alkylene; C2-C30 alkenylene; or C2-C30 alkynylene; 2026204802   22 Jun 2026 each of B2, B3, and B4 is independently an ionizable nitrogen-containing group; and R1 is independently Cg-Cso alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

[0326] In embodiments, a cationic lipid has a structure according to Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R1 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

[0327] In embodiments, a cationic lipid has a structure according to Formula (IV), or a pharmaceutically acceptable salt thereof, wherein L2, L3, and L4 are each independently C1-C30 alkylene; C2-C30 alkenylene; or C2-C30 alkynylene; each of B2, B3, and B4 is independently an ionizable nitrogen-containing group; R1A is H or Ci-Cg alkyl; and R1 is independently Cg-Cso alkyl, Cg-Cso alkenyl, or Cg-Cso alkynyl.

[0328] In embodiments, R1A is H.

[0329] In embodiments, a cationic lipid has a structure according to Formula (V), 2026204802   22 Jun 2026 or a pharmaceutically acceptable salt thereof, wherein R1 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

[0330] In embodiments, a cationic lipid has a structure according to Formula (V), or a pharmaceutically acceptable salt thereof, wherein L2, L3, and L4 are each independently Ci-Cao alkylene; C2-C30 alkenylene; or C2-C30 alkynylene; each of B2, B3, and B4 is independently an ionizable nitrogen-containing group; and R1 is independently Cg-Cso alkyl, Cg-Cso alkenyl, or Cg-Cso alkynyl.

[0331] In embodiments, a cationic lipid has a structure according to Formula (VI), or a pharmaceutically acceptable salt thereof, wherein R1 is independently Cg-Cso alkyl, Cg-Cso alkenyl, or Cg-Cso alkynyl.

[0332] In embodiments, a cationic lipid has a structure according to Formula (VI), 2026204802   22 Jun 2026 or a pharmaceutically acceptable salt thereof, wherein L2, L3, and L4 are each independently C1-C30 alkylene; C2-C30 alkenylene; or C2-C30 alkynylene; each of B2, B3, and B4 is independently an ionizable nitrogen-containing group, R1A is H or Ci-Cg alkyl; and R1 is independently Cg-Cso alkyl, Cg-Cso alkenyl, or Cg-Cso alkynyl.

[0333] In embodiments, R1A is H.

[0334] In embodiments, R1 is independently CgHi?, C10H21, C12H25, C14H29, C16H33, CigHsi, C16H29 and C16H32.

[0335] In embodiments, R1 is independently unsubstituted linear C6-C22 alkyl, unsubstituted linear C6-C22 alkenyl, or unsubstituted linear C6-C22 alkynyl.

[0336] In embodiments, R1 is independently unsubstituted linear C6-C22 alkyl, unsubstituted linear C6-C22 alkenyl, unsubstituted linear C6-C22 alkynyl, unsubstituted branched C6-C22 alkyl, unsubstituted branched C6-C22 alkenyl, or unsubstituted branched C6-C22 alkynyl.

[0337] In embodiments, R1 is independently unsubstituted C6-C22 alkyl.

[0338] In embodiments, R1 is independently -CgHis, -C7H15, -C8Hi7, -C9H19, -C10H21, -C11H23, -C12H25, -C13H27, -C14H29, -C15H31, -C16H33, -C17H35, -C18H37, -C19H39, -C20H41, -C21H43, -C22H45, -C23H47, -C24H49, or -C25H51.

[0339] In embodiments, R1 is independently C6-C12 alkyl substituted by -O(CO)R5 or -C(O)OR5, wherein R5 is unsubstituted Cg-Ci4 alkyl.

[0340] In embodiments, R1 is independently unsubstituted C6-C22 alkenyl.

[0341] In embodiments, R1 is independently -(CH2)4CH=CH2, -(CH2)sCH=CH2, -(CH2)gCH=CH2, -(CH2)7CH=CH2, -(CH2)8CH=CH2, -(CH2)9CH=CH2, -(CH2)ioCH=CH2, -(CH2)iiCH=CH2, -(CH2)i2CH=CH2, -(CH2)i3CH=CH2, -(CH2)i4CH=CH2, -(CH2)i5CH=CH2, -(CH2)i6CH=CH2, -(CH2)i7CH=CH2, -(CH2)18CH=CH2, -(CH2)7CH=CH(CH2)3CH3, -(CH2)7CH=CH(CH2)5CH3, -(CH2)4CH=CH(CH2)8CH3, -(CH2)7CH=CH(CH2)7CH3, -(CH2)6CH=CHCH2CH=CH(CH2)4CH3, -(CH2)7CH=CHCH2CH=CH(CH2)4CH3, -(CH2)7CH=CHCH2CH=CHCH2CH=CHCH2CH3, -(CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)4CH3, -(CH2)3CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH3, -(CH2)hCH=CH(CH2)7CH3, or -(CH2)2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH3.

[0342] In embodiments, C6-C22 alkenyl is a monoalkenyl, a dienyl, or a trienyl. 2026204802   22 Jun 2026

[0343] In embodiments (e.g., of Formula (III) or (IV)), R1 is independently

[0344] In embodiments (e.g., of Formula (III) or (IV)), R1 is independently 2026204802   22 Jun 2026

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0356]

[0357] In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently

[0354]

[0355] In embodiments, R1 is independently In embodiments, R1 is independently O In embodiments (e.g., of Formula (V) or (VI)), R1 is independently '0 2026204802   22 Jun 2026

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367] In embodiments (e.g., of Formula (V) or (VI)), R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently 2026204802   22 Jun 2026

[0368]

[0369]

[0370] In embodiments, R1 is independently In embodiments, R1 is independently In embodiments, R1 is independently O

[0371] In embodiments, each of L2, L3, and L4 is unsubstituted C1-C10 alkylene.

[0372] In embodiments, each of L2, L3, and L4 is (CHzh, (CFbh, (CFbh, or (Chbjs.

[0373] In embodiments, each of L2, L3, and L4 is (CH2), (CH2)b, (CHz)?, (Chbjg, (Chbjg, or (CHzho.

[0374] In embodiments, each of B2, B3, and B4 is independently NH2, guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered nitrogen-containing heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl. H . Me . Et . M zNH ,N *

[0375] In embodiments, each of B2, B3, and B4 is independently H , Me , Et , __      HN^ H Hq^N-| hn^ NCN^,or O-1. HO Me . Et .      \___. n4 n-| ho |

[0376] In embodiments, each of B2, B3, and B4 is independently Me , Et ,    \--- /    , Me

[0377] In embodiments, each of B2, B3, and B4 is independently Me

[0378] In embodiments, each of B2, B3, and B4 is independently

[0379] In embodiments, each of B2, B3, and B4 is independently

[0380] In embodiments, each of B2, B3, and B4 is independently 2026204802   22 Jun 2026 Exemplary Cationic Lipids

[0381] In embodiments, a cationic lipid is any compound described in Table A. Table A. Exemplary Compounds of Formula (I) / „ O K \=o o ( y--¼ o /   \_ / =° oj / o      m \ CM Compound TO N> II w II TO II B1 = 1 1 2 / ^1¾ 3 H0^^N\ 4 5 1 6 / ^1¾ 7 p I 8 9 1 10 2026204802   22 Jun 2026 / „ o K \=O O < ^ / °\ o /   \_ V°o3 o      m \ CM Compound II W II 70 II B1 = 11 >£ / ^ / / ^ / / ^ / / ^ / / ^ / / p X 12 >{£ / / \^ / \z / \ / ^\ / ^\ C / ^ 13 >{£ / ^^ / ^^ / / \ / ^^ / / / ^\ 1 14 >{£ / / / / / ^\ / ^ / / / \ / " / / ~ / 15 >{£ / / ^ / / ^ / - / ^- / ^ / ^^\^^\ b ) o o 1 X 16 — / / C / jN^ 17 >£ / ^ / / / / ^ / / / / ^ / / / / ^ / / 1 18 >£ / ^ / / / ^ / ^ / ~ / / ^ / ^ / ~ / / ^ / ^ / ^ / ^ / ¾ 19 >£ / ^ / / / ^z / / / ^ / / / / ^ / / / X 20 >£ / ^ / ^ / / / ^ / ^ / / / ^ / ^ / / / ^ / ^ / 21 >{£ / / / / / / / / / / / / / / / / / / / / 1 22 >£^— / / ^ / ¾ 23 2££z / / / / / z / ^ / / / / zz^ / / / z / / \ p X 2026204802   22 Jun 2026 / „ o K \=O O < ^ / °\ o /   \_ V°o3 o      m \ CM Compound II W II 70 II B1 = 24 25 1 26 27 p X 28 0½ 29 21^ / / ^ / / ^ / / / ^ / == / ^ / ^= / ^ / / / - / 1 30 31 p X 32 33 y^^-s''’''*'-^''''^-- / / -- / / -- / / 1 34 - / / - / / - / / 35 - / / - / / - / / p X 36 2026204802   22 Jun 2026 / „ o K \=O O < ^ / °\ o /   \_ V°o3 o      m \ CM Compound X II w II 70 II B1 = 37 0 1 38 0 39 0 p X 40 0 41 0 1 42 o >CVzZ\z^ / X^0^ / ^ / \z^\ 43 0 H0^^n\ HO\^ 44 la 1 lb 0 Ic p X 2026204802   22 Jun 2026

[0382] In embodiments, a cationic lipid is Compound 1. In embodiments, a cationic lipid is Compound 2. In embodiments, a cationic lipid is Compound 3. In embodiments, a cationic lipid is Compound 4.

[0383] In embodiments, a cationic lipid is Compound 5. In embodiments, a cationic lipid is Compound 6. In embodiments, a cationic lipid is Compound 7. In embodiments, a cationic lipid is Compound 8.

[0384] In embodiments, a cationic lipid is Compound 9. In embodiments, a cationic lipid is Compound 10. In embodiments, a cationic lipid is Compound 11. In embodiments, a cationic lipid is Compound 12.

[0385] In embodiments, a cationic lipid is Compound 13. In embodiments, a cationic lipid is Compound 14. In embodiments, a cationic lipid is Compound 15. In embodiments, a cationic lipid is Compound 16.

[0386] In embodiments, a cationic lipid is Compound 17. In embodiments, a cationic lipid is Compound 18. In embodiments, a cationic lipid is Compound 19. In embodiments, a cationic lipid is Compound 20.

[0387] In embodiments, a cationic lipid is Compound 21. In embodiments, a cationic lipid is Compound 22. In embodiments, a cationic lipid is Compound 23. In embodiments, a cationic lipid is Compound 24.

[0388] In embodiments, a cationic lipid is Compound 25. In embodiments, a cationic lipid is Compound 26. In embodiments, a cationic lipid is Compound 27. In embodiments, a cationic lipid is Compound 28. 2026204802   22 Jun 2026

[0389] In embodiments, a cationic lipid is Compound 29. In embodiments, a cationic lipid is Compound 30. In embodiments, a cationic lipid is Compound 31. In embodiments, a cationic lipid is Compound 32.

[0390] In embodiments, a cationic lipid is Compound 33. In embodiments, a cationic lipid is Compound 34. In embodiments, a cationic lipid is Compound 35. In embodiments, a cationic lipid is Compound 36.

[0391] In embodiments, a cationic lipid is Compound 37. In embodiments, a cationic lipid is Compound 38. In embodiments, a cationic lipid is Compound 39. In embodiments, a cationic lipid is Compound 40.

[0392] In embodiments, a cationic lipid is Compound 41. In embodiments, a cationic lipid is Compound 42. In embodiments, a cationic lipid is Compound 43. In embodiments, a cationic lipid is Compound 44.

[0393] In embodiments, a cationic lipid is Compound la. In embodiments, a cationic lipid is Compound lb. In embodiments, a cationic lipid is Compound Ic. In embodiments, a cationic lipid is Compound Id.

[0394] In embodiments, a cationic lipid is any compound described in Table B. Table B. Exemplary Compounds of Formula (III) 2026204802   22 Jun 2026 CD o ^=° O ( \ 02 \        )=o ¢0                / tn       0 CM CD Compound RJ = II CD II m CD II CM CD 48 49 1 50 51 p X 52 0^ 53 1 54 55 X 56 0^ 57 1 58 59 p X 60 >£^^— 2026204802   22 Jun 2026 CD o ^=° O ( \ 02 \        )=o ¢0                / tn       0 CM CD Compound RJ = 11 CD II m CD II CM CD 61 1 62 / m^ 63 n I 64 ^^ / / / ^^ / / ^ / ^ / / / ^ / ^ / / ^ / / 0^ 65 — / / 1 66 — / / ^ / / ^ / / / ^ / ^ / / / / ^ / / - / / / m^ 67 >^ / / ^ / / / / ^ / / / / ^ / / / / / / ^ / n I 68 ^^ / / / - / / / ^ / / / / / / ^ / / / / ^ / 0^ 69 1 70 71 & X 72 0^1½ 73 1 2026204802   22 Jun 2026 CD o ^=° O ( \ 02 \        )=o ¢0                / tn       0 CM CD Compound RJ = II CD II m CD II CM CD 74 75 n I 76 O”^ 77 1 78 \ / 79 5t^ / ^ / \^ / \^ / \x^---- n X 80 \ / 81 0 1 82 0 83 0 fl X 84 0 0^ 85 0 >O—''''^^ 1 2026204802   22 Jun 2026

[0395] In embodiments, a cationic lipid is Compound 45. In embodiments, a cationic lipid is Compound 46. In embodiments, a cationic lipid is Compound 47. In embodiments, a cationic lipid is Compound 48.

[0396] In embodiments, a cationic lipid is Compound 49. In embodiments, a cationic lipid is Compound 50. In embodiments, a cationic lipid is Compound 51. In embodiments, a cationic lipid is Compound 52. 2026204802   22 Jun 2026

[0397] In embodiments, a cationic lipid is Compound 53. In embodiments, a cationic lipid is Compound 54. In embodiments, a cationic lipid is Compound 55. In embodiments, a cationic lipid is Compound 56.

[0398] In embodiments, a cationic lipid is Compound 57. In embodiments, a cationic lipid is Compound 58. In embodiments, a cationic lipid is Compound 59. In embodiments, a cationic lipid is Compound 60.

[0399] In embodiments, a cationic lipid is Compound 61. In embodiments, a cationic lipid is Compound 62. In embodiments, a cationic lipid is Compound 63. In embodiments, a cationic lipid is Compound 64.

[0400] In embodiments, a cationic lipid is Compound 65. In embodiments, a cationic lipid is Compound 66. In embodiments, a cationic lipid is Compound 67. In embodiments, a cationic lipid is Compound 68.

[0401] In embodiments, a cationic lipid is Compound 69. In embodiments, a cationic lipid is Compound 70. In embodiments, a cationic lipid is Compound 71. In embodiments, a cationic lipid is Compound 72.

[0402] In embodiments, a cationic lipid is Compound 73. In embodiments, a cationic lipid is Compound 74. In embodiments, a cationic lipid is Compound 75. In embodiments, a cationic lipid is Compound 76.

[0403] In embodiments, a cationic lipid is Compound 77. In embodiments, a cationic lipid is Compound 78. In embodiments, a cationic lipid is Compound 79. In embodiments, a cationic lipid is Compound 80.

[0404] In embodiments, a cationic lipid is Compound 81. In embodiments, a cationic lipid is Compound 82. In embodiments, a cationic lipid is Compound 83. In embodiments, a cationic lipid is Compound 84.

[0405] In embodiments, a cationic lipid is Compound 85. In embodiments, a cationic lipid is Compound 86. In embodiments, a cationic lipid is Compound 87. In embodiments, a cationic lipid is Compound 88. 2026204802   22 Jun 2026

[0406] In embodiments, a cationic lipid is Compound Illa. In embodiments, a cationic lipid is Compound IIlb. In embodiments, a cationic lipid is Compound I He. In embodiments, a cationic lipid is Compound I lid.

[0407] In embodiments, a cationic lipid is any compound described in Table C. Table C. Exemplary Compounds of Formula (V) o \=o o ( K—- / / r° tn       o CM CD Compound RJ = co bJ II co w II co II 89 1 90 91 X 92 93 1 94 95 X 96 0½ 97 1 2026204802   22 Jun 2026 00 M o       co o o=(       5 > o—' / ° o=( o CD Compound RJ = II CD II m CD II CM CD 98 99 H0^^n\ HO^^ 100 O^ 101 1 102 103 n X 104 105 1 106 107 p X 108 109 1 110 ---X^ / \ / \ / ---\ 2026204802   22 Jun 2026 00 M o       co o o=(       5 > o—' / ° o=( o CD Compound RJ = II CD II m CD II CM CD 111 X 112 113 1 114 115 X 116 Ojn% 117 1 118 119 ------\ X 120 O"^ 121 1 122 123 p X 2026204802   22 Jun 2026 00 M o       co o o=(       5 > o—' / ° o=( o CD Compound RJ = II CD II m CD II CM CD 124 125 0 / xx-'-'Xx / X^^ 1 126 O / X / Xx^X.x-^X.x-^ 127 0 / xx-'-X^x-'x^^ 9 X 128 0 A / \Z\zX / \0A / \^ Q p¥ 129 0 1 130 o 131 o o= / X 132 0    1^^^^ ^\xXXx^^ Va 0 1 Vb 0 2026204802   22 Jun 2026

[0408] In embodiments, a cationic lipid is Compound 89. In embodiments, a cationic lipid is Compound 90. In embodiments, a cationic lipid is Compound 91. In embodiments, a cationic lipid is Compound 92.

[0409] In embodiments, a cationic lipid is Compound 93. In embodiments, a cationic lipid is Compound 94. In embodiments, a cationic lipid is Compound 95. In embodiments, a cationic lipid is Compound 96.

[0410] In embodiments, a cationic lipid is Compound 97. In embodiments, a cationic lipid is Compound 98. In embodiments, a cationic lipid is Compound 99. In embodiments, a cationic lipid is Compound 100.

[0411] In embodiments, a cationic lipid is Compound 101. In embodiments, a cationic lipid is Compound 102. In embodiments, a cationic lipid is Compound 103. In embodiments, a cationic lipid is Compound 104.

[0412] In embodiments, a cationic lipid is Compound 105. In embodiments, a cationic lipid is Compound 106. In embodiments, a cationic lipid is Compound 107. In embodiments, a cationic lipid is Compound 108.

[0413] In embodiments, a cationic lipid is Compound 109. In embodiments, a cationic lipid is Compound 110. In embodiments, a cationic lipid is Compound 111. In embodiments, a cationic lipid is Compound 112. 2026204802   22 Jun 2026

[0414] In embodiments, a cationic lipid is Compound 113. In embodiments, a cationic lipid is Compound 114. In embodiments, a cationic lipid is Compound 115. In embodiments, a cationic lipid is Compound 116.

[0415] In embodiments, a cationic lipid is Compound 117. In embodiments, a cationic lipid is Compound 118. In embodiments, a cationic lipid is Compound 119. In embodiments, a cationic lipid is Compound 120.

[0416] In embodiments, a cationic lipid is Compound 121. In embodiments, a cationic lipid is Compound 122. In embodiments, a cationic lipid is Compound 123. In embodiments, a cationic lipid is Compound 124.

[0417] In embodiments, a cationic lipid is Compound 125. In embodiments, a cationic lipid is Compound 126. In embodiments, a cationic lipid is Compound 127. In embodiments, a cationic lipid is Compound 128.

[0418] In embodiments, a cationic lipid is Compound 129. In embodiments, a cationic lipid is Compound 130. In embodiments, a cationic lipid is Compound 131. In embodiments, a cationic lipid is Compound 132.

[0419] In embodiments, a cationic lipid is Compound Va. In embodiments, a cationic lipid is Compound Vb. In embodiments, a cationic lipid is Compound Vc. In embodiments, a cationic lipid is Compound Vd.

[0420] In embodiments, a cationic lipid is any compound described in Table D. Table D. Exemplary Compounds of Formula (lib) OyR3 O. O      ]       0 r2                    r4 NH Ux ^x / B1 Compound TO N> II w II TO II B1 = 133 1 2026204802   22 Jun 2026 O' o=( o    \ co         \   X   \ °\    / --7—z   ° y° ( o     b    o N O' Compound II W II 70 II B^ 134 135 X 136 137 1 138 139 X 140 141 1 142 143 X 144 145 1 146 2026204802   22 Jun 2026 O' o=( o    \ co         \   X   \ °\    / --7—z   ° y° ( o     b    o N O' Compound II W II 70 II B^ 147 n I 148 o^ 149 1 150 151 p X 152 153 1 154 155 X 156 157 1 158 159 p X 2026204802   22 Jun 2026 OyR3 0 0 ^^O^~R4 JH y CD Compound R2 = R3 = R ^4 _ b3 = 160 161 1 162 ^=\ ^~xy 163 ^=\ X 164 ^=\ O”^ 165 x-^ 1 166 -^=\ 167 ^=\. n X 168 O”^ 169 / x / ^^S^X^Q' 0 1 170 0 171 / x^X^S^^^Q' 0 Ti X 2026204802   22 Jun 2026 O' o=( o    \ co         \   X   \ °\    / --7—z   ° y° ( o     b    o N O' Compound X bJ II X w II TO II B1 = 172 0 173 0    1^^^^ 1 174 0    1^^^^ 175 o ^x^x^^^ H0^^N\ 176 o Q llbl O 1 Ilb2 O Ilb3 0 HO^^N\ Ilb4 0

[0421] In embodiments, a cationic lipid is Compound 133. In embodiments, a cationic lipid is Compound 134. In embodiments, a cationic lipid is Compound 135. In embodiments, a cationic lipid is Compound 136. 2026204802   22 Jun 2026

[0422] In embodiments, a cationic lipid is Compound 137. In embodiments, a cationic lipid is Compound 138. In embodiments, a cationic lipid is Compound 139. In embodiments, a cationic lipid is Compound 140.

[0423] In embodiments, a cationic lipid is Compound 141. In embodiments, a cationic lipid is Compound 142. In embodiments, a cationic lipid is Compound 143. In embodiments, a cationic lipid is Compoundl44.

[0424] In embodiments, a cationic lipid is Compound 145. In embodiments, a cationic lipid is Compound 146. In embodiments, a cationic lipid is Compoundl47. In embodiments, a cationic lipid is Compound 148.

[0425] In embodiments, a cationic lipid is Compound 149. In embodiments, a cationic lipid is Compound 150. In embodiments, a cationic lipid is Compound 151. In embodiments, a cationic lipid is Compound 152.

[0426] In embodiments, a cationic lipid is Compound 153. In embodiments, a cationic lipid is Compound 154. In embodiments, a cationic lipid is Compound 155. In embodiments, a cationic lipid is Compound 156.

[0427] In embodiments, a cationic lipid is Compound 157. In embodiments, a cationic lipid is Compound 158. In embodiments, a cationic lipid is Compound 159. In embodiments, a cationic lipid is Compound 160.

[0428] In embodiments, a cationic lipid is Compound 161. In embodiments, a cationic lipid is Compound 162. In embodiments, a cationic lipid is Compound 163. In embodiments, a cationic lipid is Compound 164.

[0429] In embodiments, a cationic lipid is Compound 165. In embodiments, a cationic lipid is Compound 166. In embodiments, a cationic lipid is Compound 167. In embodiments, a cationic lipid is Compound 168.

[0430] In embodiments, a cationic lipid is Compound 169. In embodiments, a cationic lipid is Compound 170. In embodiments, a cationic lipid is Compound 171. In embodiments, a cationic lipid is Compound 172. 2026204802   22 Jun 2026

[0431] In embodiments, a cationic lipid is Compound 173. In embodiments, a cationic lipid is Compound 174. In embodiments, a cationic lipid is Compound 175. In embodiments, a cationic lipid is Compound 176.

[0432] In embodiments, a cationic lipid is Compound llbl. In embodiments, a cationic lipid is Compound Ilb2. In embodiments, a cationic lipid is Compound IIb3. In embodiments, a cationic lipid is Compound Ilb4.

[0433] In embodiments, a cationic lipid is any compound described in Table E. Table E. Exemplary Compounds of Formula (He) °5^r3 0 N r7 O O^o 0 S. Compound II QC II QC II m cr ii CM cr B1 = 177 1 178 . / \ / ^\ / ^\ / ^\ 179 p X 180 181 1 182 183 p X 2026204802   22 Jun 2026 0 7^0 N R7 o T 0^0 0 S. Compound II QC II QC II m cr ii CM cr b3 = 184 185 1 186 187 X 188 Q p¥ 189 1 190 191 n X 192 O”^ 193 1 194 195 p X 2026204802   22 Jun 2026 0 7^0 N R7 o T 0^0 0 S. Compound II QC II QC II m cr ii CM cr b3 = 196 197 1 198 199 X 200 Q p¥ 201 1 202 < / x 203 n X 204 < / \ O”^ 205 1 206 207 p X 2026204802   22 Jun 2026 0 7^0 N R7 o T 0^0 0 S. Compound II QC II QC II m cr ii CM cr b3 = 208 209 1 210 211 X 212 Q p¥ 213 0 1 214 0 A / ^s / Xz^V^qA / X / X / X 215 0 fl X 216 0 A / Xz^Xz^v^qA^s / X / X 217 o 1 218 o 2026204802   22 Jun 2026

[0434] In embodiments, a cationic lipid is Compound 177. In embodiments, a cationic lipid is Compound 178. In embodiments, a cationic lipid is Compound 179. In embodiments, a cationic lipid is Compound 180.

[0435] In embodiments, a cationic lipid is Compound 181. In embodiments, a cationic lipid is Compound 182. In embodiments, a cationic lipid is Compound 183. In embodiments, a cationic lipid is Compound 184.

[0436] In embodiments, a cationic lipid is Compound 185. In embodiments, a cationic lipid is Compound 186. In embodiments, a cationic lipid is Compound 187. In embodiments, a cationic lipid is Compound 188. 2026204802   22 Jun 2026

[0437] In embodiments, a cationic lipid is Compound 189. In embodiments, a cationic lipid is Compound 190. In embodiments, a cationic lipid is Compound 191. In embodiments, a cationic lipid is Compound 192.

[0438] In embodiments, a cationic lipid is Compound 193. In embodiments, a cationic lipid is Compound 194. In embodiments, a cationic lipid is Compound 195. In embodiments, a cationic lipid is Compound 196.

[0439] In embodiments, a cationic lipid is Compound 197. In embodiments, a cationic lipid is Compound 198. In embodiments, a cationic lipid is Compound 199. In embodiments, a cationic lipid is Compound 200.

[0440] In embodiments, a cationic lipid is Compound 201. In embodiments, a cationic lipid is Compound 202. In embodiments, a cationic lipid is Compound 203. In embodiments, a cationic lipid is Compound 204.

[0441] In embodiments, a cationic lipid is Compound 205. In embodiments, a cationic lipid is Compound 206. In embodiments, a cationic lipid is Compound 207. In embodiments, a cationic lipid is Compound 208.

[0442] In embodiments, a cationic lipid is Compound 209. In embodiments, a cationic lipid is Compound 210. In embodiments, a cationic lipid is Compound 211. In embodiments, a cationic lipid is Compound 212.

[0443] In embodiments, a cationic lipid is Compound 213. In embodiments, a cationic lipid is Compound 214. In embodiments, a cationic lipid is Compound 215. In embodiments, a cationic lipid is Compound 216.

[0444] In embodiments, a cationic lipid is Compound 217. In embodiments, a cationic lipid is Compound 218. In embodiments, a cationic lipid is Compound 219. In embodiments, a cationic lipid is Compound 220.

[0445] In embodiments, a cationic lipid is Compound llcl. In embodiments, a cationic lipid is Compound IIc2. In embodiments, a cationic lipid is Compound IIc3. In embodiments, a cationic lipid is Compound IIc4. Table F. Exemplary Compounds of Formula (I) 2026204802   22 Jun 2026 00 >        o \ ft ' X / O °-w ) O O=( o “ I / 0 Compound II W II 70 II B1 = 221 1 222 223 I 224 225 1 226 th X 228 229 1 230 231 X 232 0^1½ 233 1 2026204802   22 Jun 2026 2026204802   22 Jun 2026 % r-°Y^ 0 I <°-R= )    0 °v Compound II W II 70 ■■ B1 = 247 X 248 249 1 250 251 ^^= / ^ / / ^ / / & X 252 ^= / ^ / / ^ / / . 253 ^^=^ / / ^=^ / / 1 254 ^= / / = / ^ / 255 ^^= / ^ / ^= / ^ / & X 256 ^^= / ^ / ^= / ^ / 257 0 1 258 2026204802   22 Jun 2026 00 >        o \ ft ' X / O °-w ) O O=( o “ I / 0 Compound X bJ II X w II TO II B1 = 259 0 fl X 260 0 261 0    1^^^^ 1 262 0    1^^^^ 263 0   1^^^ fl X 264 0    1^^^^ >C''XX / XX^ Ie 1 If lg fl X Ih

[0446] In embodiments, a cationic lipid is Compound 221. In embodiments, a cationic lipid is Compound 222. 2026204802   22 Jun 2026

[0447] . In embodiments, a cationic lipid is Compound 223. In embodiments, a cationic lipid is Compound 224.

[0448] In embodiments, a cationic lipid is Compound 225. In embodiments, a cationic lipid is Compound 226. In embodiments, a cationic lipid is Compound 227. In embodiments, a cationic lipid is Compound 228.

[0449] In embodiments, a cationic lipid is Compound 229. In embodiments, a cationic lipid is Compound 230. In embodiments, a cationic lipid is Compound 231. In embodiments, a cationic lipid is Compound 232.

[0450] In embodiments, a cationic lipid is Compound 233. In embodiments, a cationic lipid is Compound 234. In embodiments, a cationic lipid is Compound 235. In embodiments, a cationic lipid is Compound 236.

[0451] In embodiments, a cationic lipid is Compound 237. In embodiments, a cationic lipid is Compound 238. In embodiments, a cationic lipid is Compound 239. In embodiments, a cationic lipid is Compound 240.

[0452] In embodiments, a cationic lipid is Compound 241. In embodiments, a cationic lipid is Compound 242. In embodiments, a cationic lipid is Compound 243. In embodiments, a cationic lipid is Compound 244.

[0453] In embodiments, a cationic lipid is Compound 245. In embodiments, a cationic lipid is Compound 246. In embodiments, a cationic lipid is Compound 247. In embodiments, a cationic lipid is Compound 248.

[0454] In embodiments, a cationic lipid is Compound 249. In embodiments, a cationic lipid is Compound 250. In embodiments, a cationic lipid is Compound 251. In embodiments, a cationic lipid is Compound 252.

[0455] In embodiments, a cationic lipid is Compound 253. In embodiments, a cationic lipid is Compound 254. In embodiments, a cationic lipid is Compound 255. In embodiments, a cationic lipid is Compound 256.

[0456] In embodiments, a cationic lipid is Compound 257. In embodiments, a cationic lipid is Compound 258. In embodiments, a cationic lipid is Compound 259. In embodiments, a cationic lipid is Compound 260. 2026204802   22 Jun 2026

[0457] In embodiments, a cationic lipid is Compound 261. In embodiments, a cationic lipid is Compound 262. In embodiments, a cationic lipid is Compound 263. In embodiments, a cationic lipid is Compound 264.

[0458] In embodiments, a cationic lipid is Compound Ie. In embodiments, a cationic lipid is Compound If. In embodiments, a cationic lipid is Compound Ig. In embodiments, a cationic lipid is Compound Ih. Synthesis of Cationic Lipids

[0459] Cationic lipids described herein can be prepared according to methods known in the art. Exemplary methods include those described in US2012 / 0276482 and WO2012 / 027038, which are incorporated herein by reference.

[0460] For example, Scheme A provides two exemplary synthetic routes for preparing cationic lipids herein. Citric acid Al can be esterified using a Lewis acid (e.g., BifOTfJa) and an alcohol A2 to provide trimester intermediate A3. Alternatively, a coupling agent (e.g., EDCI / DMAP) can be used to accomplish this transformation. Intermediate A3 can then be combined with acyl chloride A4 (where R1 is an aliphatic group comprising an ionizable nitrogen group as described herein) to provide a cationic lipid A5, where R corresponds to any group described herein. Alternatively, trimethyl citrate A6 can be combined with A4 to provide tetra-ester intermediate A7. Intermediate A7 can be trans-esterified by saponification with a base (e.g., LiOH) followed by treatment with an alcohol A2 and a coupling agent to provide cationic lipid A5. 2026204802   22 Jun 2026 Scheme A. Exemplary Synthesis ROH A2 EDCI A6                               *7                            A8 Nucleic Acids

[0461] Cationic lipids described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-1 h, I lbl-1 Ib4,1 lcl-1 Ic4,11 la-1 lid, and Va-Vd) can be used to prepare compositions useful for the delivery of nucleic acids. Synthesis of Nucleic Acids

[0462] Nucleic acids according to the present invention may be synthesized according to any known methods. For example, mRNAs according to the present invention may be synthesized via in vitro transcription (IVT). Briefly, IVT is typically performed with a linear or circular DNA template containing a promoter, a pool of ribonucleotide triphosphates, a buffer system that may include DTT and magnesium ions, and an appropriate RNA polymerase (e.g., T3, T7, mutated T7 or SP6 RNA polymerase), DNAse I, pyrophosphatase, and / or RNAse inhibitor. The exact conditions will vary according to the specific application.

[0463] In some embodiments, for the preparation of mRNA according to the invention, a DNA template is transcribed in vitro. A suitable DNA template typically has a promoter, for example a T3, T7, mutated T7 or SP6 promoter, for in vitro transcription, followed by desired nucleotide sequence for desired mRNA and a termination signal.

[0464] Desired mRNA sequence(s) according to the invention may be determined and incorporated into a DNA template using standard methods. For example, starting from a desired amino acid 2026204802   22 Jun 2026 sequence (e.g., an enzyme sequence), a virtual reverse translation is carried out based on the degenerated genetic code. Optimization algorithms may then be used for selection of suitable codons. Typically, the G / C content can be optimized to achieve the highest possible G / C content on one hand, taking into the best possible account the frequency of the tRNAs according to codon usage on the other hand. The optimized RNA sequence can be established and displayed, for example, with the aid of an appropriate display device and compared with the original (wildtype) sequence. A secondary structure can also be analyzed to calculate stabilizing and destabilizing properties or, respectively, regions of the RNA.

[0465] As described above, 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. DNA may be in the form of antisense DNA, plasmid DNA, parts of a plasmid DNA, pre-condensed DNA, a product of a polymerase chain reaction (PCR), vectors (e.g., Pl, PAC, BAC, YAC, artificial chromosomes), expression cassettes, chimeric sequences, chromosomal DNA, or derivatives of these groups. RNA may be in the form of messenger RNA (mRNA), ribosomal RNA (rRNA), signal recognition particle RNA (7 SL RNA or SRP RNA), transfer RNA (tRNA), transfer-messenger RNA (tmRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), SmY RNA, small Cajal body-specific RNA (scaRNA), guide RNA (gRNA), ribonuclease P (RNase P), Y RNA, telomerase RNA component (TERC), spliced leader RNA (SL RNA), antisense RNA (aRNA or asRNA), cis-natural antisense transcript (cis-NAT), CRISPR RNA (crRNA), long noncoding RNA (IncRNA), microRNA (miRNA), piwi-interacting RNA (piRNA), small interfering RNA (siRNA), transacting siRNA (tasiRNA), repeat associated siRNA (rasiRNA), 73K RNA, retrotransposons, a viral genome, a viroid, satellite RNA, or derivatives of these groups. In some embodiments, a nucleic acid is a mRNA encoding a protein. Synthesis of mRNA

[0466] mRNAs according to the present invention may be synthesized according to any of a variety of known methods. For example, mRNAs according to the present invention may be synthesized via in vitro transcription (IVT). Briefly, IVT is typically performed with a linear or circular DNA template containing a promoter, a pool of ribonucleotide triphosphates, a buffer system that may include DTT and magnesium ions, and an appropriate RNA polymerase (e.g., T3, T7 or SP6 RNA polymerase), DNAse I, pyrophosphatase, and / or RNAse inhibitor. The exact conditions will vary according to the specific application. The exact conditions will vary according to the specific application. The presence of these reagents is undesirable in the final product according to several embodiments and may thus be referred to as impurities and a preparation containing 2026204802   22 Jun 2026 one or more of these impurities may be referred to as an impure preparation. In some embodiments, the in vitro transcribing occurs in a single batch.

[0467] In some embodiments, for the preparation of mRNA according to the invention, a DNA template is transcribed in vitro. A suitable DNA template typically has a promoter, for example a T3, T7 or SP6 promoter, for in vitro transcription, followed by desired nucleotide sequence for desired mRNA and a termination signal.

[0468] Desired mRNA sequence(s) according to the invention may be determined and incorporated into a DNA template using standard methods. For example, starting from a desired amino acid sequence (e.g., an enzyme sequence), a virtual reverse translation is carried out based on the degenerated genetic code. Optimization algorithms may then be used for selection of suitable codons. Typically, the G / C content can be optimized to achieve the highest possible G / C content on one hand, taking into the best possible account the frequency of the tRNAs according to codon usage on the other hand. The optimized RNA sequence can be established and displayed, for example, with the aid of an appropriate display device and compared with the original (wildtype) sequence. A secondary structure can also be analyzed to calculate stabilizing and destabilizing properties or, respectively, regions of the RNA. Modified mRNA

[0469] In some embodiments, mRNA according to the present invention may be synthesized as unmodified or modified mRNA. Modified mRNA comprise nucleotide modifications in the RNA. A modified mRNA according to the invention can thus include nucleotide modification that are, for example, backbone modifications, sugar modifications or base modifications. In some embodiments, mRNAs may be synthesized from naturally occurring nucleotides and / or nucleotide analogues (modified nucleotides) including, but not limited to, purines (adenine (A), guanine (G)) or pyrimidines (thymine (T), cytosine (C), uracil (U)), and as modified nucleotides analogues or derivatives of purines and pyrimidines, such as e.g. 1-methyl-adenine, 2-methyl-adenine, 2-methylthio-N-6-isopentenyl-adenine, N6-methyl-adenine, N6-isopentenyl-adenine, 2-thio-cytosine, 3-methyl-cytosine, 4-acetyl-cytosine, 5-methyl-cytosine, 2,6-diaminopurine, 1-methyl-guanine, 2-methyl-guanine, 2,2-dimethyl-guanine, 7-methyl-guanine, inosine, 1-methyl-inosine, pseudouracil (5-uracil), dihydro-uracil, 2-thio-uracil, 4-thio-uracil, 5-carboxymethylaminomethyl-2-thio-uracil, 5-(carboxyhydroxymethyl)-uracil, 5-fluoro-uracil, 5-bromo-uracil, 5-carboxymethylaminomethyl-uracil, 5-methyl-2-thio-uracil, 5-methyl-uracil, N-uracil-5-oxyacetic acid methyl ester, 5-methylaminomethyl-uracil, 5-methoxyaminomethyl-2- 2026204802   22 Jun 2026 thio-uracil, 5'-methoxycarbonylmethyl-uracil, 5-methoxy-uracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), 1-methyl-pseudouracil, queosine, beta.-D-mannosyl-queosine, wybutoxosine, and phosphoramidates, phosphorothioates, peptide nucleotides, methylphosphonates, 7-deazaguanosine, 5-methylcytosine and inosine. The preparation of such analogues is known to a person skilled in the art e.g., from the U.S. Pat. No. 4,373,071, U.S. Pat. No. 4,401,796, U.S. Pat. No. 4,415,732, U.S. Pat. No. 4,458,066, U.S. Pat. No. 4,500,707, U.S. Pat. No. 4,668,777, U.S. Pat. No. 4,973,679, U.S. Pat. No. 5,047,524, U.S. Pat. No. 5,132,418, U.S. Pat. No. 5,153,319, U.S. Pat. Nos. 5,262,530 and 5,700,642, the disclosures of which are incorporated by reference in their entirety.

[0470] In some embodiments, mRNAs may contain RNA backbone modifications. Typically, a backbone modification is a modification in which the phosphates of the backbone of the nucleotides contained in the RNA are modified chemically. Exemplary backbone modifications typically include, but are not limited to, modifications from the group consisting of methylphosphonates, methylphosphoramidates, phosphoramidates, phosphorothioates (e.g. cytidine 5'-O-(l-thiophosphate)), boranophosphates, positively charged guanidinium groups etc., which means by replacing the phosphodiester linkage by other anionic, cationic or neutral groups.

[0471] In some embodiments, mRNAs may contain sugar modifications. A typical sugar modification is a chemical modification of the sugar of the nucleotides it contains including, but not limited to, sugar modifications chosen from the group consisting of 4'-thio-ribonucleotide (see, e.g., US Patent Application Publication No. US 2016 / 0031928, incorporated by reference herein), 2'-deoxy-2'-fluoro-oligoribonucleotide (2'-fluoro-2'-deoxycytidine 5'-triphosphate, 2'-fluoro-2'-deoxyuridine 5'-triphosphate), 2'-deoxy-2'-deamine-oligoribonucleotide (2'-amino-2'-deoxycytidine 5'-triphosphate, 2'-amino-2'-deoxyuridine 5'-triphosphate), 2'-O-alkyloligoribonucleotide, 2'-deoxy-2'-C-alkyloligoribonucleotide (2'-O-methylcytidine 5'-triphosphate, 2'-methyluridine 5'-triphosphate), 2'-C-alkyloligoribonucleotide, and isomers thereof (2'-aracytidine 5'-triphosphate, 2'-arauridine 5'-triphosphate), or azidotriphosphates (2'-azido-2'-deoxycytidine 5'-triphosphate, 2'-azido-2'-deoxyuridine 5'-triphosphate).

[0472] In some embodiments, mRNAs may contain modifications of the bases of the nucleotides (base modifications). A modified nucleotide which contains a base modification is also called a base-modified nucleotide. Examples of such base-modified nucleotides include, but are not limited to, 2-amino-6-chloropurine riboside 5'-triphosphate, 2-aminoadenosine 5'-triphosphate, 2026204802   22 Jun 2026 2-thiocytidine 5'-triphosphate, 2-thiouridine 5'-triphosphate, 4-thiouridine 5'-triphosphate, 5-aminoallylcytidine 5'-triphosphate, 5-aminoallyluridine 5'-triphosphate, 5-bromocytidine 5'-triphosphate, 5-bromouridine 5'-triphosphate, 5-iodocytidine 5'-triphosphate, 5-iodouridine 5'-triphosphate, 5-methylcytidine 5'-triphosphate, 5-methyluridine 5'-triphosphate, 6-azacytidine 5'-triphosphate, 6-azauridine 5'-triphosphate, 6-chloropurine riboside 5'-triphosphate, 7-deazaadenosine 5'-triphosphate, 7-deazaguanosine 5'-triphosphate, 8-azaadenosine 5'-triphosphate, 8-azidoadenosine 5'-triphosphate, benzimidazole riboside 5'-triphosphate, Nl-methyladenosine 5'-triphosphate, Nl-methylguanosine 5'-triphosphate, N6-methyladenosine 5'-triphosphate, O6-methylguanosine 5'-triphosphate, pseudouridine 5'-triphosphate, puromycin 5'-triphosphate or xanthosine 5'-triphosphate.

[0473] Typically, mRNA synthesis includes the addition of a "cap" on the N-terminal (5') end, and a "tail" on the C-terminal (3') end. The presence of the cap is important in providing resistance to nucleases found in most eukaryotic cells. The presence of a "tail" serves to protect the mRNA from exonuclease degradation.

[0474] Thus, in some embodiments, mRNAs include a 5' cap structure. A 5' cap is typically added as follows: first, an RNA terminal phosphatase removes one of the terminal phosphate groups from the 5' nucleotide, leaving two terminal phosphates; guanosine triphosphate (GTP) is then added to the terminal phosphates via a guanylyl transferase, producing a 5'5'5 triphosphate linkage; and the 7-nitrogen of guanine is then methylated by a methyltransferase.

[0475] In some embodiments, mRNAs include a 3' poly(A) tail structure. A poly-A tail on the 3' terminus of mRNA typically includes about 10 to 500 adenosine nucleotides. In some embodiments, mRNAs include a 3' poly(C) tail structure. In some embodiments, mRNAs include a 5' and / or 3' untranslated region. In some embodiments, a 5' untranslated region may be between about 50 and 500 nucleotides in length.

[0476] In some embodiments, a 3' untranslated region includes one or more of a polyadenylation signal. In some embodiments, a 3' untranslated region may be between 50 and 500 nucleotides in length or longer. Cap structure

[0477] In some embodiments, mRNAs include a 5' cap structure. In some embodiments, the nucleotide forming the cap is further methylated at the 3'position. In some embodiments, the nucleotide directly adjacent to the cap is further methylated at the 2' position. Examples of cap 2026204802   22 Jun 2026 structures include, but are not limited to, m7G(5')ppp(5')(2'OMeG), m7G(5')ppp(5')(2'OMeA), m7(3'OMeG)(5')ppp(5')(2'OMeG), m7(3'OMeG)(5')ppp(5')(2'OMeA), m7G(5')ppp (5'(A,G(5')ppp(5')A and G(5')ppp(5')G. In a specific embodiment, the cap structure is m7G(5')ppp(5')(2'OMeG). Additional cap structures are described in published US Application No. US 2016 / 0032356 and U.S. Provisional Application 62 / 464,327, filed February 27, 2017, which are incorporated herein by reference.

[0478] Naturally occurring cap structures comprise a 7-methyl guanosine that is linked via a triphosphate bridge to the 5'-end of the first transcribed nucleotide, resulting in a dinucleotide cap of m7G(5')ppp(5')N, where N is any nucleoside. In vivo, the cap is added enzymatically. The cap is added in the nucleus and is catalyzed by the enzyme guanylyl transferase. The addition of the cap to the 5' terminal end of RNA occurs immediately after initiation of transcription. The terminal nucleoside is typically a guanosine, and is in the reverse orientation to all the other nucleotides, i.e., G(5')ppp(5')GpNpNp.

[0479] A common cap for mRNA produced by in vitro transcription is m7G(5')ppp(5')G, which has been used as the dinucleotide cap in transcription with T7 or SP6 RNA polymerase in vitro to obtain RNAs having a cap structure in their 5'-termini. The prevailing method for the in vitro synthesis of caPPEd mRNA employs a pre-formed dinucleotide of the form m7G(5')ppp(5')G ("m7GpppG") as an initiator of transcription.

[0480] To date, a usual form of a synthetic dinucleotide cap used in in vitro translation experiments is the Anti-Reverse Cap Analog ("ARCA") or modified ARCA, which is generally a modified cap analog in which the 2' or 3' OH group is replaced with -OCH3.

[0481] Additional cap analogs include, but are not limited to, a chemical structures selected from the group consisting of m7GpppG, m7GpppA, m7GpppC; unmethylated cap analogs (e.g., GpppG); dimethylated cap analog (e.g., m2-7GpppG), trimethylated cap analog (e.g., m2-2-7GpppG), dimethylated symmetrical cap analogs (e.g., m7Gpppm7G), or anti reverse cap analogs (e.g., ARCA; m7,2 OmeGpppG, m72dGpppG, m7-3 OmeGpppG, m7-3dGpppG and their tetraphosphate derivatives) (see, e.g., Jemielity, J. et al., "Novel 'anti-reverse' cap analogs with superior translational properties", RNA, 9: 1108-1122 (2003)).

[0482] In some embodiments, a suitable cap is a 7-methyl guanylate ("m7G") linked via a triphosphate bridge to the 5'-end of the first transcribed nucleotide, resulting in 2026204802   22 Jun 2026 m7G(5')ppp(5')N, where N is any nucleoside. A preferred embodiment of a m7G cap utilized in embodiments of the invention is m7G(5')ppp(5')G.

[0483] In some embodiments, the cap is a CapO structure. CapO structures lack a 2'-O-methyl residue of the ribose attached to bases 1 and 2. In some embodiments, the cap is a Capl structure. Capl structures have a 2'-O-methyl residue at base 2. In some embodiments, the cap is a Cap2 structure. Cap2 structures have a 2'-O-methyl residue attached to both bases 2 and 3.

[0484] A variety of m7G cap analogs are known in the art, many of which are commercially available. These include the m7GpppG described above, as well as the ARCA B'-OCHa and 2'-OCHa cap analogs (Jemielity, J. et al., RNA, 9: 1108-1122 (2003)). Additional cap analogs for use in embodiments of the invention include N7-benzylated dinucleoside tetraphosphate analogs (described in Grudzien, E. et al., RNA, 10:1479-1487 (2004)), phosphorothioate cap analogs (described in Grudzien-Nogalska, E., et al., RNA, 13:1745-1755 (2007)), and cap analogs (including biotinylated cap analogs) described in U.S. Patent Nos. 8,093,367 and 8,304,529, incorporated by reference herein. Tail structure

[0485] Typically, the presence of a "tail" serves to protect the mRNA from exonuclease degradation. The poly A tail is thought to stabilize natural messengers and synthetic sense RNA. Therefore, in certain embodiments a long poly A tail can be added to an mRNA molecule thus rendering the RNA more stable. Poly A tails can be added using a variety of art-recognized techniques. For example, long poly A tails can be added to synthetic or in vitro transcribed RNA using poly A polymerase (Yokoe, et al. Nature Biotechnology. 1996; 14:1252-1256). A transcription vector can also encode long poly A tails. In addition, poly A tails can be added by transcription directly from PCR products. Poly A may also be ligated to the 3' end of a sense RNA with RNA ligase (see, e.g., Molecular Cloning A Laboratory Manual, 2nd Ed., ed. by Sambrook, Fritsch and Maniatis (Cold Spring Harbor Laboratory Press: 1991 edition)).

[0486] In some embodiments, mRNAs include a 3' poly(A) tail structure. Typically, the length of the poly A tail can be at least about 10, 50, 100, 200, 300, 400 at least 500 nucleotides. In some embodiments, a poly-A tail on the 3' terminus of mRNA typically includes about 10 to 300 adenosine nucleotides (e.g., about 10 to 200 adenosine nucleotides, about 10 to 150 adenosine nucleotides, about 10 to 100 adenosine nucleotides, about 20 to 70 adenosine nucleotides, or about 20 to 60 adenosine nucleotides). In some embodiments, mRNAs include a 3' poly(C) tail structure. A suitable poly-C tail on the 3' terminus of mRNA typically include about 10 to 200 2026204802   22 Jun 2026 cytosine nucleotides (e.g., about 10 to 150 cytosine nucleotides, about 10 to 100 cytosine nucleotides, about 20 to 70 cytosine nucleotides, about 20 to 60 cytosine nucleotides, or about 10 to 40 cytosine nucleotides). The poly-C tail may be added to the poly-A tail or may substitute the poly-A tail.

[0487] In some embodiments, the length of the poly A or poly C tail is adjusted to control the stability of a modified sense mRNA molecule of the invention and, thus, the transcription of protein. For example, since the length of the poly A tail can influence the half-life of a sense mRNA molecule, the length of the poly A tail can be adjusted to modify the level of resistance of the mRNA to nucleases and thereby control the time course of polynucleotide expression and / or polypeptide production in a target cell. 5' and 3' Untranslated Region

[0488] In some embodiments, mRNAs include a 5' and / or 3' untranslated region. In some embodiments, a 5' untranslated region includes one or more elements that affect an mRNA's stability or translation, for example, an iron responsive element. In some embodiments, a 5' untranslated region may be between about 50 and 500 nucleotides in length.

[0489] In some embodiments, a 3' untranslated region includes one or more of a polyadenylation signal, a binding site for proteins that affect an mRNA's stability of location in a cell, or one or more binding sites for miRNAs. In some embodiments, a 3' untranslated region may be between 50 and 500 nucleotides in length or longer.

[0490] Exemplary 3' and / or 5' UTR sequences can be derived from mRNA molecules which are stable (e.g., globin, actin, GAPDH, tubulin, histone, or citric acid cycle enzymes) to increase the stability of the sense mRNA molecule. For example, a 5' UTR sequence may include a partial sequence of a CMV immediate-early 1 (I El) gene, or a fragment thereof to improve the nuclease resistance and / or improve the half-life of the polynucleotide. Also contemplated is the inclusion of a sequence encoding human growth hormone (hGH), or a fragment thereof to the 3' end or untranslated region of the polynucleotide (e.g., mRNA) to further stabilize the polynucleotide. Generally, these modifications improve the stability and / or pharmacokinetic properties (e.g., half-life) of the polynucleotide relative to their unmodified counterparts, and include, for example modifications made to improve such polynucleotides' resistance to in vivo nuclease digestion. 2026204802   22 Jun 2026 Pharmaceutical Formulations of Cationic Lipids and Nucleic Acids

[0491] In certain embodiments cationic lipids described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-ll b4, I lcl-1 Ic4, 11 la-11 Id, and Va-Vd), as well as pharmaceutical and liposomal compositions comprising such lipids, can be used in formulations to facilitate the delivery of encapsulated materials (e.g., one or more polynucleotides such as mRNA) to, and subsequent transfection of one or more target cells. For example, in certain embodiments cationic lipids described herein (and compositions such as liposomal compositions comprising such lipids) are characterized as resulting in one or more of receptor-mediated endocytosis, clathrin-mediated and caveolae-mediated endocytosis, phagocytosis and macropinocytosis, fusogenicity, endosomal or lysosomal disruption and / or releasable properties that afford such compounds advantages relative other similarly classified lipids.

[0492] According to the present invention, a nucleic acid, e.g., mRNA encoding a protein (e.g., a full length, fragment or portion of a protein) as described herein may be delivered via a delivery vehicle comprising a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-1 Ib4, I lcl-1 Ic4, 11 la-11 Id, and Va-Vd).

[0493] As used herein, the terms "delivery vehicle," "transfer vehicle," "nanoparticle" or grammatical equivalent, are used interchangeably.

[0494] For example, the present invention provides a composition (e.g., a pharmaceutical composition) comprising a cationic lipid described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-ll b4, I lcl-1 Ic4, 11 la-1 lid, and Va-Vd) and one or more polynucleotides. A composition (e.g., a pharmaceutical composition) may further comprise one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and / or one or more PEG-modified lipids.

[0495] In certain embodiments a composition exhibits an enhanced (e.g., increased) ability to transfect one or more target cells. Accordingly, also provided herein are methods of transfecting one or more target cells. Such methods generally comprise the step of contacting the one or more target cells with the cationic lipids and / or pharmaceutical compositions disclosed herein (e.g., a liposomal formulation comprising a cationic lipid described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, Ilbl-1 Ib4, IIcl-I Ic4, 11 la-11 Id, and Va-Vd) encapsulating one or more polynucleotides) such that the one or more 2026204802   22 Jun 2026 target cells are transfected with the materials encapsulated therein (e.g., one or more polynucleotides). As used herein, the terms "transfect" or "transfection" refer to the intracellular introduction of one or more encapsulated materials (e.g., nucleic acids and / or polynucleotides) into a cell, or preferably into a target cell. The introduced polynucleotide may be stably or transiently maintained in the target cell. The term "transfection efficiency" refers to the relative amount of such encapsulated material (e.g., polynucleotides) up-taken by, introduced into and / or expressed by the target cell which is subject to transfection. In practice, transfection efficiency may be estimated by the amount of a reporter polynucleotide product produced by the target cells following transfection. In certain embodiments, the compounds and pharmaceutical compositions described herein demonstrate high transfection efficiencies thereby improving the likelihood that appropriate dosages of the encapsulated materials (e.g., one or more polynucleotides) will be delivered to the site of pathology and subsequently expressed, while at the same time minimizing potential systemic adverse effects or toxicity associated with the compound or their encapsulated contents.

[0496] Following transfection of one or more target cells by, for example, the polynucleotides encapsulated in the one or more lipid nanoparticles comprising the pharmaceutical or liposomal compositions disclosed herein, the production of the product (e.g., a polypeptide or protein) encoded by such polynucleotide may be preferably stimulated and the capability of such target cells to express the polynucleotide and produce, for example, a polypeptide or protein of interest is enhanced. For example, transfection of a target cell by one or more compounds or pharmaceutical compositions encapsulating mRNA will enhance (i.e., increase) the production of the protein or enzyme encoded by such mRNA.

[0497] Further, delivery vehicles described herein (e.g., liposomal delivery vehicles) may be prepared to preferentially distribute to other target tissues, cells or organs, such as the heart, lungs, kidneys, spleen. In embodiments, the lipid nanoparticles of the present invention may be prepared to achieve enhanced delivery to the target cells and tissues. For example, polynucleotides (e.g., mRNA) encapsulated in one or more of the compounds or pharmaceutical and liposomal compositions described herein can be delivered to and / or transfect targeted cells or tissues. In some embodiments, the encapsulated polynucleotides (e.g., mRNA) are capable of being expressed and functional polypeptide products produced (and in some instances excreted) by the target cell, thereby conferring a beneficial property to, for example the target cells or tissues. Such encapsulated polynucleotides (e.g., mRNA) may encode, for example, a hormone, enzyme, receptor, polypeptide, peptide or other protein of interest. 2026204802   22 Jun 2026 Liposomal Delivery Vehicles

[0498] In some embodiments, a composition is a suitable delivery vehicle. In embodiments, a composition is a liposomal delivery vehicle, e.g., a lipid nanoparticle.

[0499] The terms "liposomal delivery vehicle" and "liposomal composition" are used interchangeably.

[0500] Enriching liposomal compositions with one or more of the cationic lipids disclosed herein may be used as a means of improving (e.g., reducing) the toxicity or otherwise conferring one or more desired properties to such enriched liposomal composition (e.g., improved delivery of the encapsulated polynucleotides to one or more target cells and / or reduced in vivo toxicity of a liposomal composition). Accordingly, also contemplated are pharmaceutical compositions, and in particular liposomal compositions, that comprise one or more of the cationic lipids disclosed herein.

[0501] Thus, in certain embodiments, the compounds described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-1 h, Ilbl-1 Ib4, IIcl-I Ic4, 11 la-11 Id, and Va-Vd) are cationic lipids that may be used as a component of a liposomal composition to facilitate or enhance the delivery and release of encapsulated materials (e.g., one or more therapeutic agents) to one or more target cells (e.g., by permeating or fusing with the lipid membranes of such target cells).

[0502] As used herein, liposomal delivery vehicles, e.g., lipid nanoparticles, are usually characterized as microscopic vesicles having an interior aqua space sequestered from an outer medium by a membrane of one or more bilayers. Bilayer membranes of liposomes are typically formed by amphiphilic molecules, such as lipids of synthetic or natural origin that comprise spatially separated hydrophilic and hydrophobic domains (Lasic, Trends Biotechnol., 16: 307-321, 1998). Bilayer membranes of the liposomes can also be formed by amphophilic polymers and surfactants (e.g., polymerosomes, niosomes, etc.). In the context of the present invention, a liposomal delivery vehicle typically serves to transport a desired mRNA to a target cell or tissue.

[0503] In certain embodiments, such compositions (e.g., liposomal compositions) are loaded with or otherwise encapsulate materials, such as for example, one or more biologically-active polynucleotides (e.g., mRNA). 2026204802   22 Jun 2026

[0504] In embodiments, a composition (e.g., a pharmaceutical composition) comprises an mRNA encoding a protein, encapsulated within a liposome. In embodiments, a liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids, and at least one cationic lipid is a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, llbl-l Ib4, llcl-l Ic4,11 la-1 lid, and Va-Vd). In embodiments, a composition comprises an mRNA encoding for a protein (e.g., any protein described herein). In embodiments, a composition comprises an mRNA encoding for cystic fibrosis transmembrane conductance regulator (CFTR) protein. In embodiments, a composition comprises an mRNA encoding for ornithine transcarbamylase (OTC) protein.

[0505] In embodiments, a composition (e.g., a pharmaceutical composition) comprises a nucleic acid encapsulated within a liposome, wherein the liposome comprises any cationic lipid (e.g., a cationic lipid of Formula (A) such as any of Formulas (1)-( VI) or any of cationic lipids 1-264, la-lh, Ilbl-llb4, Ilcl-llc4, llla-llld, and Va-Vd) as described herein.

[0506] In embodiments, a nucleic acid is an mRNA encoding a peptide or polypeptide. In embodiments, an mRNA encodes a peptide or polypeptide for use in the delivery to or treatment of the lung of a subject or a lung cell (e.g., an mRNA encodes cystic fibrosis transmembrane conductance regulator (CFTR) protein). In embodiments, an mRNA encodes a peptide or polypeptide for use in the delivery to or treatment of the liver of a subject or a liver cell (e.g., an mRNA encodes ornithine transcarbamylase (OTC) protein). Still other exemplary mRNAs are described herein.

[0507] In embodiments, a liposomal delivery vehicle (e.g., a lipid nanoparticle) can have a net positive charge.

[0508] In embodiments, a liposomal delivery vehicle (e.g., a lipid nanoparticle) can have a net negative charge.

[0509] In embodiments, a liposomal delivery vehicle (e.g., a lipid nanoparticle) can have a net neutral charge.

[0510] In embodiments, a lipid nanoparticle that encapsulates a nucleic acid (e.g., mRNA encoding a peptide or polypeptide) comprises one or more cationic lipids described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, Ilbl-11b4, Ilcl-llc4, llla-llld, and Va-Vd). 2026204802   22 Jun 2026

[0511] For example, the amount of a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, Ilbl-1 Ib4, IIcl-I Ic4, 11 la-11 Id, and Va-Vd) in a composition can be described as a percentage ("wt%") of the combined dry weight of all lipids of a composition (e.g., the combined dry weight of all lipids present in a liposomal composition).

[0512] In embodiments of the pharmaceutical compositions described herein, a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (I)-(VI) or any of cationic lipids 1-264, la-lh, I I bl-l I b4, I lcl-1 Ic4, 11 la-11 Id, and Va-Vd) is present in an amount that is about 0.5 wt% to about 50 wt% (e.g., about 0.5 wt% to about 20 wt%) of the combined dry weight of all lipids present in a composition (e.g., a liposomal composition).

[0513] In embodiments, a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, 11 bl-l Ib4, I lcl-1 Ic4, 11 la-11 Id, and Va-Vd) is present in an amount that is about 1 wt% to about 50 wt%, about 1 wt% to about 40 wt%, about 1 wt% to about 30 wt%, about 1 wt% to about 20 wt%, about 1 wt% to about 15 wt%, about 1 wt% to about 10 wt%, about 5 wt% to about 25 wt%, about 10 wt% to about 30 wt %, or about 20 wt% to about 40 wt% of the combined dry weight of all lipids present in a composition (e.g., a liposomal composition). In embodiments, a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (I)-(VI) or any of cationic lipids 1-264, la-lh, 11 bl-l I b4, I lcl-1 Ic4, 11 la-1 lid, and Va-Vd) is present in an amount that is about 0.5 wt% to about 5 wt%, about 1 wt% to about 10 wt%, about 5 wt% to about 20 wt%, or about 10 wt% to about 20 wt% of the combined molar amounts of all lipids present in a composition such as a liposomal delivery vehicle.

[0514] In embodiments, the amount of a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, Ilbl-1 Ib4, IIcl-IIc4, llla-llld, and Va-Vd) is present in an amount that is at least about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, about 96 wt%, about 97 wt%, about 98 wt%, or about 99 wt% of the combined dry weight of total lipids in a composition (e.g., a liposomal composition).

[0515] In embodiments, the amount of a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, Ilbl-1 Ib4, IIcl- 2026204802   22 Jun 2026 I Ic4, 11 la-11 Id, and Va-Vd) is present in an amount that is no more than about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, about 96 wt%, about 97 wt%, about 98 wt%, or about 99 wt% of the combined dry weight of total lipids in a composition (e.g., a liposomal composition).

[0516] In embodiments, a composition (e.g., a liposomal delivery vehicle such as a lipid nanoparticle) comprises about 0.1 wt% to about 20 wt% (e.g., about 0.1 wt% to about 15 wt%) of a cationic lipid described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-11 b4, I lcl-1 Ic4,11 la-1 lid, and Va-Vd). In embodiments, a delivery vehicle (e.g., a liposomal delivery vehicle such as a lipid nanoparticle) comprises about 0.5 wt%, about 1 wt%, about 3 wt%, about 5 wt%, or about 10 wt% a cationic lipid described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-ll b4, I lcl-1 Ic4, 11 la-11 Id, and Va-Vd). In embodiments, a delivery vehicle (e.g., a liposomal delivery vehicle such as a lipid nanoparticle) comprises up to about 0.5 wt%, about 1 wt%, about 3 wt%, about 5 wt%, about 10 wt%, about 15 wt%, or about 20 wt% of a cationic lipid described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (1)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-ll b4,1 lcl-1 Ic4, 11 la-1 lid, and Va-Vd). In embodiments, the percentage results in an improved beneficial effect (e.g., improved delivery to targeted tissues such as the liver or the lung).

[0517] The amount of a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-1 Ib4, I lcl-1 Ic4, 11 la-11 Id, and Va-Vd) in a composition also can be described as a percentage ("mol%") of the combined molar amounts of total lipids of a composition (e.g., the combined molar amounts of all lipids present in a liposomal delivery vehicle).

[0518] In embodiments of pharmaceutical compositions described herein, a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (I)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-ll b4, I lcl-1 Ic4, 11 la-11 Id, and Va-Vd) is present in an amount that is about 0.5 mol% to about 50 mol% (e.g., about 0.5 mol% to about 30 mol%) of the combined molar amounts of all lipids present in a composition such as a liposomal delivery vehicle.

[0519] In embodiments, a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, 11 bl-l Ib4, I lcl-1 Ic4, llla-llld, and 2026204802   22 Jun 2026 Va-Vd) is present in an amount that is about 0.5 mol% to about 5 mol%, about 1 mol% to about 10 mol%, about 5 mol% to about 20 mol%, about 10 mol% to about 20 mol%, about 20 mol% to about 30 mol%, about 30 mol% to about 40 mol%, about 40 mol% to about 50 mol%, or about 50 mol% to about 60 mol% of the combined molar amounts of all lipids present in a composition such as a liposomal delivery vehicle. In embodiments, a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (1)-( VI) or any of cationic lipids 1-264, la-1 h, I lbl-11 b4, I lcl-1 Ic4, 11 la-1 lid, and Va-Vd) is present in an amount that is about 1 mol% to about 50 mol%, about 1 mol% to about 40 mol%, about 1 mol% to about 30 mol%, about 1 mol% to about 20 mol%, about 1 mol% to about 15 mol%, about 1 mol% to about 10 mol%, or about 5 mol% to about 25 mol% of the combined dry weight of all lipids present in a composition such as a liposomal delivery vehicle

[0520] In certain embodiments, a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-11b4, Ilcl-1 Ic4,11la-11 Id, and Va-Vd) can comprise from about 0.1 mol% to about 50 mol%, or from 0.5 mol% to about 50 mol%, or from about 1 mol% to about 25 mol%, or from about 1 mol% to about 10 mol% of the total amount of lipids in a composition (e.g., a liposomal delivery vehicle).

[0521] In certain embodiments, a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-11b4, Ilcl-1 Ic4,11la-11 Id, and Va-Vd) can comprise greater than about 0.1 mol%, or greater than about 0.5 mol%, or greater than about 1 mol%, or greater than about 5 mol%, or greater than about 10 mol%, or greater than about 15 mol%, or greater than about 20 mol%, or greater than 25 mol%, or greater than 30 mol%, or greater than 35 mol%, or greater than 40 mol%, or greater than 45 mol%, or greater than 50 mol% of the total amount of lipids in the lipid nanoparticle.

[0522] In certain embodiments, a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-11b4, Ilcl-1 Ic4,11la-11 Id, and Va-Vd) can comprise less than about 50 mol%, or less than about 45mol%, or less than about 40 mol% or less than about 30%, less than about 25 mol%, or less than about 20 mol%, or less than about 10 mol%, or less than about 5 mol%, or less than about 1 mol% of the total amount of lipids in a composition (e.g., a liposomal delivery vehicle).

[0523] In embodiments, the amount of a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, Ilbl-1 Ib4, IIcl-I Ic4, 11 la-11 Id, and Va-Vd) is present in an amount that is at least about 5 mol%, about 10 mol%, 2026204802   22 Jun 2026 about 15 mol%, about 20 mol%, about 25 mol%, about 30 mol%, about 35 mol%, about 40 mol%, about 45 mol%, about 50 mol%, about 55 mol%, about 60 mol%, about 65 mol%, about 70 mol%, about 75 mol%, about 80 mol%, about 85 mol%, about 90 mol%, about 95 mol%, about 96 mol%, about 97 mol%, about 98 mol%, or about 99 mol% of the combined dry weight of total lipids in a composition (e.g., a liposomal composition).

[0524] In embodiments, the amount of a cationic lipid as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-1 h, Ilbl-1 Ib4, IIcl-I Ic4, 11 la-11 Id, and Va-Vd) is present in an amount that is no more than about 5 mol%, about 10 mol%, about 15 mol%, about 20 mol%, about 25 mol%, about 30 mol%, about 35 mol%, about 40 mol%, about 45 mol%, about 50 mol%, about 55 mol%, about 60 mol%, about 65 mol%, about 70 mol%, about 75 mol%, about 80 mol%, about 85 mol%, about 90 mol%, about 95 mol%, about 96 mol%, about 97 mol%, about 98 mol%, or about 99 mol% of the combined dry weight of total lipids in a composition (e.g., a liposomal composition).

[0525] In embodiments, the percentage results in an improved beneficial effect (e.g., improved delivery to targeted tissues such as the liver or the lung).

[0526] In embodiments, a composition further comprises one more lipids (e.g., one more lipids selected from the group consisting of one or more cationic lipids, one or more non-cationic lipids, and one or more PEG-modified lipids).

[0527] In certain embodiments, such pharmaceutical (e.g., liposomal) compositions comprise one or more of a PEG-modified lipid, a non-cationic lipid and a cholesterol lipid. In embodiments, such pharmaceutical (e.g., liposomal) compositions comprise: one or more PEG-modified lipids; one or more non-cationic lipids; and one or more cholesterol lipids. In embodiments, such pharmaceutical (e.g., liposomal) compositions comprise: one or more PEG-modified lipids and one or more cholesterol lipids.

[0528] In embodiments, a composition (e.g., lipid nanoparticle) that encapsulates a nucleic acid (e.g., mRNA encoding a peptide or polypeptide) comprises one or more cationic lipids as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (I)-(VI) or any of cationic lipids 1-264, la-lh, IIbl-llb4, IIcl-llc4, Illa-llId, and Va-Vd) and one or more lipids selected from the group consisting of a cationic lipid, a non-cationic lipid, and a PEGylated lipid.

[0529] In embodiments, a composition (e.g., lipid nanoparticle) that encapsulates a nucleic acid (e.g., mRNA encoding a peptide or polypeptide) comprises one or more cationic lipids as 2026204802   22 Jun 2026 described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, Ilbl-llb4, IIcl-llc4, llla-llld, and Va-Vd); one or more lipids selected from the group consisting of a cationic lipid, a non-cationic lipid, and a PEGylated lipid; and further comprises a cholesterol-based lipid.

[0530] In embodiments, a lipid nanoparticle that encapsulates a nucleic acid (e.g., mRNA encoding a peptide or polypeptide) comprises one or more cationic lipids as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (1)-( VI) or any of cationic lipids 1-264, la-lh, Ilbl-llb4, Ilcl-1 Ic4, llla-llld, and Va-Vd), as well as one or more lipids selected from the group consisting of a cationic lipid, a non-cationic lipid, a PEGylated lipid, and a cholesterol-based lipid.

[0531] According to various embodiments, the selection of cationic lipids, non-cationic lipids and / or PEG-modified lipids which comprise the lipid nanoparticle, as well as the relative molar ratio of such lipids to each other, is based upon the characteristics of the selected lipid(s), the nature of the intended target cells, the characteristics of the mRNA to be delivered. Additional considerations include, for example, the saturation of the alkyl chain, as well as the size, charge, pH, pKa, fusogenicity and toxicity of the selected lipid(s). Thus, the molar ratios may be adjusted accordingly. Further Cationic Lipids

[0532] In addition to any of the cationic lipids as described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, Ilbl-11b4, Ilcl-1 Ic4, llla-llld, and Va-Vd), a composition may comprise one or more further cationic lipids.

[0533] In some embodiments, liposomes may comprise one or more further cationic lipids. As used herein, the phrase "cationic lipid" refers to any of a number of lipid species that have a net positive charge at a selected pH, such as physiological pH. Several cationic lipids have been described in the literature, many of which are commercially available.

[0534] Suitable additional cationic lipids for use in the compositions include the cationic lipids as described in International Patent Publication WO 2010 / 144740, which is incorporated herein by reference. In certain embodiments, the compositions include a cationic lipid, (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino) butanoate, having a compound structure of: 2026204802   22 Jun 2026 and pharmaceutically acceptable salts thereof.

[0535] Other suitable additional cationic lipids for use in the compositions include ionizable cationic lipids as described in International Patent Publication WO 2013 / 149140, which is incorporated herein by reference. In some embodiments, the compositions include a cationic lipid of one of the following formulas: or a pharmaceutically acceptable salt thereof, wherein Ri and R2 are each independently selected from the group consisting of hydrogen, an optionally substituted, variably saturated or unsaturated C1-C20 alkyl and an optionally substituted, variably saturated or unsaturated C6-C20 acyl; wherein Li and L2 are each independently selected from the group consisting of hydrogen, an optionally substituted C1-C30 alkyl, an optionally substituted variably unsaturated C1-C30 alkenyl, and an optionally substituted C1-C30 alkynyl; wherein m and 0 are each independently selected from the group consisting of zero and any positive integer (e.g., where m is three); and wherein n is zero or any positive integer (e.g., where n is one). In certain embodiments, the compositions include the cationic lipid (15Z, 18Z)-N,N-dimethyl-6-(9Z,12Z)-octadeca-9,12-dien-l -yl) tetracosa- 15,18-dien-l-amine ("HGT5000"), having a compound structure of: and pharmaceutically acceptable salts thereof. In certain embodiments, the compositions include the cationic lipid (15Z, 18Z)-N,N-dimethyl-6-((9Z,12Z)-octadeca-9,12-dien-l-yl) tetracosa-4,15,18-trien-l -amine ("HGT5001"), having a compound structure of: (HGT-5001) 2026204802   22 Jun 2026 and pharmaceutically acceptable salts thereof. In certain embodiments, the include the cationic lipid and (15Z,18Z)-N,N-dimethyl-6-((9Z,12Z)-octadeca-9,12-dien-l-yl) tetracosa-5,15,18-trien-1 -amine ("HGT5002"), having a compound structure of: (HGT-5002) and pharmaceutically acceptable salts thereof.

[0536] Other suitable additional cationic lipids for use in the compositions include cationic lipids described as aminoalcohol lipidoids in International Patent Publication WO 2010 / 053572, which is incorporated herein by reference. In certain embodiments, the compositions include a cationic lipid having a compound structure of: and pharmaceutically acceptable salts thereof.

[0537] Other suitable additional cationic lipids for use in the compositions include the cationic lipids as described in International Patent Publication WO 2016 / 118725, which is incorporated herein by reference. In certain embodiments, the compositions include a cationic lipid having a compound structure of: and pharmaceutically acceptable salts thereof.

[0538] Other suitable additional cationic lipids for use in the compositions include the cationic lipids as described in International Patent Publication WO 2016 / 118724, which is incorporated herein by reference. In certain embodiments, the compositions include a cationic lipid having a compound structure of: 2026204802   22 Jun 2026 and pharmaceutically acceptable salts thereof.

[0539] Other suitable cationic lipids for use in the compositions include a cationic lipid having the formula of 14,25-ditridecyl 15,18,21,24-tetraaza-octatriacontane, and pharmaceutically acceptable salts thereof.

[0540] Other suitable additional cationic lipids for use in the compositions include the cationic lipids as described in International Patent Publications WO 2013 / 063468 and WO 2016 / 205691, each of which are incorporated herein by reference. In some embodiments, the compositions include a cationic lipid of the following formula: OH OH or pharmaceutically acceptable salts thereof, wherein each instance of RL is independently optionally substituted C6-C40 alkenyl. In certain embodiments, the compositions include a cationic lipid having a compound structure of: and pharmaceutically acceptable salts thereof. 2026204802   22 Jun 2026

[0541] In certain embodiments, the compositions include a cationic lipid having a compound structure of: and pharmaceutically acceptable salts thereof. (OF-02)

[0542] In certain embodiments, the compositions include a cationic lipid having a compound structure of: and pharmaceutically acceptable salts thereof. 2026204802   22 Jun 2026

[0543] In certain embodiments, the compositions include a cationic lipid having a compound structure of: and pharmaceutically acceptable salts thereof.

[0544] Other suitable additional cationic lipids for use in the compositions include the cationic lipids as described in International Patent Publication WO 2015 / 184256, which is incorporated herein by reference. In some embodiments, the compositions include a cationic lipid of the following formula: H3C-(CH2)m OH H3C-(CH2)m (CRARB)n (CRaRb)^ | OH HO ^(CH2)m-CH3 or a pharmaceutically acceptable salt thereof, wherein each X independently is O or S; each Y independently is O or S; each m independently is 0 to 20; each n independently is 1 to 6; each Ra is independently hydrogen, optionally substituted Cl-50 alkyl, optionally substituted C2-50 2026204802   22 Jun 2026 alkenyl, optionally substituted C2-50 alkynyl, optionally substituted C3-10 carbocyclyl, optionally substituted 3-14 membered heterocyclyl, optionally substituted C6-14 aryl, optionally substituted 5-14 membered heteroaryl or halogen; and each RB is independently hydrogen, optionally substituted Cl-50 alkyl, optionally substituted C2-50 alkenyl, optionally substituted C2-50 alkynyl, optionally substituted C3-10 carbocyclyl, optionally substituted 3-14 membered heterocyclyl, optionally substituted C6-14 aryl, optionally substituted 5-14 membered heteroaryl or halogen. In certain embodiments, the compositions include a cationic lipid, "Target 23", having a compound structure of: OH uri (Target 23) and pharmaceutically acceptable salts thereof.

[0545] Other suitable additional cationic lipids for use in the compositions include the cationic lipids as described in International Patent Publication WO 2016 / 004202, which is incorporated herein by reference. In some embodiments, the compositions include a cationic lipid having the compound structure: or a pharmaceutically acceptable salt thereof. 2026204802   22 Jun 2026

[0546] In some embodiments, the compositions include a cationic lipid having the compound structure: or a pharmaceutically acceptable salt thereof.

[0547] In some embodiments, the compositions include a cationic lipid having the compound structure: or a pharmaceutically acceptable salt thereof.

[0548] Other suitable additional cationic lipids for use in the compositions include the cationic lipids as described in J. McClellan, M. C. King, Cell 2010,141, 210-217 and in Whitehead et al., Nature Communications (2014) 5:4277, which is incorporated herein by reference. In certain embodiments, the cationic lipids of the compositions include a cationic lipid having a compound structure of: Cl3H27                      C13H27 and pharmaceutically acceptable salts thereof. 2026204802   22 Jun 2026

[0549] Other suitable additional cationic lipids for use in the compositions include the cationic lipids as described in International Patent Publication WO 2015 / 199952, which is incorporated herein by reference. In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0550] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0551] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof. 2026204802   22 Jun 2026

[0552] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0553] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0554] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof. 2026204802   22 Jun 2026

[0555] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0556] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0557] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof. 2026204802   22 Jun 2026

[0558] In some embodiments, the compositions include a cationic lipid having the compound structure:

[0559] and pharmaceutically acceptable salts thereof.

[0560] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0561] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof. 2026204802   22 Jun 2026

[0562] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0563] Other suitable additional cationic lipids for use in the compositions include the cationic lipids as described in International Patent Publication WO 2017 / 004143, which is incorporated herein by reference.

[0564] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0565] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof. 2026204802   22 Jun 2026

[0566] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0567] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0568] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0569] In some embodiments, the compositions include a cationic lipid having the compound structure: 2026204802   22 Jun 2026 and pharmaceutically acceptable salts thereof.

[0570] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0571] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0572] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof. 2026204802   22 Jun 2026

[0573] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0574] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0575] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof. 2026204802   22 Jun 2026

[0576] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0577] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0578] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof. 2026204802   22 Jun 2026

[0579] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0580] In some embodiments, the compositions include a cationic lipid having the compound structure: O and pharmaceutically acceptable salts thereof.

[0581] Other suitable additional cationic lipids for use in the compositions include the cationic lipids as described in International Patent Publication WO 2017 / 075531, which is incorporated herein by reference. In some embodiments, the compositions include a cationic lipid of the following formula: .Q R "G1 G2 R2 or a pharmaceutically acceptable salt thereof, wherein one of L1 or L2 is -O(C=O)-, -(C=O)O-, -0(=0)-, -O-, -S(O)x, -S-S-, -C(=O)S-, -SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, NRaC(=O)NRa-, -OC(=O)NRa-, or -NRaC(=O)O-; and the other of L1 or L2 is -0(0=0)-, -(0=0)0-, -0(=0)-, -0-, -S(O)X, -S-S-, -C(=O)S-, SC(=O)-, -NRaC(=O)-, -C(=O)NRa-, ,NRaC(=O)NRa-, -OC(=O)NRa- or -NRaC(=O)O- or a direct bond; G1 and G2 are each independently unsubstituted C1-C12 alkylene or C1-C12 alkenylene; G3 is C1-C24 alkylene, C1-C24 alkenylene, Ca-Cg cycloalkylene, Ca-Cg cycloalkenylene; Ra is H or C1-C12 alkyl; R1 2026204802   22 Jun 2026 and R2 are each independently C6-C24 alkyl or C6-C24 alkenyl; R3 is H, OR5, CN, -C(=O)OR4, -OC(=O)R4 or -NR5 C(=O)R4; R4 is C1-C12 alkyl; R5 is H or Ci-C6 alkyl; and x is 0, 1 or 2.

[0582] Other suitable additional cationic lipids for use in the compositions include the cationic lipids as described in International Patent Publication WO 2017 / 117528, which is incorporated herein by reference. In some embodiments, the compositions include a cationic lipid having the compound structure: O and pharmaceutically acceptable salts thereof.

[0583] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0584] In some embodiments, the compositions include a cationic lipid having the compound structure: and pharmaceutically acceptable salts thereof.

[0585] Other suitable additional cationic lipids for use in the compositions include the cationic lipids as described in International Patent Publication WO 2017 / 049245, which is incorporated herein by reference. In some embodiments, the cationic lipids of the compositions and methods of the present invention include a compound of one of the following formulas: 2026204802   22 Jun 2026 and pharmaceutically acceptable salts thereof. For any one of these four formulas, R4 is independently selected from -(CH2)nQ and -(CH2) nCHQR; Q is selected from the group consisting of -OR, -OH, -O(CH2)nN(R)2, -OC(O)R, -CX3, -CN, -N(R)C(O)R, -N(H)C(O)R, -N(R)S(O)2R, -N(H)S(O)2R, -N(R)C(O)N(R)2, -N(H)C(O)N(R)2, -N(H)C(O)N(H)(R), -N(R)C(S)N(R)2, -N(H)C(S)N(R)2, -N(H)C(S)N(H)(R), and a heterocycle; R is independently selected from the group consisting of C1-3 alkyl, C2-3 alkenyl, and H; and n is 1, 2, or 3.

[0586] In certain embodiments, the compositions include a cationic lipid having a compound structure of: and pharmaceutically acceptable salts thereof. 2026204802   22 Jun 2026

[0587] In certain embodiments, the compositions include a cationic lipid having a compound structure of: and pharmaceutically acceptable salts thereof.

[0588] In certain embodiments, the compositions include a cationic lipid having a compound structure of: and pharmaceutically acceptable salts thereof.

[0589] In certain embodiments, the compositions include a cationic lipid having a compound structure of: and pharmaceutically acceptable salts thereof.

[0590] Other suitable additional cationic lipids for use in the compositions include the cationic lipids as described in International Patent Publication WO 2017 / 173054 and WO 2015 / 095340, each of which is incorporated herein by reference.

[0591] In certain embodiments, the compositions include a cationic lipid having a compound structure of: 2026204802   22 Jun 2026 and pharmaceutically acceptable salts thereof.

[0592] In certain embodiments, the compositions include a cationic lipid having a compound structure of: O and pharmaceutically acceptable salts thereof.

[0593] In certain embodiments, the compositions include a cationic lipid having a compound structure of: and pharmaceutically acceptable salts thereof. 2026204802   22 Jun 2026

[0594] In certain embodiments, the compositions include a cationic lipid having a compound structure of: and pharmaceutically acceptable salts thereof.

[0595] Other suitable additional cationic lipids for use in the compositions include cholesterol-based cationic lipids. In certain embodiments, the compositions include imidazole cholesterol ester or "ICE", having a compound structure of: and pharmaceutically acceptable salts thereof.

[0596] Other suitable additional cationic lipids for use in the compositions include cleavable cationic lipids as described in International Patent Publication WO 2012 / 170889, which is incorporated herein by reference. In some embodiments, the compositions include a cationic lipid of the following formula: wherein Ri is selected from the group consisting of imidazole, guanidinium, amino, imine, enamine, an optionally-substituted alkyl amino (e.g., an alkyl amino such as dimethylamino) and pyridyl; wherein R2 is selected from the group consisting of one of the following two formulas: 2026204802   22 Jun 2026 and wherein R3 and R4are each independently selected from the group consisting of an optionally substituted, variably saturated or unsaturated C6-C20 alkyl and an optionally substituted, variably saturated or unsaturated C6-C20 acyl; and wherein n is zero or any positive integer (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more).

[0597] In certain embodiments, the compositions include a cationic lipid, "HGT4001", having a compound structure of: and pharmaceutically acceptable salts thereof.

[0598] In certain embodiments, the compositions include a cationic lipid, "HGT4002", having a compound structure of: NH2 (HGT4002) and pharmaceutically acceptable salts thereof.

[0599] In certain embodiments, the compositions include a cationic lipid, "HGT4003", having a compound structure of: (HGT4003) 2026204802   22 Jun 2026 and pharmaceutically acceptable salts thereof.

[0600] In certain embodiments, the compositions include a cationic lipid, "HGT4004", having a compound structure of: (HGT4004) and pharmaceutically acceptable salts thereof.

[0601] In certain embodiments, the compositions include a cationic lipid "HGT4005", having a compound structure of: (HGT4005) and pharmaceutically acceptable salts thereof.

[0602] In some embodiments, the compositions include the cationic lipid, N-[l-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride ("DOTMA"). Feigner et al. (Proc. Nat'l Acad. Sci. 84, 7413 (1987); U.S. Pat. No. 4,897,355, each of which is incorporated herein by reference. DOTMA can be formulated alone or can be combined with a neutral lipid (e.g., dioleoylphosphatidyl-ethanolamine or "DOPE") or still other cationic or non-cationic lipids into a liposomal transfer vehicle or a lipid nanoparticle, and such liposomes can be used to enhance the delivery of nucleic acids into target cells. Other cationic lipids suitable for the compositions include, for example, 5-carboxyspermylglycinedioctadecylamide ("DOGS"); 2,3-dioleyloxy-N-[2(spermine-carboxamido)ethyl]-N,N-dimethyl-l-propanaminium ("DOSPA") (Behr et al. Proc. Nat.'l Acad. Sci. 86, 6982 (1989), U.S. Pat. No. 5,171,678; U.S. Pat. No. 5,334,761); l,2-Dioleoyl-3-Dimethylammonium-Propane ("DODAP"); l,2-Dioleoyl-3-Trimethylammonium-Propane ("DOTAP").

[0603] Additional exemplary cationic lipids suitable for the compositions also include: 1,2-distearyloxy-N,N-dimethyl-3-aminopropane ( "DSDMA"); l,2-dioleyloxy-N,N-dimethyl-3-aminopropane ("DODMA"); 1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane ("DLinDMA"); 1,2-dilinolenyloxy-N,N-dimethyl-3-aminopropane ("DLenDMA"); N-dioleyl-N,N-dimethylammonium chloride ("DODAC"); N,N-distearyl-N,N-dimethylarnrnonium bromide ("DDAB"); N-(l,2-dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethyl ammonium bromide ("DMRIE"); 3-dimethylamino-2-(cholest-5-en-3-beta-oxybutan-4-oxy)-l-(cis,cis-9,12-octadecadienoxy)propane ("CLinDMA"); 2-[5'-(cholest-5-en-3-beta-oxy)-3'-oxapentoxy)-3-dimethy l-l-(cis,cis-9', 1-2'- 2026204802   22 Jun 2026 octadecadienoxy)propane ("CpLinDMA"); N,N-dimethyl-3,4-dioleyloxybenzylamine ("DMOBA"); 1,2-N,N'-dioleylcarbamyl-3-dimethylaminopropane ("DOcarbDAP"); 2,3-Dilinoleoyloxy-N,N-dimethylpropylamine ("DLinDAP"); l,2-N,N'-Dilinoleylcarbamyl-3-dimethylaminopropane ("DLincarbDAP"); 1,2-Dilinoleoylcarbamyl-3-dimethylaminopropane ("DLinCDAP"); 2,2-dilinoleyl-4-dimethylaminomethyl-[l,3]-dioxolane ("DLin-K-DMA"); 2-((8-[(3P)-cholest-5-en-3-yloxy]octyl)oxy)-N, N-dimethyl-3-[(9Z, 12Z)-octadeca-9, 12-dien-l -yloxy]propane-l-amine ("Octyl-CLinDMA"); (2R)-2-((8-[(3beta)-cholest-5-en-3-yloxy]octyl)oxy)-N, N-dimethyl-3-[(9Z, 12Z)-octadeca-9, 12-dien-l-yloxy]propan-l -amine ("Octyl-CLinDMA (2R)"); (2S)-2-((8-[(3P)-cholest-5-en-3-yloxy]octyl)oxy)-N, fsl-dimethyh3-[(9Z, 12Z)-octadeca-9,12-dien-l -yloxy]propan-1 -amine ("Octyl-CLinDMA (2S)"); 2,2-dilinoleyl-4-dimethylaminoethyl-[l,3]-dioxolane ("DLin-K-XTC2-DMA"); and 2-(2,2-di((9Z,12Z)-octadeca-9,l 2-dien- l-yl)-l ,3-dioxolan-4-yl)-N,N-dimethylethanamine ("DLin-KC2-DMA") (see, WO 2010 / 042877, which is incorporated herein by reference; Semple et al., Nature Biotech. 28:172-176 (2010)). (Heyes, J., et al., J Controlled Release 107: 276-287 (2005); Morrissey, DV., et al., Nat. Biotechnol. 23(8): 1003-1007 (2005); International Patent Publication WO 2005 / 121348). In some embodiments, one or more of the cationic lipids comprise at least one of an imidazole, dialkylamino, or guanidinium moiety.

[0604] In some embodiments, one or more cationic lipids suitable for the compositions include 2,2-Dilinoleyl-4-dimethylaminoethyl-[l,3]-dioxolane ("XTC"); (3aR,5s,6aS)-N,N-dimethyl-2,2-di((9Z,12Z)-octadeca-9,12-dienyl)tetrahydro-3aH-cyclopenta[d] [1,3]dioxol-5-amine ("ALNY-100") and / or 4,7,13-tris(3-oxo-3-(undecylamino)propyl)-Nl,N16-diundecyl-4,7,10,13-tetraazahexadecane-l,16-diamide ("NC98-5").

[0605] In some embodiments, the percentage of total cationic lipids in a composition (e.g., a liposomal composition) may be no more than 10%, no more than 20%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, or no more than 95% of total lipids as measured by molar ratios (mol%) or by weight (wt%).

[0606] In some embodiments, the percentage of total cationic lipids in a composition (e.g., a liposomal composition) may be greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, or greater than 95% of total lipids as measured by molar ratios (mol%) or by weight (wt%).

[0607] In some embodiments, total cationic lipid(s) constitute(s) about 30-50 % (e.g., about 30-45%, about 30-40%, about 35-50%, about 35-45%, or about 35-40%) of the liposome by weight. In 2026204802   22 Jun 2026 some embodiments, the cationic lipid constitutes about 30%, about 35%, about 40 %, about 45%, or about 50% of a composition (e.g., a liposomal composition) by molar ratio. In some embodiments, total cationic lipid(s) constitute(s) about 30-50 % (e.g., about 30-45%, about 3040%, about 35-50%, about 35-45%, or about 35-40%) of the liposome by weight. In some embodiments, the cationic lipid constitutes about 30%, about 35%, about 40 %, about 45%, or about 50% of a composition (e.g., a liposomal composition) by weight. Non-cationic / Helper Lipids

[0608] Compositions (e.g., liposomal compositions) may also comprise one or more non-cationic ("helper") lipids. As used herein, the phrase "non-cationic lipid" refers to any neutral, zwitterionic or anionic lipid. As used herein, the phrase "anionic lipid" refers to any of a number of lipid species that carry a net negative charge at a selected pH, such as physiological pH. Noncationic lipids include, but are not limited to, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-l-carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidyl-ethanolamine (DSPE), 16-O-monomethyl PE, 16-O-dimethyl PE, 18-1-trans PE, l-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), or a mixture thereof.

[0609] In embodiments, a non-cationic or helper lipid is dioleoylphosphatidylethanolamine (DOPE).

[0610] In some embodiments, a non-cationic lipid is a neutral lipid, i.e., a lipid that does not carry a net charge in the conditions under which the composition is formulated and / or administered.

[0611] In some embodiments, a non-cationic lipid may be present in a molar ratio (mol%) of about 5% to about 90%, about 5% to about 70%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 10 % to about 70%, about 10% to about 50%, or about 10% to about 40% of the total lipids present in a composition. In some embodiments, total non-cationic lipids may be present in a molar ratio (mol%) of about 5% to about 90%, about 5% to about 70%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 10 % to about 70%, about 10% to about 50%, or about 10% to about 40% of the total lipids present in a composition. In some embodiments, the percentage of non-cationic lipid in a liposome may be greater than about 5 mol%, greater than about 10 mol%, greater than about 20 mol%, greater 2026204802   22 Jun 2026 than about 30 mol%, or greater than about 40 mol%. In some embodiments, the percentage total non-cationic lipids in a liposome may be greater than about 5 mol%, greater than about 10 mol%, greater than about 20 mol%, greater than about 30 mol%, or greater than about 40 mol%. In some embodiments, the percentage of non-cationic lipid in a liposome is no more than about 5 mol%, no more than about 10 mol%, no more than about 20 mol%, no more than about 30 mol%, or no more than about 40 mol%. In some embodiments, the percentage total noncationic lipids in a liposome may be no more than about 5 mol%, no more than about 10 mol%, no more than about 20 mol%, no more than about 30 mol%, or no more than about 40 mol%.

[0612] In some embodiments, a non-cationic lipid may be present in a weight ratio (wt%) of about 5% to about 90%, about 5% to about 70%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 10 % to about 70%, about 10% to about 50%, or about 10% to about 40% of the total lipids present in a composition. In some embodiments, total non-cationic lipids may be present in a weight ratio (wt%) of about 5% to about 90%, about 5% to about 70%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 10 % to about 70%, about 10% to about 50%, or about 10% to about 40% of the total lipids present in a composition. In some embodiments, the percentage of non-cationic lipid in a liposome may be greater than about 5 wt%, greater than about 10 wt%, greater than about 20 wt%, greater than about 30 wt%, or greater than about 40 wt%. In some embodiments, the percentage total noncationic lipids in a liposome may be greater than about 5 wt%, greater than about 10 wt%, greater than about 20 wt%, greater than about 30 wt%, or greater than about 40 wt%. In some embodiments, the percentage of non-cationic lipid in a liposome is no more than about 5 wt%, no more than about 10 wt%, no more than about 20 wt%, no more than about 30 wt%, or no more than about 40 wt%. In some embodiments, the percentage total non-cationic lipids in a liposome may be no more than about 5 wt%, no more than about 10 wt%, no more than about 20 wt%, no more than about 30 wt%, or no more than about 40 wt%. Cholesterol-based Lipids

[0613] In some embodiments, a composition (e.g., a liposomal composition) comprises one or more cholesterol-based lipids. For example, suitable cholesterol-based lipids include cholesterol and, for example, DC-Chol (N,N-dimethyl-N-ethylcarboxamidocholesterol), l,4-bis(3-N-oleylamino-propyl)piperazine (Gao, et al. Biochem. Biophys. Res. Comm. 179, 280 (1991); Wolf et al. 2026204802   22 Jun 2026 BioTechniques 23, 139 (1997); U.S. Pat. No. 5,744,335), or imidazole cholesterol ester (ICE), which has the following structure,

[0614] In embodiments, a cholesterol-based lipid is cholesterol.

[0615] In some embodiments, a cholesterol-based lipid may be present in a molar ratio (mol%) of about 1% to about 30%, or about 5% to about 20% of the total lipids present in a liposome. In some embodiments, the percentage of cholesterol-based lipid in the lipid nanoparticle may be greater than about 5 mol%, greater than about 10 mol%, greater than about 20 mol%, greater than about 30 mol%, or greater than about 40 mol%. In some embodiments, the percentage of cholesterol-based lipid in the lipid nanoparticle may be no more than about 5 mol%, no more than about 10 mol%, no more than about 20 mol%, no more than about 30 mol%, or no more than about 40 mol%.

[0616] In some embodiments, a cholesterol-based lipid may be present in a weight ratio (wt%) of about 1% to about 30%, or about 5% to about 20% of the total lipids present in a liposome. In some embodiments, the percentage of cholesterol-based lipid in the lipid nanoparticle may be greater than about 5 wt%, greater than about 10 wt%, greater than about 20 wt%, greater than about 30 wt%, or greater than about 40 wt%. In some embodiments, the percentage of cholesterol-based lipid in the lipid nanoparticle may be no more than about 5 wt%, no more than about 10 wt%, no more than about 20 wt%, no more than about 30 wt%, or no more than about 40 wt%. PEGylated Lipids

[0617] In some embodiments, a composition (e.g., a liposomal composition) comprises one or more PEGylated lipids. 2026204802   22 Jun 2026

[0618] For example, the use of polyethylene glycol (PEG)-modified phospholipids and derivatized lipids such as derivatized ceramides (PEG-CER), including N-octanoyl-sphingosine-1-[succinyl(methoxy polyethylene glycol)-2000] (C8 PEG-2000 ceramide) is also contemplated by the present invention in combination with one or more of the cationic and, in some embodiments, other lipids together which comprise the liposome. In some embodiments, particularly useful exchangeable lipids are PEG-ceramides having shorter acyl chains (e.g., C14 or Ci8).

[0619] In embodiments, a PEG-modified lipid is 1,2-dimyristoyl-sn-glycerol, methoxypolyethylene glycol (DMG-PEG2000).

[0620] Contemplated PEG-modified lipids (also referred to herein as a PEGylated lipid, which term is interchangeable with PEG-modified lipid) include, but are not limited to, a polyethylene glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C20 length. In some embodiments, a PEG-modified or PEGylated lipid is PEGylated cholesterol or PEG-2K. The addition of such components may prevent complex aggregation and may also provide a means for increasing circulation lifetime and increasing the delivery of the lipid-nucleic acid composition to the target cell, (Klibanov et al. (1990) FEBS Letters, 268 (1): 235-237), or they may be selected to rapidly exchange out of the formulation in vivo (see U.S. Pat. No. 5,885,613).

[0621] A PEG-modified phospholipid and derivatized lipids of the present invention may be present in a molar ratio (mol%) from about 0% to about 15%, about 0.5% to about 15%, about 1% to about 15%, about 4% to about 10%, or about 2% of the total lipid present in the composition (e.g., a liposomal composition).

[0622] A PEG-modified phospholipid and derivatized lipids of the present invention may be present in a weight ratio (wt%) from about 0% to about 15%, about 0.5% to about 15%, about 1% to about 15%, about 4% to about 10%, or about 2% of the total lipid present in the composition (e.g., a liposomal composition). Pharmaceutical Formulations and Therapeutic Uses

[0623] Cationic lipids described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-1 Ib4, I lcl-1 Ic4, 11 la-11 Id, and Va-Vd) may be used in the preparation of compositions (e.g., to construct liposomal compositions) that facilitate or 2026204802   22 Jun 2026 enhance the delivery and release of encapsulated materials (e.g., one or more therapeutic polynucleotides) to one or more target cells (e.g., by permeating or fusing with the lipid membranes of such target cells).

[0624] For example, when a liposomal composition (e.g., a lipid nanoparticle) comprises or is otherwise enriched with one or more of the compounds disclosed herein, the phase transition in the lipid bilayer of the one or more target cells may facilitate the delivery of the encapsulated materials (e.g., one or more therapeutic polynucleotides encapsulated in a lipid nanoparticle) into the one or more target cells.

[0625] Similarly, in certain embodiments cationic lipids described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-1 h, Ilbl-1 Ib4, IIcl-I Ic4, 11 la-11 Id, and Va-Vd) may be used to prepare liposomal vehicles that are characterized by their reduced toxicity in vivo. In certain embodiments, the reduced toxicity is a function of the high transfection efficiencies associated with the compositions disclosed herein, such that a reduced quantity of such composition may administered to the subject to achieve a desired therapeutic response or outcome.

[0626] Thus, pharmaceutical formulations comprising a cationic lipid described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (1)-(VI) or any of cationic lipids 1-264, la-1 h, I lbl-ll b4, I lcl-1 Ic4, 11 la-1 lid, and Va-Vd) and nucleic acids provided by the present invention may be used for various therapeutic purposes. To facilitate delivery of nucleic acids in vivo, a cationic lipid described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-ll b4, I lcl-1 Ic4, 11 la-11 Id, and Va-Vd) and nucleic acids can be formulated in combination with one or more additional pharmaceutical carriers, targeting ligands or stabilizing reagents. In some embodiments, a cationic lipid described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (1)-(VI) or any of cationic lipids 1-264, la-lh, I lbl-llb4, I lcl-1 Ic4,11 la-ll Id, and Va-Vd) can be formulated via pre-mixed lipid solution. In other embodiments, a composition comprising a cationic lipid described herein (e.g., a cationic lipid of Formula (A) such as any of Formulas (l)-(VI) or any of cationic lipids 1-264, la-lh, Ilbl-1 Ib4, IIcl-IIc4, llla-llld, and Va-Vd) can be formulated using post-insertion techniques into the lipid membrane of the nanoparticles. Techniques for formulation and administration of drugs may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., latest edition.

[0627] Suitable routes of administration include, for example, oral, rectal, vaginal, transmucosal, pulmonary including intratracheal or inhaled, or intestinal administration; parenteral delivery, 2026204802   22 Jun 2026 including intradermal, transdermal (topical), intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, or intranasal. In particular embodiments, the intramuscular administration is to a muscle selected from the group consisting of skeletal muscle, smooth muscle and cardiac muscle. In some embodiments the administration results in delivery of the nucleic acids to a muscle cell. In some embodiments the administration results in delivery of the nucleic acids to a hepatocyte (i.e., liver cell).

[0628] Alternatively or additionally, pharmaceutical formulations of the invention may be administered in a local rather than systemic manner, for example, via injection of the pharmaceutical formulation directly into a targeted tissue, preferably in a sustained release formulation. Local delivery can be affected in various ways, depending on the tissue to be targeted. Exemplary tissues in which delivered mRNA may be delivered and / or expressed include, but are not limited to the liver, kidney, heart, spleen, serum, brain, skeletal muscle, lymph nodes, skin, and / or cerebrospinal fluid. In embodiments, the tissue to be targeted in the liver. For example, aerosols containing compositions of the present invention can be inhaled (for nasal, tracheal, or bronchial delivery); compositions of the present invention can be injected into the site of injury, disease manifestation, or pain, for example; compositions can be provided in lozenges for oral, tracheal, or esophageal application; can be supplied in liquid, tablet or capsule form for administration to the stomach or intestines, can be supplied in suppository form for rectal or vaginal application; or can even be delivered to the eye by use of creams, drops, or even injection.

[0629] The present invention provides methods for delivering a composition having full-length mRNA molecules encoding a peptide or polypeptide of interest for use in the treatment of a subject, e.g., a human subject or a cell of a human subject or a cell that is treated and delivered to a human subject.

[0630] Accordingly, in certain embodiments the present invention provides a method for producing a therapeutic composition comprising full-length mRNA that encodes a peptide or polypeptide for use in the delivery to or treatment of the lung of a subject or a lung cell. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for cystic fibrosis transmembrane conductance regulator (CFTR) protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for ATP-binding cassette sub- 2026204802   22 Jun 2026 family A member 3 protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for dynein axonemal intermediate chain 1 protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for dynein axonemal heavy chain 5 (DNAH5) protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for alpha-l-antitrypsin protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for forkhead box P3 (FOXP3) protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes one or more surfactant protein, e.g., one or more of surfactant A protein, surfactant B protein, surfactant C protein, and surfactant D protein.

[0631] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes a peptide or polypeptide for use in the delivery to or treatment of the liver of a subject or a liver cell. Such peptides and polypeptides can include those associated with a urea cycle disorder, associated with a lysosomal storage disorder, with a glycogen storage disorder, associated with an amino acid metabolism disorder, associated with a lipid metabolism or fibrotic disorder, associated with methylmalonic acidemia, or associated with any other metabolic disorder for which delivery to or treatment of the liver or a liver cell with enriched full-length mRNA provides therapeutic benefit.

[0632] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a protein associated with a urea cycle disorder. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for ornithine transcarbamylase (OTC) protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for arginosuccinate synthetase 1 protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for carbamoyl phosphate synthetase I protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for arginosuccinate lyase protein. In certain embodiments the present invention 2026204802   22 Jun 2026 provides a method for producing a therapeutic composition having full-length mRNA that encodes for arginase protein.

[0633] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a protein associated with a lysosomal storage disorder. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for alpha galactosidase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for glucocerebrosidase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for iduronate-2-sulfatase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for iduronidase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for N-acetyl-alpha-D-glucosaminidase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for heparan N-sulfatase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for galactosamine-6 sulfatase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for betagalactosidase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for lysosomal lipase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for arylsulfatase B (N-acetylgalactosamine-4-sulfatase) protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for transcription factor EB (TFEB).

[0634] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a protein associated with a glycogen storage disorder. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for acid alphaglucosidase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for glucose-6- 2026204802   22 Jun 2026 phosphatase (G6PC) protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for liver glycogen phosphorylase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for muscle phosphoglycerate mutase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for glycogen debranching enzyme.

[0635] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a protein associated with amino acid metabolism. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for phenylalanine hydroxylase enzyme. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for glutaryl-CoA dehydrogenase enzyme. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for propionyl-CoA caboxylase enzyme. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for oxalase alanineglyoxylate aminotransferase enzyme.

[0636] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a protein associated with a lipid metabolism or fibrotic disorder. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a mTOR inhibitor. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for ATPase phospholipid transporting 8B1 (ATP8B1) protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for one or more NF-kappa B inhibitors, such as one or more of l-kappa B alpha, interferon-related development regulator 1 (IFRD1), and Sirtuin 1 (SIRT1). In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for PPAR-gamma protein or an active variant.

[0637] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a protein associated with 2026204802   22 Jun 2026 methylmalonic acidemia. For example, in certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for methylmalonyl CoA mutase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for methylmalonyl CoA epimerase protein.

[0638] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA for which delivery to or treatment of the liver can provide therapeutic benefit. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for ATP7B protein, also known as Wilson disease protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for porphobilinogen deaminase enzyme. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for one or clotting enzymes, such as Factor VIII, Factor IX, Factor VII, and Factor X. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for human hemochromatosis (HFE) protein.

[0639] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes a peptide or polypeptide for use in the delivery to or treatment of the cardiovasculature of a subject or a cardiovascular cell. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for vascular endothelial growth factor A protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for relaxin protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for bone morphogenetic protein-9 protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for bone morphogenetic protein-2 receptor protein.

[0640] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes a peptide or polypeptide for use in the delivery to or treatment of the muscle of a subject or a muscle cell. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for dystrophin protein. In certain embodiments the 2026204802   22 Jun 2026 present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for frataxin protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes a peptide or polypeptide for use in the delivery to or treatment of the cardiac muscle of a subject or a cardiac muscle cell. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a protein that modulates one or both of a potassium channel and a sodium channel in muscle tissue or in a muscle cell. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a protein that modulates a Kv7.1 channel in muscle tissue or in a muscle cell. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a protein that modulates a Navi.5 channel in muscle tissue or in a muscle cell.

[0641] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes a peptide or polypeptide for use in the delivery to or treatment of the nervous system of a subject or a nervous system cell. For example, in certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for survival motor neuron 1 protein. For example, in certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for survival motor neuron 2 protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for frataxin protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for ATP binding cassette subfamily D member 1 (ABCD1) protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for CLN3 protein.

[0642] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes a peptide or polypeptide for use in the delivery to or treatment of the blood or bone marrow of a subject or a blood or bone marrow cell. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for beta globin protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for Bruton's tyrosine kinase protein. In certain embodiments the present invention provides a method for producing a therapeutic composition 2026204802   22 Jun 2026 having full-length mRNA that encodes for one or clotting enzymes, such as Factor VIII, Factor IX, Factor VII, and Factor X.

[0643] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes a peptide or polypeptide for use in the delivery to or treatment of the kidney of a subject or a kidney cell. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for collagen type IV alpha 5 chain (COL4A5) protein.

[0644] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes a peptide or polypeptide for use in the delivery to or treatment of the eye of a subject or an eye cell. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for ATP-binding cassette sub-family A member 4 (ABCA4) protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for retinoschisin protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for retinal pigment epithelium-specific 65 kDa (RPE65) protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for centrosomal protein of 290 kDa (CEP290).

[0645] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes a peptide or polypeptide for use in the delivery of or treatment with a vaccine for a subject or a cell of a subject. For example, in certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen from an infectious agent, such as a virus. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen from influenza virus. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen from respiratory syncytial virus. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen from rabies virus. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen from cytomegalovirus. In certain embodiments the present invention provides a method for producing a therapeutic 2026204802   22 Jun 2026 composition having full-length mRNA that encodes for an antigen from rotavirus. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen from a hepatitis virus, such as hepatitis A virus, hepatitis B virus, or hepatis C virus. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen from human papillomavirus. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen from a herpes simplex virus, such as herpes simplex virus 1 or herpes simplex virus 2. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen from a human immunodeficiency virus, such as human immunodeficiency virus type 1 or human immunodeficiency virus type 2. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen from a human metapneumovirus. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen from a human parainfluenza virus, such as human parainfluenza virus type 1, human parainfluenza virus type 2, or human parainfluenza virus type 3. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen from malaria virus. In certain embodiments the present invention provides a method for producing a therapeutic composition having fulllength mRNA that encodes for an antigen from zika virus. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen from chikungunya virus.

[0646] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen associated with a cancer of a subject or identified from a cancer cell of a subject. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen determined from a subject's own cancer cell, i.e., to provide a personalized cancer vaccine. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antigen expressed from a mutant KRAS gene.

[0647] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antibody. In certain 2026204802   22 Jun 2026 embodiments, the antibody can be a bi-specific antibody. In certain embodiments, the antibody can be part of a fusion protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antibody to OX40. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antibody to VEGF. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antibody to tissue necrosis factor alpha. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antibody to CD3. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an antibody to CD19.

[0648] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an immunomodulator. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for Interleukin 12. In certain embodiments the present invention provides a method for producing a therapeutic composition having fulllength mRNA that encodes for Interleukin 23. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for Interleukin 36 gamma. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a constitutively active variant of one or more stimulator of interferon genes (STING) proteins.

[0649] In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an endonuclease. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for an RNA-guided DNA endonuclease protein, such as Cas 9 protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a meganuclease protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a transcription activator-like effector nuclease protein. In certain embodiments the present invention provides a method for producing a therapeutic composition having full-length mRNA that encodes for a zinc finger nuclease protein. 2026204802   22 Jun 2026

[0650] In embodiments, exemplary therapeutic uses result from the delivery of mRNA encoding a secreted protein. Accordingly, in embodiments, the compositions and methods of the invention provide for delivery of mRNA encoding a secreted protein. In some embodiments, the compositions and methods of the invention provide for delivery of mRNA encoding one or more secreted proteins listed in Table 1; thus, compositions of the invention may comprise an mRNA encoding a protein listed in Table 1 (or a homolog thereof) along with other components set out herein, and methods of the invention may comprise preparing and / or administering a composition comprising an mRNA encoding a protein listed in Table 1 (or a homolog thereof) along with other components set out herein Table 1. Secreted Proteins Uniprot ID Protein Name Gene Name A1E959 Odontogenic ameloblast-associated protein ODAM A1KZ92 Peroxidasin-like protein PXDNL A1L453 Serine protease 38 PRSS38 A1L4H1 Soluble scavenger receptor cysteine-rich domain-containing protein SSC5D SSC5D A2RUU4 Colipase-like protein 1 CLPSL1 A2VDF0 Fucose mutarotase FUOM A2VEC9 SCO-spondin SSPO A3KMH1 von Willebrand factor A domain-containing protein 8 VWA8 A4D0S4 Laminin subunit beta-4 LAMB4 A4D1T9 Probable inactive serine protease 37 PRSS37 A5D8T8 C-type lectin domain family 18 member A CLEC18A A6NC86 phospholipase A2 inhibitor and Ly6 / PLAUR domain-containing protein PINLYP A6NCI4 von Willebrand factor A domain-containing protein 3A VWA3A A6ND01 Probable folate receptor delta F0LR4 A6NDD2 Beta-defensin 108B-like A6NE02 BTB / POZ domain-containing protein 17 BTBD17 A6NEF6 Growth hormone 1 GH1 A6NF02 NPIP-like protein LOC730153 A6NFB4 HCG1749481, isoform CRA_k CSH1 A6NFZ4 Protein FAM24A FAM24A A6NG13 Glycosyltransferase 54 domain-containing protein A6NGN9 IgLON family member 5 IGLON5 A6NHN0 Otolin-1 OTO LI 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name A6NHN6 Nuclear pore complex-interacting protein-like 2 NPIPL2 A6NI73 Leukocyte immunoglobulin-like receptor subfamily A member 5 LILRA5 A6NIT4 Chorionic somatomammotropin hormone 2 isoform 2 CSH2 A6NJ69 IgA-inducing protein homolog IGIP A6NKQ.9 Choriogonadotropin subunit beta variant 1 CGB1 A6NMZ7 Collagen alpha-6(VI) chain COL6A6 A6NNS2 Dehydrogenase / reductase SDR family member 7C DHRS7C A6XGL2 Insulin A chain INS A8K0G1 Protein Wnt WNT7B A8K2U0 Alpha-2-macroglobulin-like protein 1 A2ML1 A8K7I4 Calcium-activated chloride channel regulator 1 CLCA1 A8MTL9 Serpin-like protein HMSD HMSD A8MV23 Serpin E3 SERPINE3 A8MZH6 Oocyte-secreted protein 1 homolog OOSP1 A8TX70 Collagen alpha-5(VI) chain COL6A5 B0ZBE8 Natriuretic peptide NPPA B1A4G9 Somatotropin GH1 B1A4H2 HCG1749481, isoform CRA_d CSH1 B1A4H9 Chorionic somatomammotropin hormone CSH2 B1AJZ6 Protein Wnt WNT4 B1AKI9 lsthmin-1 ISM1 B2RNN3 Complement Clq and tumor necrosis factor-related protein 9B C1Q.TNF9B B2RUY7 von Willebrand factor C domain-containing protein 2-like VWC2L B3GLJ2 Prostate and testis expressed protein 3 PATE3 B4DI03 SECll-like 3 (S. cerevisiae), isoform CRA_a SEC11L3 B4DJF9 Protein Wnt WNT4 B4DUL4 SECll-like 1 (S. cerevisiae), isoform CRA_d SEC11L1 B5MCC8 Protein Wnt WNT10B B8A595 Protein Wnt WNT7B B8A597 Protein Wnt WNT7B B8A598 Protein Wnt WNT7B B9A064 Immunoglobulin lambda-like polypeptide 5 IGLL5 C9J3H3 Protein Wnt WNT10B C9J8I8 Protein Wnt WNT5A C9JAF2 Insulin-like growth factor II Ala-25 Del IGF2 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name C9JCI2 Protein Wnt WNT10B C9JL84 HERV-H LTR-associating protein 1 HHLA1 C9JNR5 Insulin A chain INS C9JUI2 Protein Wnt WNT2 D6RF47 Protein Wnt WNT8A D6RF94 Protein Wnt WNT8A E2RYF7 Protein PBMUCL2 HCG22 E5RFR1 PENK(114-133) PENK E7EML9 Serine protease 44 PRSS44 E7EPC3 Protein Wnt WNT9B E7EVP0 Nociceptin PNOC E9PD02 Insulin-like growth factor 1 IGF1 E9PH60 Protein Wnt WNT16 E9PJL6 Protein Wnt WNT11 F5GYM2 Protein Wnt WNT5B F5H034 Protein Wnt WNT5B F5H364 Protein Wnt WNT5B F5H7Q.6 Protein Wnt WNT5B F8WCM5 Protein INS-IGF2 INS-IGF2 F8WDR1 Protein Wnt WNT2 H0Y663 Protein Wnt WNT4 H0YK72 Signal peptidase complex catalytic subunit SEC11A SEC11A H0YK83 Signal peptidase complex catalytic subunit SEC11A SEC11A H0YM39 Chorionic somatomammotropin hormone CSH2 H0YMT7 Chorionic somatomammotropin hormone CSH1 H0YN17 Chorionic somatomammotropin hormone CSH2 H0YNA5 Signal peptidase complex catalytic subunit SEC11A SEC11A H0YNG3 Signal peptidase complex catalytic subunit SEC11A SEC11A H0YNX5 Signal peptidase complex catalytic subunit SEC11A SEC11A H7BZB8 Protein Wnt WNT10A H9KV56 Choriogonadotropin subunit beta variant 2 CGB2 I3L0L8 Protein Wnt WNT9B J3KNZ1 Choriogonadotropin subunit beta variant 1 CGB1 J3KP00 Choriogonadotropin subunit beta CGB7 J3Q.T02 Choriogonadotropin subunit beta variant 1 CGB1 000175 C-C motif chemokine 24 CCL24 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name 000182 Galectin-9 LGALS9 000187 Mannan-binding lectin serine protease 2 MASP2 000230 Cortistatin CORT 000253 Agouti-related protein AGRP 000270 12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid receptor GPR31 000292 Left-right determination factor 2 LEFTY2 000294 Tubby-related protein 1 TULP1 000295 Tubby-related protein 2 TULP2 000300 Tumor necrosis factor receptor superfamily member 11B TNFRSF11B 000339 Matrilin-2 MATN2 000391 Sulfhydryl oxidase 1 Q.SOX1 000468 Agrin AGRN 000515 Ladinin-1 LAD1 000533 Processed neural cell adhesion molecule Ll-like protein CHL1 000584 Ribonuclease T2 RNASET2 000585 C-C motif chemokine 21 CCL21 000602 Ficolin-1 FCN1 000622 Protein CYR61 CYR61 000626 MDC(5-69) CCL22 000634 Netrin-3 NTN3 000744 Protein Wnt-lOb WNT10B 000755 Protein Wnt-7a WNT7A 014498 Immunoglobulin superfamily containing leucine-rich repeat protein ISLR 014511 Pro-neuregulin-2, membrane-bound isoform NRG2 014594 Neurocan core protein NCAN 014625 C-X-C motif chemokine 11 CXCL11 014638 Ectonucleotide pyrophosphatase / phosphodiesterase family member 3 ENPP3 014656 Torsin-IA TOR1A 014657 Torsin-IB T0R1B 014786 Neuropilin-1 NRP1 014788 Tumor necrosis factor ligand superfamily member 11, membrane form TNFSF11 014791 Apolipoprotein LI AP0L1 014793 Growth / differentiation factor 8 MSTN 014904 Protein Wnt-9a WNT9A 014905 Protein Wnt-9b WNT9B 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name 014944 Proepiregulin EREG 014960 Leukocyte cell-derived chemotaxin-2 LECT2 015018 Processed PDZ domain-containing protein 2 PDZD2 015041 Semaphorin-3E SEMA3E 015072 A disintegrin and metalloproteinase with thrombospondin motifs 3 ADAMTS3 015123 Angiopoietin-2 ANGPT2 015130 Neuropeptide FF NPFF 015197 Ephrin type-B receptor 6 EPHB6 015204 ADAM DECI ADAMDEC1 015230 Laminin subunit alpha-5 LAMA5 015232 Matrilin-3 MATN3 015240 Neuroendocrine regulatory peptide-1 VGF 015263 Beta-defensin 4A DEFB4A 015335 Chondroadherin CHAD 015393 Transmembrane protease serine 2 catalytic chain TMPRSS2 015444 C-C motif chemokine 25 CCL25 015467 C-C motif chemokine 16 CCL16 015496 Group 10 secretory phospholipase A2 PLA2G10 015520 Fibroblast growth factor 10 FGF10 015537 Retinoschisin RSI 043157 Plexin-Bl PLXNB1 043184 Disintegrin and metalloproteinase domaincontaining protein 12 ADAM12 043240 Kallikrein-10 KLK10 043278 Kunitz-type protease inhibitor 1 SPINT1 043320 Fibroblast growth factor 16 FGF16 043323 Desert hedgehog protein C-product DHH 043405 Cochlin COCH 043508 Tumor necrosis factor ligand superfamily member 12, membrane form TNFSF12 043555 Progonadoliberin-2 GNRH2 043557 Tumor necrosis factor ligand superfamily member 14, soluble form TNFSF14 043692 Peptidase inhibitor 15 PI15 043699 Sialic acid-binding Ig-like lectin 6 SIGLEC6 043820 Hyaluronidase-3 HYAL3 043827 Angiopoietin-related protein 7 ANGPTL7 043852 Calumenin CALU 043854 EGF-like repeat and discoidin l-like domaincontaining protein 3 EDIL3 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name 043866 CD5 antigen-like CD5L 043897 Tolloid-like protein 1 TLL1 043915 Vascular endothelial growth factor D FIGF 043927 C-X-C motif chemokine 13 CXCL13 060218 Aldo-keto reductase family 1 member BIO AKR1B10 060235 Transmembrane protease serine 11D TMPRSS11D 060258 Fibroblast growth factor 17 FGF17 060259 Kallikrein-8 KLK8 060383 Growth / differentiation factor 9 GDF9 060469 Down syndrome cell adhesion molecule DSCAM 060542 Persephin PSPN 060565 Gremlin-1 GREM1 060575 Serine protease inhibitor Kazal-type 4 SPINK4 060676 Cystatin-8 CST8 060687 Sushi repeat-containing protein SRPX2 SRPX2 060844 Zymogen granule membrane protein 16 ZG16 060882 Matrix metalloproteinase-20 MMP20 060938 Keratocan KERA 075015 Low affinity immunoglobulin gamma Fc region receptor lll-B FCGR3B 075077 Disintegrin and metalloproteinase domaincontaining protein 23 ADAM23 075093 Slit homolog 1 protein SLIT1 075094 Slit homolog 3 protein SLIT3 075095 Multiple epidermal growth factor-like domains protein 6 MEGF6 075173 A disintegrin and metalloproteinase with thrombospondin motifs 4 ADAMTS4 075200 Nuclear pore complex-interacting protein-like 1 NPIPL1 075339 Cartilage intermediate layer protein 1 Cl CILP 075354 Ectonucleoside triphosphate diphosphohydrolase 6 ENTPD6 075386 Tubby-related protein 3 TULP3 075398 Deformed epidermal autoregulatory factor 1 homolog DEAFI 075443 Alpha-tectorin TECTA 075445 Usherin USH2A 075462 Cytokine receptor-like factor 1 CRLF1 075487 Glypican-4 GPC4 075493 Carbonic anhydrase-related protein 11 CA11 075594 Peptidoglycan recognition protein 1 PGLYRP1 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name 075596 C-type lectin domain family 3 member A CLEC3A 075610 Left-right determination factor 1 LEFTY1 075629 Protein CREG1 CREG1 075636 Ficolin-3 FCN3 075711 Scrapie-responsive protein 1 SCRG1 075715 Epididymal secretory glutathione peroxidase GPX5 075718 Cartilage-associated protein CRTAP 075829 Chondrosurfactant protein LECT1 075830 Serpin 12 SERPINI2 075882 Attractin ATRN 075888 Tumor necrosis factor ligand superfamily member 13 TNFSF13 075900 Matrix metalloproteinase-23 MMP23A 075951 Lysozyme-like protein 6 LYZL6 075973 Clq-related factor C1Q.L1 076038 Secretagogin SCGN 076061 Stanniocalcin-2 STC2 076076 WNTl-inducible-signaling pathway protein 2 WISP2 076093 Fibroblast growth factor 18 FGF18 076096 Cystatin-F CST7 094769 Extracellular matrix protein 2 ECM2 094813 Slit homolog 2 protein C-product SLIT2 094907 Dickkopf-related protein 1 DKK1 094919 Endonuclease domain-containing 1 protein END0D1 094964 N-terminal form SOGA1 095025 Semaphorin-3D SEMA3D 095084 Serine protease 23 PRSS23 095150 Tumor necrosis factor ligand superfamily member 15 TNFSF15 095156 Neurexophilin-2 NXPH2 095157 Neurexophilin-3 NXPH3 095158 Neurexophilin-4 NXPH4 095388 WNTl-inducible-signaling pathway protein 1 WISP1 095389 WNTl-inducible-signaling pathway protein 3 WISP3 095390 Growth / differentiation factor 11 GDF11 095393 Bone morphogenetic protein 10 BMP10 095399 Urotensin-2 UTS2 095407 Tumor necrosis factor receptor superfamily member 6B TNFRSF6B 095428 Papilin PAPLN 095445 Apolipoprotein M APOM 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name 095450 A disintegrin and metalloproteinase with thrombospondin motifs 2 ADAMTS2 095460 Matrilin-4 MATN4 095467 LHAL tetrapeptide GNAS 095631 Netrin-1 NTN1 095633 Follistatin-related protein 3 FSTL3 095711 Lymphocyte antigen 86 LY86 095715 C-X-C motif chemokine 14 CXCL14 095750 Fibroblast growth factor 19 FGF19 095760 Interleukin-33 IL33 095813 Cerberus CER1 095841 Angiopoietin-related protein 1 ANGPTL1 095897 Noelin-2 0LFM2 095925 Eppin EPPIN 095965 Integrin beta-like protein 1 ITGBL1 095967 EGF-containing fibulin-like extracellular matrix protein 2 EFEMP2 095968 Secretoglobin family ID member 1 SCGB1D1 095969 Secretoglobin family ID member 2 SCGB1D2 095970 Leucine-rich glioma-inactivated protein 1 LGI1 095972 Bone morphogenetic protein 15 BMP15 095994 Anterior gradient protein 2 homolog AGR2 095998 lnterleukin-18-binding protein IL18BP 096009 Napsin-A NAPSA 096014 Protein Wnt-11 WNT11 P00450 Ceruloplasmin CP P00451 Factor Villa light chain F8 P00488 Coagulation factor XIII A chain F13A1 P00533 Epidermal growth factor receptor EGFR P00709 Alpha-lactalbumin LALBA P00734 Prothrombin F2 P00738 Haptoglobin beta chain HP P00739 Haptoglobin-related protein HPR P00740 Coagulation factor IXa heavy chain F9 P00742 Factor X heavy chain F10 P00746 Complement factor D CFD P00747 Plasmin light chain B PLG P00748 Coagulation factor XIla light chain F12 P00749 Urokinase-type plasminogen activator long chain A PLAU P00750 Tissue-type plasminogen activator PLAT 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P00751 Complement factor B Ba fragment CFB P00797 Renin REN P00973 2'-5'-oligoadenylate synthase 1 OAS1 P00995 Pancreatic secretory trypsin inhibitor SPINK1 P01008 Antithrombin-Ill SERPINC1 P01009 Alpha-l-antitrypsin SERPINA1 P01011 Alpha-l-antichymotrypsin His-Pro-less SERPINA3 P01019 Angiotensin-1 AGT P01023 Alpha-2-macroglobulin A2M P01024 Acylation stimulating protein C3 P01031 Complement C5 beta chain C5 P01033 Metalloproteinase inhibitor 1 TIMP1 P01034 Cystatin-C CST3 P01036 Cystatin-S CST4 P01037 Cystatin-SN CST1 P01042 Kininogen-1 light chain KNG1 P01127 Platelet-derived growth factor subunit B PDGFB P01135 Transforming growth factor alpha TGFA P01137 Transforming growth factor beta-1 TGFB1 P01138 Beta-nerve growth factor NGF P01148 Gonadoliberin-1 GNRH1 P01160 Atrial natriuretic factor NPPA P01178 Oxytocin OXT P01185 Vasopressin-neurophysin 2-copeptin AVP P01189 Corticotropin POMC P01210 PENK(237-258) PENK P01213 Alpha-neoendorphin PDYN P01215 Glycoprotein hormones alpha chain CGA P01222 Thyrotropin subunit beta TSHB P01225 Foilitropin subunit beta FSHB P01229 Lutropin subunit beta LHB P01233 Choriogonadotropin subunit beta CGB8 P01236 Prolactin PRL P01241 Somatotropin GH1 P01242 Growth hormone variant GH2 P01243 Chorionic somatomammotropin hormone CSH2 P01258 Katacalcin CALCA P01266 Thyroglobulin TG P01270 Parathyroid hormone PTH P01275 Glucagon GCG P01282 Intestinal peptide PHM-27 VIP 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P01286 Somatoliberin GHRH P01298 Pancreatic prohormone PPY P01303 C-flanking peptide of NPY NPY P01308 Insulin INS P01344 Insulin-like growth factor II IGF2 P01350 Big gastrin GAST P01374 Lymphotoxin-alpha LTA P01375 C-domain 1 TNF P01562 Interferon alpha-1 / 13 IFNA1 P01563 Interferon alpha-2 IFNA2 P01566 Interferon alpha-10 IFNA10 P01567 Interferon alpha-7 IFNA7 P01568 Interferon alpha-21 IFNA21 P01569 Interferon alpha-5 IFNA5 P01570 Interferon alpha-14 IFNA14 P01571 Interferon alpha-17 IFNA17 P01574 Interferon beta IFNB1 P01579 Interferon gamma IFNG P01583 lnterleukin-1 alpha ILIA P01584 lnterleukin-1 beta IL1B P01588 Erythropoietin EPO P01591 Immunoglobulin J chain IGJ P01732 T-cell surface glycoprotein CD8 alpha chain CD8A P01833 Polymeric immunoglobulin receptor PIGR P01857 Ig gamma-1 chain C region IGHG1 P01859 Ig gamma-2 chain C region IGHG2 P01860 Ig gamma-3 chain C region IGHG3 P01861 Ig gamma-4 chain C region IGHG4 P01871 Ig mu chain C region IGHM P01880 Ig delta chain C region IGHD P02452 Collagen alpha-l(l) chain COL1A1 P02458 Chondrocalcin COL2A1 P02461 Collagen alpha-l(lll) chain COL3A1 P02462 Collagen alpha-l(IV) chain COL4A1 P02647 Apolipoprotein A-l APOA1 P02649 Apolipoprotein E APOE P02652 Apolipoprotein A-ll APOA2 P02654 Apolipoprotein C-l APOCI P02655 Apolipoprotein C-ll APOC2 P02656 Apolipoprotein C-ll 1 APOC3 P02671 Fibrinogen alpha chain FGA 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P02675 Fibrinopeptide B FGB P02679 Fibrinogen gamma chain FGG P02741 C-reactive protein CRP P02743 Serum amyloid P-component(l-203) APCS P02745 Complement Clq subcomponent subunit A C1Q.A P02746 Complement Clq subcomponent subunit B C1Q.B P02747 Complement Clq subcomponent subunit C C1Q.C P02748 Complement component C9b C9 P02749 Beta-2-glycoprotein 1 APOH P02750 Leucine-rich alpha-2-glycoprotein LRG1 P02751 Ugl-Y2 FN1 P02753 Retinol-binding protein 4 RBP4 P02760 Trypstatin AMBP P02763 Alpha-l-acid glycoprotein 1 ORM1 P02765 Alpha-2-HS-glycoprotein chain A AHSG P02766 Transthyretin TTR P02768 Serum albumin ALB P02771 Alpha-fetoprotein AFP P02774 Vitamin D-binding protein GC P02775 Connective tissue-activating peptide III PPBP P02776 Platelet factor 4 PF4 P02778 CXCL10(l-73) CXCL10 P02786 Transferrin receptor protein 1 TFRC P02787 Serotransferrin TF P02788 Lactoferroxin-C LTF P02790 Hemopexin HPX P02808 Statherin STATH P02810 Salivary acidic proline-rich phosphoprotein 1 / 2 PRH2 P02812 Basic salivary proline-rich protein 2 PRB2 P02814 Peptide DIA SMR3B P02818 Osteocalcin BGLAP P03950 Angiogenin ANG P03951 Coagulation factor Xia heavy chain Fil P03952 Plasma kallikrein KLKB1 P03956 T1 kDa interstitial collagenase MMPl P03971 Muellerian-inhibiting factor AMH P03973 Antileukoproteinase SLPI P04003 C4b-binding protein alpha chain C4BPA P04004 Somatomedin-B VTN P04054 Phospholipase A2 PLA2G1B 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P04085 Platelet-derived growth factor subunit A PDGFA P04090 Relaxin A chain RLN2 P04114 Apolipoprotein B-100 APOB P04118 Colipase CLPS P04141 Granulocyte-macrophage colony-stimulating factor CSF2 P04155 Trefoil factor 1 TFF1 P04180 Phosphatidylcholine-sterol acyltransferase LCAT P04196 Histidine-rich glycoprotein HRG P04217 Alpha-lB-glycoprotein A1BG P04275 von Willebrand antigen 2 VWF P04278 Sex hormone-binding globulin SHBG P04279 Alpha-inhibin-31 SEMG1 P04280 Basic salivary proline-rich protein 1 PRB1 P04628 Proto-oncogene Wnt-1 WNT1 P04745 Alpha-amylase 1 AMY1A P04746 Pancreatic alpha-amylase AMY2A P04808 Prorelaxin Hl RLN1 P05000 Interferon omega-1 IFNW1 P05013 Interferon alpha-6 IFNA6 P05014 Interferon alpha-4 IFNA4 P05015 Interferon alpha-16 IFNA16 P05019 Insulin-like growth factor 1 IGF1 P05060 GAWK peptide CHGB P05090 Apolipoprotein D APOD P05109 Protein S100-A8 S100A8 P05111 Inhibin alpha chain INHA P05112 lnterleukin-4 IL4 P05113 lnterleukin-5 IL5 P05120 Plasminogen activator inhibitor 2 SERPINB2 P05121 Plasminogen activator inhibitor 1 SERPINE1 P05154 Plasma serine protease inhibitor SERPINA5 P05155 Plasma protease Cl inhibitor SERPING1 P05156 Complement factor 1 heavy chain CFI P05160 Coagulation factor XIII B chain F13B P05161 Ubiquitin-like protein ISG15 ISG15 P05230 Fibroblast growth factor 1 FGF1 P05231 lnterleukin-6 IL6 P05305 Big endothelin-1 EDN1 P05408 C-terminal peptide SCG5 P05451 Lithostathine-l-alpha REGIA 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P05452 Tetranectin CLEC3B P05543 Thyroxine-binding globulin SERPINA7 P05814 Beta-casein CSN2 P05997 Collagen alpha-2(V) chain COL5A2 P06276 Cholinesterase BCHE P06307 Cholecystokinin-12 CCK P06396 Gelsolin GSN P06681 Complement C2 C2 P06702 Protein S100-A9 S100A9 P06727 Apolipoprotein A-IV APOA4 P06734 Low affinity immunoglobulin epsilon Fc receptor soluble form FCER2 P06744 Glucose-6-phosphate isomerase GPI P06850 Corticoliberin CRH P06858 Lipoprotein lipase LPL P06881 Calcitonin gene-related peptide 1 CALCA P07093 Glia-derived nexin SERPINE2 P07098 Gastric triacylglycerol lipase LIPF P07225 Vitamin K-dependent protein S PROS1 P07237 Protein disulfide-isomerase P4HB P07288 Prostate-specific antigen KLK3 P07306 Asialoglycoprotein receptor 1 ASGR1 P07355 Annexin A2 ANXA2 P07357 Complement component C8 alpha chain C8A P07358 Complement component C8 beta chain C8B P07360 Complement component C8 gamma chain C8G P07477 Alpha-trypsin chain 2 PRSS1 P07478 Trypsin-2 PRSS2 P07492 Neuromedin-C GRP P07498 Kappa-casein CSN3 P07585 Decorin DCN P07911 Uromodulin UMOD P07942 Laminin subunit beta-1 LAMB1 P07988 Pulmonary surfactant-associated protein B SFTPB P07998 Ribonuclease pancreatic RNASE1 P08118 Beta-microseminoprotein MSMB P08123 Collagen alpha-2(l) chain COL1A2 P08185 Corticosteroid-binding globulin SERPINA6 P08217 Chymotrypsin-like elastase family member 2A CELA2A P08218 Chymotrypsin-like elastase family member 2B CELA2B P08253 72 kDa type IV collagenase MIVIP2 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P08254 Stromelysin-1 MMP3 P08294 Extracellular superoxide dismutase [Cu-Zn] SOD3 P08476 Inhibin beta A chain INHBA P08493 Matrix Gia protein MGP P08572 Collagen alpha-2(IV) chain COL4A2 P08581 Hepatocyte growth factor receptor MET P08603 Complement factor H CFH P08620 Fibroblast growth factor 4 FGF4 P08637 Low affinity immunoglobulin gamma Fc region receptor lll-A FCGR3A P08697 Alpha-2-antiplasmin SERPINF2 P08700 lnterleukin-3 IL3 P08709 Coagulation factor VII F7 P08833 Insulin-like growth factor-binding protein 1 IGFBP1 P08887 lnterleukin-6 receptor subunit alpha IL6R P08949 Neuromedin-B-32 NMB P08F94 Fibrocystin PKHD1 P09038 Fibroblast growth factor 2 FGF2 P09228 Cystatin-SA CST2 P09237 Matrilysin MMP7 P09238 Stromelysin-2 MMP10 P09341 Growth-regulated alpha protein CXCL1 P09382 Galectin-1 LGALS1 P09466 Glycodelin PAEP P09486 SPARC SPARC P09529 Inhibin beta B chain INHBB P09544 Protein Wnt-2 WNT2 P09603 Processed macrophage colony-stimulating factor 1 CSF1 P09681 Gastric inhibitory polypeptide GIP P09683 Secretin SCT P09919 Granulocyte colony-stimulating factor CSF3 P0C091 FRASl-related extracellular matrix protein 3 FREM3 P0C0L4 C4d-A C4A P0C0L5 Complement C4-B alpha chain C4B P0C0P6 Neuropeptide S NPS P0C7L1 Serine protease inhibitor Kazal-type 8 SPINK8 P0C862 Complement Clq and tumor necrosis factor-related protein 9A C1Q.TNF9 P0C8F1 Prostate and testis expressed protein 4 PATE4 P0CG01 Gastrokine-3 GKN3P 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P0CG36 Cryptic family protein IB CFC1B P0CG37 Cryptic protein CFC1 P0CJ68 Humanin-like protein 1 MTRNR2L1 P0CJ69 Humanin-like protein 2 MTRNR2L2 P0CJ70 Humanin-like protein 3 MTRNR2L3 P0CJ71 Humanin-like protein 4 MTRNR2L4 P0CJ72 Humanin-like protein 5 MTRNR2L5 P0CJ73 Humanin-like protein 6 MTRNR2L6 P0CJ74 Humanin-like protein 7 MTRNR2L7 P0CJ75 Humanin-like protein 8 MTRNR2L8 P0CJ76 Humanin-like protein 9 MTRNR2L9 P0CJ77 Humanin-like protein 10 MTRNR2L10 P0DJD7 Pepsin A-4 PGA4 P0DJD8 Pepsin A-3 PGA3 P0DJD9 Pepsin A-5 PGA5 P0DJI8 Amyloid protein A SAA1 P0DJI9 Serum amyloid A-2 protein SAA2 P10082 Peptide YY(3-36) PYY P10092 Calcitonin gene-related peptide 2 CALCB P10124 Serglycin SRGN P10145 MDNCF-a IL8 P10147 MIP-l-alpha(4-69) CCL3 P10163 Peptide P-D PRB4 P10451 Osteopontin SPP1 P10599 Thioredoxin TXN P10600 Transforming growth factor beta-3 TGFB3 P10643 Complement component C7 C7 P10645 Vasostatin-2 CHGA P10646 Tissue factor pathway inhibitor TFPI P10720 Platelet factor 4 variant(4-74) PF4V1 P10745 Retinol-binding protein 3 RBP3 P10767 Fibroblast growth factor 6 FGF6 P10909 Clusterin alpha chain CLU P10912 Growth hormone receptor GHR P10915 Hyaluronan and proteoglycan link protein 1 HAPLN1 P10966 T-cell surface glycoprotein CD8 beta chain CD8B P10997 Islet amyloid polypeptide IAPP P11047 Laminin subunit gamma-1 LAMC1 P11150 Hepatic triacylglycerol lipase LIPC P11226 Mannose-binding protein C MBL2 P11464 Pregnancy-specific beta-l-glycoprotein 1 PSG1 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P11465 Pregnancy-specific beta-l-glycoprotein 2 PSG2 P11487 Fibroblast growth factor 3 FGF3 P11597 Cholesteryl ester transfer protein CETP P11684 Uteroglobin SCGB1A1 P11686 Pulmonary surfactant-associated protein C SFTPC P12034 Fibroblast growth factor 5 FGF5 P12107 Collagen alpha-l(XI) chain COL11A1 P12109 Collagen alpha-l(VI) chain COL6A1 P12110 Collagen alpha-2(VI) chain COL6A2 P12111 Collagen alpha-3(VI) chain COL6A3 P12259 Coagulation factor V F5 P12272 PTHrP[l-36] PTHLH P12273 Prolactin-inducible protein PIP P12544 Granzyme A GZMA P12643 Bone morphogenetic protein 2 BMP2 P12644 Bone morphogenetic protein 4 BMP4 P12645 Bone morphogenetic protein 3 BMP3 P12724 Eosinophil cationic protein RNASE3 P12821 Angiotensin-converting enzyme, soluble form ACE P12838 Neutrophil defensin 4 DEFA4 P12872 Motilin MLN P13232 lnterleukin-7 IL7 P13236 C-C motif chemokine 4 CCL4 P13284 Gamma-interferon-inducible lysosomal thiol reductase IFI30 P13500 C-C motif chemokine 2 CCL2 P13501 C-C motif chemokine 5 CCL5 P13521 Secretogranin-2 SCG2 P13591 Neural cell adhesion molecule 1 NCAM1 P13611 Versican core protein VCAN P13671 Complement component C6 C6 P13688 Carcinoembryonic antigen-related cell adhesion molecule 1 CEACAM1 P13725 Oncostatin-M OSM P13726 Tissue factor F3 P13727 Eosinophil granule major basic protein PRG2 P13942 Collagen alpha-2(XI) chain COL11A2 P13987 CD59 glycoprotein CD59 P14138 Endothelin-3 EDN3 P14174 Macrophage migration inhibitory factor MIF P14207 Folate receptor beta F0LR2 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P14222 Perforin-1 PRF1 P14543 Nidogen-1 NIDI P14555 Phospholipase A2, membrane associated PLA2G2A P14625 Endoplasmin HSP90B1 P14735 Insulin-degrading enzyme IDE P14778 lnterleukin-1 receptor type 1, soluble form IL1R1 P14780 82 kDa matrix metalloproteinase-9 MMP9 P15018 Leukemia inhibitory factor LIF P15085 Carboxypeptidase Al CPA1 P15086 Carboxypeptidase B CPB1 P15151 Poliovirus receptor PVR P15169 Carboxypeptidase N catalytic chain CPN1 P15248 lnterleukin-9 IL9 P15291 N-acetyllactosamine synthase B4GALT1 P15309 PAPf39 ACPP P15328 Folate receptor alpha FOLRI P15374 Ubiquitin carboxyl-terminal hydrolase isozyme L3 UCHL3 P15502 Elastin ELN P15509 Granulocyte-macrophage colony-stimulating factor receptor subunit alpha CSF2RA P15515 Histatin-1 HTN1 P15516 His3-(31-51)-peptide HTN3 P15692 Vascular endothelial growth factor A VEGFA P15814 Immunoglobulin lambda-like polypeptide 1 IGLL1 P15907 Beta-galactoside alpha-2,6-sialyltransferase 1 ST6GAL1 P15941 Mucin-1 subunit beta MUC1 P16035 Metalloproteinase inhibitor 2 TIMP2 P16112 Aggrecan core protein 2 ACAN P16233 Pancreatic triacylglycerol lipase PNLIP P16442 Histo-blood group ABO system transferase ABO P16471 Prolactin receptor PRLR P16562 Cysteine-rich secretory protein 2 CRISP2 P16619 C-C motif chemokine 3-1 ike 1 CCL3L1 P16860 BNP(3-29) NPPB P16870 Carboxypeptidase E CPE P16871 lnterleukin-7 receptor subunit alpha IL7R P17213 Bactericidal permeability-increasing protein BPI P17538 Chymotrypsinogen B CTRB1 P17931 Galectin-3 LGALS3 P17936 Insulin-like growth factor-binding protein 3 IGFBP3 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P17948 Vascular endothelial growth factor receptor 1 FLT1 P18065 Insulin-like growth factor-binding protein 2 IGFBP2 P18075 Bone morphogenetic protein 7 BMP7 P18428 Lipopolysaccharide-binding protein LBP P18509 PACAP-related peptide ADCYAP1 P18510 lnterleukin-1 receptor antagonist protein IL1RN P18827 Syndecan-1 SDC1 P19021 Peptidylglycine alpha-hydroxylating monooxygenase PAM P19235 Erythropoietin receptor EPOR P19438 Tumor necrosis factor-binding protein 1 TNFRSF1A P19652 Alpha-l-acid glycoprotein 2 ORM2 P19801 Amiloride-sensitive amine oxidase [copper-containing] ABP1 P19823 Inter-alpha-trypsin inhibitor heavy chain H2 ITIH2 P19827 Inter-alpha-trypsin inhibitor heavy chain Hl ITIH1 P19835 Bile salt-activated lipase CEL P19875 C-X-C motif chemokine 2 CXCL2 P19876 C-X-C motif chemokine 3 CXCL3 P19883 Follistatin FST P19957 Elafin PI3 P19961 Alpha-amylase 2B AMY2B P20061 Transcobalamin-1 TCN1 P20062 Transcobalamin-2 TCN2 P20142 Gastricsin PGC P20155 Serine protease inhibitor Kazal-type 2 SPINK2 P20231 Tryptase beta-2 TPSB2 P20333 Tumor necrosis factor receptor superfamily member IB TNFRSF1B P20366 Substance P TAC1 P20382 Melanin-concentrating hormone PMCH P20396 Thyroliberin TRH P20742 Pregnancy zone protein PZP P20774 Mimecan OGN P20783 Neurotrophin-3 NTF3 P20800 Endothelin-2 EDN2 P20809 Interleukin-11 IL11 P20827 Ephrin-Al EFNA1 P20849 Collagen alpha-l(IX) chain COL9A1 P20851 C4b-binding protein beta chain C4BPB P20908 Collagen alpha-l(V) chain COL5A1 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P21128 Poly(U)-specific endoribonuclease ENDOU P21246 Pleiotrophin PTN P21583 Kit ligand KITLG P21741 Midkine MDK P21754 Zona pellucida sperm-binding protein 3 ZP3 P21781 Fibroblast growth factor 7 FGF7 P21802 Fibroblast growth factor receptor 2 FGFR2 P21810 Biglycan BGN P21815 Bone sialoprotein 2 IBSP P21860 Receptor tyrosine-protein kinase erbB-3 ERBB3 P21941 Cartilage matrix protein MATN1 P22003 Bone morphogenetic protein 5 BMP5 P22004 Bone morphogenetic protein 6 BMP6 P22079 Lactoperoxidase LPO P22105 Tenascin-X TNXB P22301 Interleukin-10 IL10 P22303 Acetylcholinesterase ACHE P22352 Glutathione peroxidase 3 GPX3 P22362 C-C motif chemokine 1 CCL1 P22455 Fibroblast growth factor receptor 4 FGFR4 P22466 Galanin message-associated peptide GAL P22692 Insulin-like growth factor-binding protein 4 IGFBP4 P22749 Granulysin GNLY P22792 Carboxypeptidase N subunit 2 CPN2 P22891 Vitamin K-dependent protein Z PROZ P22894 Neutrophil collagenase MIVIP8 P23142 Fibulin-1 FBLN1 P23280 Carbonic anhydrase 6 CA6 P23352 Anosmin-1 KALI P23435 Cerebellin-1 CBLN1 P23560 Brain-derived neurotrophic factor BDNF P23582 C-type natriuretic peptide NPPC P23946 Chymase CMA1 P24043 Laminin subunit alpha-2 LAMA2 P24071 Immunoglobulin alpha Fc receptor FCAR P24347 Stromelysin-3 MMP11 P24387 Corticotropin-releasing factor-binding protein CRHBP P24592 Insulin-like growth factor-binding protein 6 IGFBP6 P24593 Insulin-like growth factor-binding protein 5 IGFBP5 P24821 Tenascin TNC P24855 Deoxyribonuclease-1 DNASE1 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P25067 Collagen alpha-2(VII 1) chain COL8A2 P25311 Zinc-alpha-2-glycoprotein AZGP1 P25391 Laminin subunit alpha-1 LAMA1 P25445 Tumor necrosis factor receptor superfamily member 6 FAS P25940 Collagen alpha-3(V) chain COL5A3 P25942 Tumor necrosis factor receptor superfamily member 5 CD40 P26022 Pentraxin-related protein PTX3 PTX3 P26927 Hepatocyte growth factor-like protein beta chain MST1 P27169 Serum paraoxonase / arylesterase 1 PON1 P27352 Gastric intrinsic factor GIF P27487 Dipeptidyl peptidase 4 membrane form DPP4 P27539 Embryonic growth / differentiation factor 1 GDF1 P27658 Vastatin COL8A1 P27797 Calreticulin CALR P27918 Properdin CFP P28039 Acyloxyacyl hydrolase AOAH P28300 Protein-lysine 6-oxidase LOX P28325 Cystatin-D CST5 P28799 Granulin-1 GRN P29122 Proprotein convertase subtilisin / kexin type 6 PCSK6 P29279 Connective tissue growth factor CTGF P29320 Ephrin type-A receptor 3 EPHA3 P29400 Collagen alpha-5(IV) chain COL4A5 P29459 Interleukin-12 subunit alpha IL12A P29460 Interleukin-12 subunit beta IL12B P29508 Serpin B3 SERPINB3 P29622 Kallistatin SERPINA4 P29965 CD40 ligand, soluble form CD40LG P30990 Neurotensin / neuromedin N NTS P31025 Lipocalin-1 LCN1 P31151 Protein S100-A7 S100A7 P31371 Fibroblast growth factor 9 FGF9 P31431 Syndecan-4 SDC4 P31947 14-3-3 protein sigma SFN P32455 Interferon-induced guanylate-binding protein 1 GBP1 P32881 Interferon alpha-8 IFNA8 P34096 Ribonuclease 4 RNASE4 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P34130 Neurotrophin-4 NTF4 P34820 Bone morphogenetic protein 8B BMP8B P35030 Trypsin-3 PRSS3 P35052 Secreted glypican-1 GPC1 P35070 Betacellulin BTC P35225 Interleukin-13 IL13 P35247 Pulmonary surfactant-associated protein D SFTPD P35318 ADM ADM P35542 Serum amyloid A-4 protein SAA4 P35555 Fibrillin-1 FBN1 P35556 Fibrillin-2 FBN2 P35625 Metalloproteinase inhibitor 3 TIMP3 P35858 Insulin-like growth factor-binding protein complex acid labile subunit IGFALS P35916 Vascular endothelial growth factor receptor 3 FLT4 P35968 Vascular endothelial growth factor receptor 2 KDR P36222 Chitinase-3-like protein 1 CHI3L1 P36952 Serpin B5 SERPINB5 P36955 Pigment epithelium-derived factor SERPINF1 P36980 Complement factor H-related protein 2 CFHR2 P39059 Collagen alpha-l(XV) chain COL15A1 P39060 Collagen alpha-l(XVIII) chain COL18A1 P39877 Calcium-dependent phospholipase A2 PLA2G5 P39900 Macrophage metalloelastase MMP12 P39905 Glial cell line-derived neurotrophic factor GDNF P40225 Thrombopoietin THPO P40967 M-alpha PMEL P41159 Leptin LEP P41221 Protein Wnt-5a WNT5A P41222 Prostaglandin-H2 D-isomerase PTGDS P41271 Neuroblastoma suppressor of tumorigenicity 1 NBL1 P41439 Folate receptor gamma FOLR3 P42127 Agouti-signaling protein ASIP P42702 Leukemia inhibitory factor receptor LIFR P42830 ENA-78(9-78) CXCL5 P43026 Growth / differentiation factor 5 GDF5 P43251 Biotinidase BTD P43652 Afamin AFM P45452 Collagenase 3 MMP13 P47710 Casoxin-D CSN1S1 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P47929 Galectin-7 LGALS7B P47972 Neuronal pentraxin-2 NPTX2 P47989 Xanthine oxidase XDH P47992 Lymphotactin XCL1 P48023 Tumor necrosis factor ligand superfamily member 6, membrane form FAS LG P48052 Carboxypeptidase A2 CPA2 P48061 Stromal cell-derived factor 1 CXCL12 P48304 Lithostathine-l-beta REGIB P48307 Tissue factor pathway inhibitor 2 TFPI2 P48357 Leptin receptor LEPR P48594 Serpin B4 SERPINB4 P48645 Neuromedin-U-25 NMU P48740 Mannan-binding lectin serine protease 1 MASP1 P48745 Protein NOV homolog NOV P48960 CD97 antigen subunit beta CD97 P49223 Kunitz-type protease inhibitor 3 SPINT3 P49747 Cartilage oligomeric matrix protein COMP P49763 Placenta growth factor PGF P49765 Vascular endothelial growth factor B VEGFB P49767 Vascular endothelial growth factor C VEGFC P49771 Fms-related tyrosine kinase 3 ligand FLT3LG P49862 Kallikrein-7 KLK7 P49863 Granzyme K GZMK P49908 Selenoprotein P SEPPI P49913 Antibacterial protein FALL-39 CAMP P50607 Tubby protein homolog TUB P51124 Granzyme M GZMM P51512 Matrix metalloproteinase-16 MMP16 P51654 Glypican-3 GPC3 P51671 Eotaxin CCL11 P51884 Lumican LUM P51888 Prolargin PRELP P52798 Ephrin-A4 EFNA4 P52823 Stanniocalcin-1 STC1 P53420 Collagen alpha-4(IV) chain COL4A4 P53621 Coatomer subunit alpha CO PA P54108 Cysteine-rich secretory protein 3 CRISP3 P54315 Pancreatic lipase-related protein 1 PNLIPRP1 P54317 Pancreatic lipase-related protein 2 PNLIPRP2 P54793 Arylsulfatase F ARSF 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P55000 Secreted Ly-6 / uPAR-related protein 1 SLURP1 P55001 Microfibrillar-associated protein 2 MFAP2 P55056 Apolipoprotein C-IV APOC4 P55058 Phospholipid transfer protein PLTP P55075 Fibroblast growth factor 8 FGF8 P55081 Microfibrillar-associated protein 1 MFAP1 P55083 Microfibril-associated glycoprotein 4 MFAP4 P55107 Bone morphogenetic protein 3B GDF10 P55145 Mesencephalic astrocyte-derived neurotrophic factor MANF P55259 Pancreatic secretory granule membrane major glycoprotein GP2 GP2 P55268 Laminin subunit beta-2 LAMB2 P55773 CCL23(30-99) CCL23 P55774 C-C motif chemokine 18 CCL18 P55789 FAD-linked sulfhydryl oxidase ALR GFER P56703 Proto-oncogene Wnt-3 WNT3 P56704 Protein Wnt-3a WNT3A P56705 Protein Wnt-4 WNT4 P56706 Protein Wnt-7b WNT7B P56730 Neurotrypsin PRSS12 P56851 Epididymal secretory protein E3-beta EDDM3B P56975 Neuregulin-3 NRG3 P58062 Serine protease inhibitor Kazal-type 7 SPINK7 P58215 Lysyl oxidase homolog 3 LOXL3 P58294 Prokineticin-1 PROK1 P58335 Anthrax toxin receptor 2 ANTXR2 P58397 A disintegrin and metalloproteinase with thrombospondin motifs 12 ADAMTS12 P58417 Neurexophilin-1 NXPH1 P58499 Protein FAM3B FAM3B P59510 A disintegrin and metalloproteinase with thrombospondin motifs 20 ADAMTS20 P59665 Neutrophil defensin 1 DEFA1B P59666 Neutrophil defensin 3 DEFA3 P59796 Glutathione peroxidase 6 GPX6 P59826 BPI fold-containing family B member 3 BPIFB3 P59827 BPI fold-containing family B member 4 BPIFB4 P59861 Beta-defensin 131 DEFB131 P60022 Beta-defensin 1 DEFBI P60153 Inactive ribonuclease-like protein 9 RNASE9 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P60827 Complement Clq tumor necrosis factor-related protein 8 C1Q.TNF8 P60852 Zona pellucida sperm-binding protein 1 ZP1 P60985 Keratinocyte differentiation-associated protein KRTDAP P61109 Kidney androgen-regulated protein KAP P61278 Somatostatin-14 SST P61366 Osteocrin OSTN P61626 Lysozyme C LYZ P61769 Beta-2-microglobulin B2M P61812 Transforming growth factor beta-2 TGFB2 P61916 Epididymal secretory protein El NPC2 P62502 Epididymal-specific 1 ipocalin-6 LCN6 P62937 Peptidyl-prolyl cis-trans isomerase A PPIA P67809 Nuclease-sensitive element-binding protein 1 YBX1 P67812 Signal peptidase complex catalytic subunit SEC11A SEC11A P78310 Coxsackievirus and adenovirus receptor CXADR P78333 Secreted glypican-5 GPC5 P78380 Oxidized low-density lipoprotein receptor 1 OLR1 P78423 Processed fractalkine CX3CL1 P78509 Reelin RELN P78556 CCL20(2-70) CCL20 P80075 MCP-2(6-76) CCL8 P80098 C-C motif chemokine 7 CCL7 P80108 Phosphatidylinositol-glycan-specific phospholipase D GPLD1 P80162 C-X-C motif chemokine 6 CXCL6 P80188 Neutrophil gelatinase-associated lipocalin LCN2 P80303 Nucleobindin-2 NUCB2 P80511 Calcitermin S100A12 P81172 Hepcidin-25 HAMP P81277 Prolactin-releasing peptide PRLH P81534 Beta-defensin 103 DEFB103A P81605 Dermcidin DCD P82279 Protein crumbs homolog 1 CRB1 P82987 ADAMTS-like protein 3 ADAMTSL3 P83105 Serine protease HTRA4 HTRA4 P83110 Serine protease HTRA3 HTRA3 P83859 Orexigenic neuropeptide Q.RFP Q.RFP P98088 Mucin-5AC MUC5AC 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name P98095 Fibulin-2 FBLN2 P98160 Basement membrane-specific heparan sulfate proteoglycan core protein HSPG2 P98173 Protein FAM3A FAM3A Q.00604 Norrin NDP Q00796 Sorbitol dehydrogenase SORD Q00887 Pregnancy-specific beta-l-glycoprotein 9 PSG9 Q00888 Pregnancy-specific beta-l-glycoprotein 4 PSG4 Q00889 Pregnancy-specific beta-l-glycoprotein 6 PSG6 Q01523 HD5(56-94) DEFA5 Q01524 Defensin-6 DEFA6 Q01955 Collagen alpha-3(IV) chain COL4A3 Q02297 Pro-neuregulin-1, membrane-bound isoform NRG1 Q02325 Plasminogen-like protein B PLGLB1 Q02383 Semenogelin-2 SEMG2 Q02388 Collagen alpha-l(VII) chain COL7A1 Q02505 Mucin-3A MUC3A Q02509 Otoconin-90 OC90 Q02747 Guanylin GUCA2A Q02763 Angiopoietin-1 receptor TEK Q02817 Mucin-2 MUC2 Q02985 Complement factor H-related protein 3 CFHR3 Q03167 Transforming growth factor beta receptor type 3 TGFBR3 Q03403 Trefoil factor 2 TFF2 Q03405 Urokinase plasminogen activator surface receptor PLAUR Q03591 Complement factor H-related protein 1 CFHR1 Q03692 Collagen alpha-l(X) chain COL10A1 Q04118 Basic salivary proline-rich protein 3 PRB3 Q04756 Hepatocyte growth factor activator short chain HGFAC Q04900 Sialomucin core protein 24 CD164 Q05315 Eosinophil lysophospholipase CLC Q05707 Collagen alpha-l(XIV) chain COL14A1 Q05996 Processed zona pellucida sperm-binding protein 2 ZP2 Q06033 Inter-alpha-trypsin inhibitor heavy chain H3 ITIH3 Q06141 Regenerating islet-derived protein 3-alpha REG3A Q06828 Fibromodulin FMOD Q07092 Collagen alpha-l(XVI) chain COL16A1 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.07325 C-X-C motif chemokine 9 CXCL9 Q07507 Dermatopontin DPT Q075Z2 Binder of sperm protein homolog 1 BSPH1 Q07654 Trefoil factor 3 TFF3 Q07699 Sodium channel subunit beta-1 SCN1B Q08345 Epithelial discoidin domain-containing receptor 1 DDR1 Q08380 Galectin-3-binding protein LGALS3BP Q08397 Lysyl oxidase homolog 1 L0XL1 Q08431 Lactadherin MFGE8 Q08629 Testican-1 SPOCK1 Q08648 Sperm-associated antigen 11B SPAG11B Q08830 Fibrinogen-like protein 1 FGL1 Q10471 Polypeptide N- acetylgalactosaminyltransferase 2 GALNT2 Q10472 Polypeptide N- acetylgalactosaminyltransferase 1 GALNT1 Q11201 CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 ST3GAL1 Q11203 CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase ST3GAL3 Q11206 CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 4 ST3GAL4 Q12794 Hyaluronidase-1 HYAL1 Q12805 EGF-containing fibulin-like extracellular matrix protein 1 EFEMP1 Q12836 Zona pellucida sperm-binding protein 4 ZP4 Q12841 Follistatin-related protein 1 FSTL1 Q12904 Aminoacyl tRNA synthase complexinteracting multifunctional protein 1 AIMP1 Q13018 Soluble secretory phospholipase A2 receptor PLA2R1 Q13072 B melanoma antigen 1 BAGE Q13093 Platelet-activating factor acetylhydrolase PLA2G7 Q13103 Secreted phosphoprotein 24 SPP2 Q13162 Peroxiredoxin-4 PRDX4 Q13201 Platelet glycoprotein la* MMRN1 Q13214 Semaphorin-3B SEMA3B Q13219 Pappalysin-1 PAPPA Q13231 Chitotriosidase-1 CHIT1 Q13253 Noggin NOG Q13261 Interleukin-15 receptor subunit alpha IL15RA Q13275 Semaphorin-3F SEMA3F 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.13291 Signaling lymphocytic activation molecule SLAMF1 Q.13316 Dentin matrix acidic phosphoprotein 1 DMP1 Q.13361 Microfibrillar-associated protein 5 MFAP5 Q.13410 Butyrophilin subfamily 1 member Al BTN1A1 Q13421 Mesothelin, cleaved form MSLN Q13429 Insulin-like growth factor 1 IGF-I 0.13443 Disintegrin and metalloproteinase domaincontaining protein 9 ADAM9 Q13519 Neuropeptide 1 PNOC Q13751 Laminin subunit beta-3 LAMB3 Q13753 Laminin subunit gamma-2 LAMC2 Q13790 Apolipoprotein F APOF Q13822 Ectonucleotide pyrophosphatase / phosphodiesterase family member 2 ENPP2 Q14031 Collagen alpha-6(IV) chain COL4A6 Q14050 Collagen alpha-3(IX) chain COL9A3 Q14055 Collagen alpha-2(IX) chain COL9A2 Q14112 Nidogen-2 NID2 Q14114 Low-density lipoprotein receptor-related protein 8 LRP8 Q14118 Dystroglycan DAG1 Q14314 Fibroleukin FGL2 Q14393 Growth arrest-specific protein 6 GAS6 0.14406 Chorionic somatomammotropin hormone-like 1 CSHL1 Q14507 Epididymal secretory protein E3-alpha EDDM3A Q14508 WAP four-disulfide core domain protein 2 WFDC2 Q14512 Fibroblast growth factor-binding protein 1 FGFBP1 Q14515 SPARC-like protein 1 SPARCL1 Q14520 Hyaluronan-binding protein 2 T1 kDa light chain HABP2 0.14563 Semaphorin-3A SEMA3A 0.14623 Indian hedgehog protein IHH 0.14624 Inter-alpha-trypsin inhibitor heavy chain H4 ITIH4 0.14667 UPF0378 protein KIAA0100 KIAA0100 Q14703 Membrane-bound transcription factor site-1 protease MBTPS1 0.14766 Latent-transforming growth factor betabinding protein 1 LTBP1 0.14767 Latent-transforming growth factor betabinding protein 2 LTBP2 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.14773 Intercellular adhesion molecule 4 ICAM4 0.14993 Collagen alpha-l(XIX) chain COL19A1 Q.14CN2 Calcium-activated chloride channel regulator 4, 110 kDa form CLCA4 0.15046 Lysine-tRNA ligase KARS 0.15063 Periostin POSTN Q15109 Advanced glycosylation end product-specific receptor AGER Q15113 Procollagen C-endopeptidase enhancer 1 PCOLCE Q.15166 Serum paraoxonase / lactonase 3 PON3 Q15195 Plasminogen-like protein A PLGLA Q15198 Platelet-derived growth factor receptor-like protein PDGFRL 0.15223 Poliovirus receptor-related protein 1 PVRL1 Q15238 Pregnancy-specific beta-l-glycoprotein 5 PSG5 0.15363 Transmembrane emp24 domain-containing protein 2 TMED2 Q15375 Ephrin type-A receptor 7 EPHA7 Q15389 Angiopoietin-1 ANGPT1 0.15465 Sonic hedgehog protein SHH Q15485 Ficolin-2 FCN2 Q15517 Corneodesmosin CDSN Q15582 Transforming growth factor-beta-induced protein ig-h3 TGFBI Q.15661 Tryptase alpha / beta-1 TPSAB1 0.15726 Metastin KISSI Q15782 Chitinase-3-like protein 2 CHI3L2 Q15828 Cystatin-M CST6 0.15846 Clusterin-like protein 1 CLUL1 Q15848 Adiponectin ADIPOQ. 0.16206 Protein disulfide-thiol oxidoreductase ENOX2 0.16270 Insulin-like growth factor-binding protein 7 IGFBP7 0.16363 Laminin subunit alpha-4 LAMA4 0.16378 Proline-rich protein 4 PRR4 0.16557 Pregnancy-specific beta-l-glycoprotein 3 PSG3 0.16568 CART(42-89) CARTPT Q.16610 Extracellular matrix protein 1 ECM1 Q.16619 Cardiotrophin-1 CTF1 0.16623 Syntaxin-IA STX1A 0.16627 HCC-l(9-74) CCL14 Q.16651 Prostasin light chain PRSS8 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.16661 Guanylate cyclase C-activating peptide 2 GUCA2B 0.16663 CCL15(29-92) CCL15 0.16674 Melanoma-derived growth regulatory protein MIA 0.16769 Glutaminyl-peptide cyclotransferase Q.PCT Q16787 Laminin subunit alpha-3 LAM A3 Q16842 CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 ST3GAL2 Q17RR3 Pancreatic lipase-related protein 3 PNLIPRP3 Q17RW2 Collagen alpha-l(XXIV) chain COL24A1 Q.17RY6 Lymphocyte antigen 6K LY6K Q1L6U9 Prostate-associated microseminoprotein MSMP Q1W4C9 Serine protease inhibitor Kazal-type 13 SPINK13 Q1ZYL8 Izumo sperm-egg fusion protein 4 IZUMO4 Q29960 HLA class 1 histocompatibility antigen, Cw-16 alpha chain HLA-C Q.2I0M5 R-spondin-4 RSPO4 Q2L4Q9 Serine protease 53 PRSS53 Q.2MKA7 R-spondin-1 RSPO1 Q.2MV58 Tectonic-1 TCTN1 Q2TAL6 Brorin VWC2 Q2UY09 Collagen alpha-l(XXVIII) chain COL28A1 Q2VPA4 Complement component receptor 1-like protein CR1L Q.2WEN9 Carcinoembryonic antigen-related cell adhesion molecule 16 CEACAM16 Q.30KP8 Beta-defensin 136 DEFB136 Q.30KP9 Beta-defensin 135 DEFB135 Q30KQ1 Beta-defensin 133 DEFB133 Q30KQ2 Beta-defensin 130 DEFB130 Q30KQ4 Beta-defensin 116 DEFB116 Q.30KQ.5 Beta-defensin 115 DEFB115 Q30KQ6 Beta-defensin 114 DEFB114 Q30KQ7 Beta-defensin 113 DEFB113 Q30KQ8 Beta-defensin 112 DEFB112 Q30KQ9 Beta-defensin 110 DEFB110 Q.30KR1 Beta-defensin 109 DEFB109P1 Q32P28 Prolyl 3-hydroxylase 1 LEPRE1 Q3B7J2 Glucose-fructose oxidoreductase domaincontaining protein 2 GFOD2 Q3SY79 Protein Wnt WNT3A Q3T906 N-acetylglucosamine-l-phosphotransferase subunits alpha / beta GNPTAB 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.495T6 Membrane metallo-endopeptidase-like 1 MMEL1 Q.49AH0 Cerebral dopamine neurotrophic factor CDNF Q.4G0G5 Secretoglobin family 2B member 2 SCGB2B2 Q.4G0M1 Protein FAM132B FAM132B Q.4LDE5 Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 SVEP1 Q.4Q.Y38 Beta-defensin 134 DEFB134 Q.4VAJ4 Protein Wnt WNT10B Q.4W5P6 Protein TMEM155 TMEM155 Q.4ZHG4 Fibronectin type III domain-containing protein 1 FNDC1 Q.53H76 Phospholipase Al member A PLA1A Q.53RD9 Fibulin-7 FBLN7 Q.53S33 BolA-like protein 3 BOLA3 Q.5BLP8 Neuropeptide-like protein C4orf48 C4orf48 Q.5DT21 Serine protease inhibitor Kazal-type 9 SPINK9 Q.5EBL8 PDZ domain-containing protein 11 PDZD11 Q.5FYB0 Arylsulfatase J ARSJ Q.5FYB1 Arylsulfatase 1 ARSI Q.5GAN3 Ribonuclease-like protein 13 RNASE13 Q.5GAN4 Ribonuclease-like protein 12 RNASE12 Q.5GAN6 Ribonuclease-like protein 10 RNASE10 Q.5GFL6 von Willebrand factor A domain-containing protein 2 VWA2 Q.5H8A3 Neuromedin-S NMS Q.5H8C1 FRASl-related extracellular matrix protein 1 FREM1 Q.5IJ48 Protein crumbs homolog 2 CRB2 Q.5J5C9 Beta-defensin 121 DEFB121 Q.5JS37 NHL repeat-containing protein 3 NHLRC3 Q.5JTB6 Placenta-specific protein 9 PLAC9 Q.5JU69 Torsin-2A TOR2A Q.5JXM2 Methyltransferase-like protein 24 METTL24 Q.5JZY3 Ephrin type-A receptor 10 EPHA10 Q.5K4E3 Polyserase-2 PRSS36 Q.5SRR4 Lymphocyte antigen 6 complex locus protein G5c LY6G5C Q.5T1H1 Protein eyes shut homolog EYS Q.5T4F7 Secreted frizzled-related protein 5 SFRP5 Q.5T4W7 Artemin ARTN Q.5T7M4 Protein FAM132A FAM132A Q.5TEH8 Protein Wnt WNT2B 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.5TIE3 von Willebrand factor A domain-containing protein 5B1 VWA5B1 Q.5UCC4 ER membrane protein complex subunit 10 EMC10 Q.5VST6 Abhydrolase domain-containing protein FAM108B1 FAM108B1 Q.5VTL7 Fibronectin type III domain-containing protein 7 FNDC7 Q.5VUM1 UPF0369 protein C6orf57 C6orf57 Q.5VV43 Dyslexia-associated protein KIAA0319 KIAA0319 Q.5VWW1 Complement Clq-like protein 3 C1Q.L3 Q.5VXI9 Lipase member N LIPN Q.5VXJ0 Lipase member K LIPK Q.5VXM1 CUB domain-containing protein 2 CDCP2 Q.5VYX0 Renalase RNLS Q.5VYY2 Lipase member M LIPM Q.5W186 Cystatin-9 CST9 Q.5W5W9 Regulated endocrine-specific protein 18 RESP18 Q.5XG92 Carboxylesterase 4A CES4A Q.63HQ.2 Pikachurin EGFLAM Q.641Q.3 Meteorin-like protein METRNL Q.66K79 Carboxypeptidase Z CPZ Q.685J3 Mucin-17 MUC17 Q.68BL7 Olfactomedin-like protein 2A OLFML2A Q.68BL8 Olfactomedin-like protein 2B OLFML2B Q.68DV7 E3 ubiquitin-protein ligase RNF43 RNF43 Q.6B9Z1 Insulin growth factor-like family member 4 IGFL4 Q.6BAA4 Fc receptor-like B FCRLB Q.6E0U4 Dermokine DMKN Q.6EMK4 Vasorin VASN Q.6FHJ7 Secreted frizzled-related protein 4 SFRP4 Q6GPI1 Chymotrypsin B2 chain B CTRB2 Q.6GTS8 Probable carboxypeptidase PM20D1 PM20D1 Q.6H9L7 lsthmin-2 ISM2 Q.6IE36 Ovostatin homolog 2 OVOS2 Q.6IE37 Ovostatin homolog 1 OVOS1 Q.6IE38 Serine protease inhibitor Kazal-type 14 SPINK14 Q.6ISS4 Leukocyte-associated immunoglobulin-like receptor 2 LAIR2 Q.6JVE5 Epididymal-specific 1 ipocalin-12 LCN12 Q.6JVE6 Epididymal-specific 1 ipocalin-10 LCN10 Q.6JVE9 Epididymal-specific 1 ipocalin-8 LCN8 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.6KF10 Growth / differentiation factor 6 GDF6 Q.6MZW2 Follistatin-related protein 4 FSTL4 Q.6NSX1 Coiled-coil domain-containing protein 70 CCDC70 Q.6NT32 Carboxylesterase 5A CES5A Q.6NT52 Choriogonadotropin subunit beta variant 2 CGB2 Q.6NUI6 Chondroadherin-like protein CHADL Q.6NUJ1 Saposin A-like PSAPL1 Q.6P093 Arylacetamide deacetylase-like 2 AADACL2 Q.6P4A8 Phospholipase B-like 1 PLBD1 Q.6P5S2 UPF0762 protein C6orf58 C6orf58 Q.6P988 Protein notum homolog NOTUM Q.6PCB0 von Willebrand factor A domain-containing protein 1 VWA1 Q.6PDA7 Sperm-associated antigen 11A SPAG11A Q.6PEW0 Inactive serine protease 54 PRSS54 Q.6PEZ8 Podocan-like protein 1 PODNL1 Q.6PKH6 Dehydrogenase / reductase SDR family member 4-like 2 DHRS4L2 Q.6Q.788 Apolipoprotein A-V APOA5 Q.6SPF0 Atherin SAMD1 Q.6UDR6 Kunitz-type protease inhibitor 4 SPINT4 Q.6URK8 Testis, prostate and placenta-expressed protein TEPP Q.6UW01 Cerebellin-3 CBLN3 Q.6UW10 Surfactant-associated protein 2 SFTA2 Q.6UW15 Regenerating islet-derived protein 3-gamma REG3G Q.6UW32 Insulin growth factor-like family member 1 IGFL1 Q.6UW78 UPF0723 protein Cllorf83 Cllorf83 Q.6UW88 Epigen EPGN Q.6UWE3 Colipase-like protein 2 CLPSL2 Q.6UWF7 NXPE family member 4 NXPE4 Q.6UWF9 Protein FAM180A FAM180A Q.6UWM5 GLIPRl-like protein 1 GLIPR1L1 Q.6UWN8 Serine protease inhibitor Kazal-type 6 SPINK6 Q.6UWP2 Dehydrogenase / reductase SDR family member 11 DHRS11 Q.6UWP8 Suprabasin SBSN Q.6UWQ.5 Lysozyme-like protein 1 LYZL1 Q.6UWQ.7 Insulin growth factor-like family member 2 IGFL2 Q.6UWR7 Ectonucleotide pyrophosphatase / phosphodiesterase family member 6 soluble form ENPP6 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q6UWT2 Adropin ENHO Q6UWU2 Beta-galactosidase-l-like protein GLB1L Q6UWW0 Lipocalin-15 LCN15 Q6UWX4 HHIP-like protein 2 HHIPL2 Q6UWY0 Arylsulfatase K ARSK Q6UWY2 Serine protease 57 PRSS57 Q6UWY5 Olfactomedin-like protein 1 OLFML1 Q6UX06 Olfactomedin-4 OLFM4 Q6UX07 Dehydrogenase / reductase SDR family member 13 DHRS13 Q6UX39 Amelotin AMTN Q6UX46 Protein FAM150B FAM150B Q6UX73 UPF0764 protein C16orf89 C16orf89 Q6UXB0 Protein FAM131A FAM131A Q6UXB1 Insulin growth factor-like family member 3 IGFL3 Q6UXB2 VEGF co-regulated chemokine 1 CXCL17 Q6UXF7 C-type lectin domain family 18 member B CLEC18B Q6UXH0 Hepatocellular carcinoma-associated protein TD26 C19orf80 Q6UXH1 Cysteine-rich with EGF-like domain protein 2 CRELD2 Q6UXH8 Collagen and calcium-binding EGF domaincontaining protein 1 CCBE1 Q6UXH9 Inactive serine protease PAM RI PAMR1 Q6UXI7 Vitrin VIT Q6UXI9 Nephronectin NPNT Q6UXN2 Trem-like transcript 4 protein TREML4 Q6UXS0 C-type lectin domain family 19 member A CLEC19A Q6UXT8 Protein FAM150A FAM150A Q6UXT9 Abhydrolase domain-containing protein 15 ABHD15 Q6UXV4 Apolipoprotein O-like APOOL Q6UXX5 Inter-alpha-trypsin inhibitor heavy chain H6 ITIH6 Q6UXX9 R-spondin-2 RSPO2 Q6UY14 ADAMTS-like protein 4 ADAMTSL4 Q6UY27 Prostate and testis expressed protein 2 PATE2 Q.6W4X9 Mucin-6 MUC6 Q6WN34 Chordin-like protein 2 CHRDL2 Q6WRI0 Immunoglobulin superfamily member 10 IGSF10 Q6X4U4 Sclerostin domain-containing protein 1 SOSTDC1 Q.6X784 Zona pellucida-binding protein 2 ZPBP2 Q6XE38 Secretoglobin family ID member 4 SCGB1D4 Q6XPR3 Repetin RPTN 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q6XZB0 Lipase member 1 LIPI Q6ZMM2 ADAMTS-like protein 5 ADAMTSL5 Q6ZMP0 Thrombospondin type-1 domain-containing protein 4 THSD4 Q6ZNF0 Iron / zinc purple acid phosphatase-like protein PAPL Q6ZRI0 Otogelin OTOG Q6ZRP7 Sulfhydryl oxidase 2 QSOX2 Q6ZWJ8 Kielin / chordin-like protein KCP Q75N90 Fibrillin-3 FBN3 Q765I0 Urotensin-2B UTS2D Q76B58 Protein FAM5C FAM5C Q76LX8 A disintegrin and metalloproteinase with thrombospondin motifs 13 ADAMTS13 Q76M96 Coiled-coil domain-containing protein 80 CCDC80 Q7L1S5 Carbohydrate sulfotransferase 9 CHST9 Q7L513 Fc receptor-like A FCRLA Q7L8A9 Vasohibin-1 VAS Hl Q7RTM1 Otopetrin-1 OTO Pl Q7RTW8 Otoancorin OTOA Q7RTY5 Serine protease 48 PRSS48 Q7RTY7 Ovochymase-1 OVCH1 Q7RTZ1 Ovochymase-2 OVCH2 Q7Z304 MAM domain-containing protein 2 MAMDC2 Q7Z3S9 Notch homolog 2 N-terminal-like protein NOTCH2NL Q7Z4H4 Intermedin-short ADM2 Q7Z4P5 Growth / differentiation factor 7 GDF7 Q7Z4R8 UPF0669 protein C6orfl20 C6orfl20 Q7Z4W2 Lysozyme-like protein 2 LYZL2 Q7Z5A4 Serine protease 42 PRSS42 Q7Z5A7 Protein FAM19A5 FAM19A5 Q7Z5A8 Protein FAM19A3 FAM19A3 Q7Z5A9 Protein FAM19A1 FAM19A1 Q7Z5J1 Hydroxysteroid 11-beta-dehydrogenase 1-like protein HSD11B1L Q7Z5L0 Vitelline membrane outer layer protein 1 homolog VMO1 Q7Z5L3 Complement Clq-like protein 2 C1QL2 Q7Z5L7 Podocan PGDN Q7Z5P4 17-beta-hydroxysteroid dehydrogenase 13 HSD17B13 Q7Z5P9 Mucin-19 MUC19 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.7Z5Y6 Bone morphogenetic protein 8A BMP8A Q.7Z7B7 Beta-defensin 132 DEFB132 Q.7Z7B8 Beta-defensin 128 DEFB128 Q.7Z7C8 Transcription initiation factor TFIID subunit 8 TAF8 Q.7Z7H5 Transmembrane emp24 domain-containing protein 4 TMED4 Q.86SG7 Lysozyme g-like protein 2 LYG2 Q.86SI9 Protein CEI C5orf38 Q.86TE4 Leucine zipper protein 2 LUZP2 Q.86TH1 ADAMTS-like protein 2 ADAMTSL2 Q.86U17 Serpin All SERPINA11 Q.86UU9 Endokinin-A TAC4 Q.86UW8 Hyaluronan and proteoglycan link protein 4 HAPLN4 Q.86UX2 Inter-alpha-trypsin inhibitor heavy chain H5 ITIH5 Q.86V24 Adiponectin receptor protein 2 ADIPOR2 Q.86VB7 Soluble CD163 CD163 Q.86VR8 Four-jointed box protein 1 FJX1 Q.86WD7 Serpin A9 SERPINA9 Q.86WN2 Interferon epsilon IFNE Q.86WS3 Placenta-specific 1-1 ike protein PLAC1L Q.86X52 Chondroitin sulfate synthase 1 CHSY1 Q86XP6 Gastrokine-2 GKN2 Q86XS5 Angiopoietin-related protein 5 ANGPTL5 Q86Y27 B melanoma antigen 5 BAGE5 Q86Y28 B melanoma antigen 4 BAGE4 Q86Y29 B melanoma antigen 3 BAGE3 Q86Y30 B melanoma antigen 2 BAGE2 Q86Y38 Xylosyltransferase 1 XYLT1 Q86Y78 Ly6 / PLAUR domain-containing protein 6 LYPD6 Q86YD3 Transmembrane protein 25 TMEM25 Q86YJ6 Threonine synthase-like 2 THNSL2 Q86YW7 Glycoprotein hormone beta-5 GPHB5 Q86Z23 Complement Clq-like protein 4 C1Q.L4 Q8IU57 Interleukin-28 receptor subunit alpha IL28RA Q8IUA0 WAP four-disulfide core domain protein 8 WFDC8 Q8IUB2 WAP four-disulfide core domain protein 3 WFDC3 Q8IUB3 Protein WFDC10B WFDC10B Q8IUB5 WAP four-disulfide core domain protein 13 WFDC13 Q8IUH2 Protein CREG2 CREG2 Q8IUK5 Plexin domain-containing protein 1 PLXDC1 Q8IUL8 Cartilage intermediate layer protein 2 C2 CILP2 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.8IUX7 Adipocyte enhancer-binding protein 1 AEBP1 Q.8IUX8 Epidermal growth factor-like protein 6 EGFL6 Q.8IVL8 Carboxypeptidase O CPO Q.8IVN8 Somatomedin-B and thrombospondin type-1 domain-containing protein SBSPON Q.8IVW8 Protein spinster homolog 2 SPNS2 Q.8IW75 Serpin A12 SERPINA12 Q.8IW92 Beta-galactosidase-l-like protein 2 GLB1L2 Q8IWL1 Pulmonary surfactant-associated protein A2 SFTPA2 Q.8IWL2 Pulmonary surfactant-associated protein Al SFTPA1 Q.8IWV2 Contactin-4 CNTN4 Q.8IWY4 Signal peptide, CUB and EGF-like domaincontaining protein 1 SCUBE1 Q.8IX30 Signal peptide, CUB and EGF-like domaincontaining protein 3 SCUBE3 Q.8IXA5 Sperm acrosome membrane-associated protein 3, membrane form SPACA3 Q.8IXB1 DnaJ homolog subfamily C member 10 DNAJC10 Q.8IXL6 Extracellular serine / threonine protein kinase Fam20C FAM20C Q.8IYD9 Lung adenoma susceptibility protein 2 LAS2 Q.8IYP2 Serine protease 58 PRSS58 Q.8IYS5 Osteoclast-associated immunoglobulin-like receptor OSCAR Q.8IZC6 Collagen alpha-l(XXVII) chain COL27A1 Q.8IZJ3 C3 and PZP-like alpha-2-macroglobulin domain-containing protein 8 CPAMD8 Q.8IZN7 Beta-defensin 107 DEFB107B Q.8N0V4 Leucine-rich repeat LGI family member 2 LGI2 Q.8N104 Beta-defensin 106 DEFB106B Q8N119 Matrix metalloproteinase-21 MMP21 Q.8N129 Protein canopy homolog 4 CNPY4 Q.8N135 Leucine-rich repeat LGI family member 4 LG 14 Q.8N145 Leucine-rich repeat LGI family member 3 LGI3 Q.8N158 Glypican-2 GPC2 Q.8N1E2 Lysozyme g-like protein 1 LYG1 Q.8N2E2 von Willebrand factor D and EGF domaincontaining protein VWDE Q.8N2E6 Prosalusin TOR2A Q.8N2S1 Latent-transforming growth factor betabinding protein 4 LTBP4 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.8N302 Angiogenic factor with G patch and FHA domains 1 AGGF1 Q.8N307 Mucin-20 MUC20 Q.8N323 NXPE family member 1 NXPE1 Q.8N387 Mucin-15 MUC15 Q.8N3Z0 Inactive serine protease 35 PRSS35 Q.8N436 Inactive carboxypeptidase-like protein X2 CPXM2 Q.8N474 Secreted frizzled-related protein 1 SFRP1 Q.8N475 Follistatin-related protein 5 FSTL5 Q.8N4F0 BPI fold-containing family B member 2 BPIFB2 Q.8N4T0 Carboxypeptidase A6 CPA6 Q.8N5W8 Protein FAM24B FAM24B Q.8N687 Beta-defensin 125 DEFB125 Q.8N688 Beta-defensin 123 DEFB123 Q.8N690 Beta-defensin 119 DEFB119 Q.8N6C5 Immunoglobulin superfamily member 1 IGSF1 Q.8N6C8 Leukocyte immunoglobulin-like receptor subfamily A member 3 LILRA3 Q.8N6G6 ADAMTS-like protein 1 ADAMTSL1 Q.8N6Y2 Leucine-rich repeat-containing protein 17 LRRC17 Q.8N729 Neuropeptide W-23 NPW Q.8N8U9 BMP-binding endothelial regulator protein BMPER Q.8N907 DAN domain family member 5 DAND5 Q.8NAT1 Glycosyltransferase-like domain-containing protein 2 GTDC2 Q.8NAU1 Fibronectin type III domain-containing protein 5 FNDC5 Q.8NB37 Parkinson disease 7 domain-containing protein 1 PDDC1 Q.8NBI3 Draxin DRAXIN Q.8NBM8 Prenylcysteine oxidase-like PCYOX1L Q.8NBP7 Proprotein convertase subtilisin / kexin type 9 PCSK9 Q.8NBQ.5 Estradiol 17-beta-dehydrogenase 11 HSD17B11 Q.8NBV8 Synaptotagmin-8 SYT8 Q.8NCC3 Group XV phospholipase A2 PLA2G15 Q.8NCF0 C-type lectin domain family 18 member C CLEC18C Q.8NCW5 NAD(P)H-hydrate epimerase APOA1BP Q.8NDA2 Hemicentin-2 HMCN2 Q.8NDX9 Lymphocyte antigen 6 complex locus protein G5b LY6G5B Q.8NDZ4 Deleted in autism protein 1 C3orf58 Q.8NEB7 Acrosin-binding protein ACRBP 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.8NES8 Beta-defensin 124 DEFB124 Q.8NET1 Beta-defensin 108B DEFB108B Q.8NEX5 Protein WFDC9 WFDC9 Q.8NEX6 Protein WFDC11 WFDC11 Q.8NF86 Serine protease 33 PRSS33 Q.8NFM7 Interleukin-17 receptor D IL17RD Q.8NFQ.5 BPI fold-containing family B member 6 BPIFB6 Q.8NFQ.6 BPI fold-containing family C protein BPIFC Q.8NFU4 Follicular dendritic cell secreted peptide FDCSP Q.8NFW1 Collagen alpha-l(XXII) chain COL22A1 Q.8NG35 Beta-defensin 105 DEFB105B Q.8NG41 Neuropeptide B-23 NPB Q.8NHW6 Otospiralin OTOS Q.8NI99 Angiopoietin-related protein 6 ANGPTL6 Q.8TAA1 Probable ribonuclease 11 RNASE11 Q.8TAG5 V-set and transmembrane domain-containing protein 2A VSTM2A Q.8TAL6 Fin bud initiation factor homolog FIBIN Q.8TAT2 Fibroblast growth factor-binding protein 3 FGFBP3 Q.8TAX7 Mucin-7 MUC7 Q.8TB22 Spermatogenesis-associated protein 20 SPATA20 Q.8TB73 Protein NDNF NDNF Q.8TB96 T-cell immunomodulatory protein ITFG1 Q.8TC92 Protein disulfide-thiol oxidoreductase ENOXI Q.8TCV5 WAP four-disulfide core domain protein 5 WFDC5 Q.8TD06 Anterior gradient protein 3 homolog AGR3 Q.8TD33 Secretoglobin family IC member 1 SCGB1C1 Q.8TD46 Cell surface glycoprotein CD200 receptor 1 CD200R1 Q.8TDE3 Ribonuclease 8 RNASE8 Q.8TDF5 Neuropilin and tolloid-like protein 1 NETO1 Q.8TDL5 BPI fold-containing family B member 1 BPIFB1 Q.8TE56 A disintegrin and metalloproteinase with thrombospondin motifs 17 ADAMTS17 Q.8TE57 A disintegrin and metalloproteinase with thrombospondin motifs 16 ADAMTS16 Q.8TE58 A disintegrin and metalloproteinase with thrombospondin motifs 15 ADAMTS15 Q.8TE59 A disintegrin and metalloproteinase with thrombospondin motifs 19 ADAMTS19 Q.8TE60 A disintegrin and metalloproteinase with thrombospondin motifs 18 ADAMTS18 Q.8TE99 Acid phosphatase-like protein 2 ACPL2 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.8TER0 Sushi, nidogen and EGF-like domaincontaining protein 1 SNED1 Q.8TEU8 WAP, kazal, immunoglobulin, kunitz and NTR domain-containing protein 2 WFIKKN2 Q.8WTQ.1 Beta-defensin 104 DEFB104B Q.8WTR8 Netrin-5 NTN5 Q.8WTU2 Scavenger receptor cysteine-rich domaincontaining group B protein SRCRB4D Q.8WU66 Protein TSPEAR TSPEAR Q.8WUA8 Tsukushin TSKU Q.8WUF8 Protein FAM172A FAM172A Q.8WUJ1 Neuferricin CYB5D2 Q.8WUY1 UPF0670 protein THEM6 THEM6 Q.8WVN6 Secreted and transmembrane protein 1 SECTM1 Q.8WVQ.1 Soluble calcium-activated nucleotidase 1 CANT1 Q.8WWA0 lntelectin-1 ITLN1 Q.8WWG1 Neuregulin-4 NRG4 Q.8WWQ.2 Inactive heparanase-2 HPSE2 Q.8WWU7 lntelectin-2 ITLN2 Q.8WWY7 WAP four-disulfide core domain protein 12 WFDC12 Q.8WWY8 Lipase member H LIPH Q.8WWZ8 Oncoprotein-induced transcript 3 protein OIT3 Q.8WX39 Epididymal-specific 1 ipocalin-9 LCN9 Q.8WXA2 Prostate and testis expressed protein 1 PATE1 Q.8WXD2 Secretogranin-3 SCG3 Q.8WXF3 Relaxin-3 A chain RLN3 Q.8WXI7 Mucin-16 MUC16 Q.8WXQ.8 Carboxypeptidase A5 CPA5 Q.8WXS8 A disintegrin and metalloproteinase with thrombospondin motifs 14 ADAMTS14 Q.92484 Acid sphingomyelinase-like phosphodiesterase 3a SMPDL3A Q.92485 Acid sphingomyelinase-like phosphodiesterase 3b SMPDL3B Q.92496 Complement factor H-related protein 4 CFHR4 Q.92520 Protein FAM3C FAM3C 0.92563 Testican-2 SPOCK2 Q92583 C-C motif chemokine 17 CCL17 Q92626 Peroxidasin homolog PXDN Q92743 Serine protease HTRA1 HTRA1 Q92752 Tenascin-R TNR Q92765 Secreted frizzled-related protein 3 FRZB 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.92819 Hyaluronan synthase 2 HAS2 Q92820 Gamma-glutamyl hydrolase GGH Q92824 Proprotein convertase subtilisin / kexin type 5 PCSK5 Q92832 Protein kinase C-binding protein NELLI NELLI Q92838 Ectodysplasin-A, membrane form EDA Q92874 Deoxyribonuclease-l-like 2 DNASE1L2 Q92876 Kallikrein-6 KLK6 Q92913 Fibroblast growth factor 13 FGF13 Q92954 Proteoglycan 4 C-terminal part PRG4 Q93038 Tumor necrosis factor receptor superfamily member 25 TNFRSF25 Q93091 Ribonuclease K6 RNASE6 Q93097 Protein Wnt-2b WNT2B Q93098 Protein Wnt-8b WNT8B Q95460 Major histocompatibility complex class 1-related gene protein MR1 Q969D9 Thymic stromal lymphopoietin TSLP Q969E1 Liver-expressed antimicrobial peptide 2 LEAP2 Q969H8 UPF0556 protein C19orfl0 C19orfl0 Q969Y0 NXPE family member 3 NXPE3 Q96A54 Adiponectin receptor protein 1 ADIPORI Q96A83 Collagen alpha-l(XXVI) chain EMID2 Q96A84 EMI domain-containing protein 1 EMIDI Q96A98 Tuberoinfundibular peptide of 39 residues PTH2 Q96A99 Pentraxin-4 PTX4 Q96BH3 Epididymal sperm-binding protein 1 ELSPBP1 Q96BQ1 Protein FAM3D FAM3D Q96CG8 Collagen triple helix repeat-containing protein 1 CTHRC1 Q96DA0 Zymogen granule protein 16 homolog B ZG16B Q96DN2 von Willebrand factor C and EGF domaincontaining protein VWCE Q96DR5 BPI fold-containing family A member 2 BPIFA2 Q96DR8 Mucin-like protein 1 MUCL1 Q96DX4 RING finger and SPRY domain-containing protein 1 RSPRY1 Q96EE4 Coiled-coil domain-containing protein 126 CCDC126 Q96GS6 Abhydrolase domain-containing protein FAM 108 Al FAM108A1 Q96GW7 Brevican core protein BCAN Q96HF1 Secreted frizzled-related protein 2 SFRP2 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.96I82 Kazal-type serine protease inhibitor domaincontaining protein 1 KAZALD1 Q.96ID5 Immunoglobulin superfamily member 21 IGSF21 Q.96II8 Leucine-rich repeat and calponin homology domain-containing protein 3 LRCH3 Q.96IY4 Carboxypeptidase B2 CPB2 Q.96JB6 Lysyl oxidase homolog 4 LOXL4 Q.96JK4 HHIP-like protein 1 HHIPL1 Q.96KN2 Beta-Ala-His dipeptidase CNDP1 Q.96KW9 Protein SPACA7 SPACA7 Q.96KX0 Lysozyme-like protein 4 LYZL4 Q.96L15 Ecto-ADP-ribosyltransferase 5 ART5 Q.96LB8 Peptidoglycan recognition protein 4 PGLYRP4 Q.96LB9 Peptidoglycan recognition protein 3 PGLYRP3 Q.96LC7 Sialic acid-binding Ig-like lectin 10 SIGLEC10 Q.96LR4 Protein FAM19A4 FAM19A4 Q.96MK3 Protein FAM20A FAM20A Q.96MS3 Glycosyltransferase 1 domain-containing protein 1 GLT1D1 Q.96NY8 Processed poliovirus receptor-related protein 4 PVRL4 Q.96NZ8 WAP, kazal, immunoglobulin, kunitz and NTR domain-containing protein 1 WFIKKN1 Q.96NZ9 Proline-rich acidic protein 1 PRAP1 Q.96P44 Collagen alpha-l(XXI) chain COL21A1 Q.96PB7 Noelin-3 OLFM3 Q.96PC5 Melanoma inhibitory activity protein 2 MIA2 Q.96PD5 N-acetylmuramoyl-L-alanine amidase PGLYRP2 Q.96PH6 Beta-defensin 118 DEFB118 Q.96PL1 Secretoglobin family 3A member 2 SCGB3A2 Q.96PL2 Beta-tectorin TECTB Q.96Q.H8 Sperm acrosome-associated protein 5 SPACA5 Q.96Q.R1 Secretoglobin family 3A member 1 SCGB3A1 Q.96Q.U1 Protocadherin-15 PCDH15 Q.96Q.V1 Hedgehog-interacting protein HHIP Q.96RW7 Hemicentin-1 HMCN1 Q.96S42 Nodal homolog NODAL Q.96S86 Hyaluronan and proteoglycan link protein 3 HAPLN3 Q.96SL4 Glutathione peroxidase 7 GPX7 Q.96SM3 Probable carboxypeptidase XI CPXM1 Q.96T91 Glycoprotein hormone alpha-2 GPHA2 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.99062 Granulocyte colony-stimulating factor receptor CSF3R Q99102 Mucin-4 alpha chain MUC4 0.99217 Amelogenin, X isoform AMELX Q99218 Amelogenin, Y isoform AMELY Q99435 Protein kinase C-binding protein NELL2 NELL2 Q99470 Stromal cell-derived factor 2 SDF2 Q99542 Matrix metalloproteinase-19 MMP19 Q99574 Neuroserpin SERPINI1 Q99584 Protein S100-A13 S100A13 Q99616 C-C motif chemokine 13 CCL13 Q99645 Epiphycan EPYC Q99674 Cell growth regulator with EF hand domain protein 1 CGREF1 Q99715 Collagen alpha-l(XII) chain COL12A1 Q99727 Metalloproteinase inhibitor 4 TIMP4 Q99731 C-C motif chemokine 19 CCL19 Q99748 Neurturin NRTN Q99935 Proline-rich protein 1 PR0L1 Q99942 E3 ubiquitin-protein ligase RNF5 RNF5 Q99944 Epidermal growth factor-like protein 8 EGFL8 Q99954 Submaxillary gland androgen-regulated protein 3A SMR3A Q99969 Retinoic acid receptor responder protein 2 RARRES2 Q99972 Myocilin MYOC Q99983 Osteomodulin OMD Q99985 Semaphorin-3C SEMA3C Q99988 Growth / differentiation factor 15 GDF15 Q9BPW4 Apolipoprotein L4 APOL4 Q9BQ08 Resistin-like beta RETNLB Q9BQ16 Testican-3 SPOCK3 Q9BQ51 Programmed cell death 1 ligand 2 PDCD1LG2 Q9BQB4 Sclerostin SOST Q9BQI4 Coiled-coil domain-containing protein 3 CCDC3 Q9BQP9 BPI fold-containing family A member 3 BPIFA3 Q9BQR3 Serine protease T1 PRSS27 Q9BQY6 WAP four-disulfide core domain protein 6 WFDC6 Q9BRR6 ADP-dependent glucokinase ADPGK Q9BS86 Zona pellucida-binding protein 1 ZPBP Q9BSG0 Protease-associated domain-containing protein 1 PRADC1 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q9BSG5 Retbindin RTBDN Q9BT30 Probable alpha-ketoglutarate-dependent dioxygenase ABH7 ALKBH7 Q9BT56 Spexin C12orf39 Q9BT67 NEDD4 family-interacting protein 1 NDFIP1 Q9BTY2 Plasma alpha-L-fucosidase FUCA2 Q9BU40 Chordin-like protein 1 CHRDL1 Q9BUD6 Spondin-2 SPON2 Q9BUN1 Protein MENT MENT Q9BUR5 Apolipoprotein O APOO Q9BV94 ER degradation-enhancing alpha-mannosidase-like 2 EDEM2 Q9BWP8 Collectin-11 COLEC11 Q9BWS9 Chitinase domain-containing protein 1 CHID1 Q9BX67 Junctional adhesion molecule C JAM3 Q9BX93 Group XIIB secretory phospholipase A2-Iike protein PLA2G12B Q9BXI9 Complement Clq tumor necrosis factor-related protein 6 C1QTNF6 Q9BXJ0 Complement Clq tumor necrosis factor-related protein 5 C1QTNF5 Q9BXJ1 Complement Clq tumor necrosis factor-related protein 1 C1QTNF1 Q9BXJ2 Complement Clq tumor necrosis factor-related protein 7 C1QTNF7 Q9BXJ3 Complement Clq tumor necrosis factor-related protein 4 C1QTNF4 Q9BXJ4 Complement Clq tumor necrosis factor-related protein 3 C1QTNF3 Q9BXJ5 Complement Clq tumor necrosis factor-related protein 2 C1QTNF2 Q9BXN1 Asporin ASPN Q9BXP8 Pappalysin-2 PAPPA2 Q9BXR6 Complement factor H-related protein 5 CFHR5 Q9BXS0 Collagen alpha-l(XXV) chain COL25A1 Q9BXX0 EMILIN-2 EMILIN2 Q9BXY4 R-spondin-3 RSPO3 Q9BY15 EGF-like module-containing mucin-like hormone receptor-like 3 subunit beta EMR3 Q9BY50 Signal peptidase complex catalytic subunit SEC11C SEC11C Q9BY76 Angiopoietin-related protein 4 ANGPTL4 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.9BYF1 Processed angiotensin-converting enzyme 2 ACE2 Q.9BYJ0 Fibroblast growth factor-binding protein 2 FGFBP2 Q.9BYW3 Beta-defensin 126 DEFB126 Q.9BYX4 Interferon-induced helicase C domaincontaining protein 1 IFIH1 Q.9BYZ8 Regenerating islet-derived protein 4 REG4 Q.9BZ76 Contactin-associated protein-like 3 CNTNAP3 Q.9BZG9 Ly-6 / neurotoxin-like protein 1 LYNX1 Q.9BZJ3 Tryptase delta TPSD1 Q.9BZM1 Group XIIA secretory phospholipase A2 PLA2G12A Q.9BZM2 Group HF secretory phospholipase A2 PLA2G2F Q.9BZM5 NKG2D ligand 2 ULBP2 Q.9BZP6 Acidic mammalian chitinase CHIA Q.9BZZ2 Sialoadhesin SIGLEC1 Q.9C0B6 Protein FAM5B FAM5B Q.9GZM7 Tubulointerstitial nephritis antigen-like TINAGL1 Q.9GZN4 Brain-specific serine protease 4 PRSS22 Q.9GZP0 Platelet-derived growth factor D, receptorbinding form PDGFD Q.9GZT5 Protein Wnt-lOa WNT10A Q.9GZU5 Nyctalopin NYX Q.9GZV7 Hyaluronan and proteoglycan link protein 2 HAPLN2 Q.9GZV9 Fibroblast growth factor 23 FGF23 Q.9GZX9 Twisted gastrulation protein homolog 1 TWSG1 Q.9GZZ7 GDNF family receptor alpha-4 GFRA4 Q.9GZZ8 Extracellular glycoprotein lacritin LACRT Q.9H0B8 Cysteine-rich secretory protein LCCL domaincontaining 2 CRISPLD2 Q.9H106 Signal-regulatory protein delta SIRPD Q9H114 Cystatin-like 1 CSTL1 Q.9H173 Nucleotide exchange factor SIL1 SIL1 Q9H1E1 Ribonuclease 7 RNASE7 Q.9H1F0 WAP four-disulfide core domain protein 10A WFDC10A Q.9H1J5 Protein Wnt-8a WNT8A Q.9H1J7 Protein Wnt-5b WNT5B Q.9H1M3 Beta-defensin 129 DEFB129 Q.9H1M4 Beta-defensin 127 DEFB127 Q.9H1Z8 Augurin C2orf40 Q.9H239 Matrix metalloproteinase-28 MMP28 Q.9H2A7 C-X-C motif chemokine 16 CXCL16 Q.9H2A9 Carbohydrate sulfotransferase 8 CHST8 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.9H2R5 Kallikrein-15 KLK15 Q.9H2X0 Chordin CHRD Q.9H2X3 C-type lectin domain family 4 member M CLEC4M Q.9H306 Matrix metalloproteinase-27 MMP27 Q.9H324 A disintegrin and metalloproteinase with thrombospondin motifs 10 ADAMTS10 Q.9H336 Cysteine-rich secretory protein LCCL domaincontaining 1 CRISPLD1 Q.9H3E2 Sorting nexin-25 SNX25 Q.9H3R2 Mucin-13 MUC13 Q.9H3U7 SPARC-related modular calcium-binding protein 2 SMOC2 Q.9H3Y0 Peptidase inhibitor R3HDML R3HDML Q.9H4A4 Aminopeptidase B RNPEP Q.9H4F8 SPARC-related modular calcium-binding protein 1 SMOC1 Q.9H4G1 Cystatin-9-like CST9L Q.9H5V8 CUB domain-containing protein 1 CDCP1 Q.9H6B9 Epoxide hydrolase 3 EPHX3 Q.9H6E4 Coiled-coil domain-containing protein 134 CCDC134 Q.9H741 UPF0454 protein C12orf49 C12orf49 Q.9H772 Gremlin-2 GREM2 Q.9H7Y0 Deleted in autism-related protein 1 CXorf36 Q.9H8L6 Multimerin-2 MMRN2 Q.9H9S5 Fukutin-related protein FKRP Q.9HAT2 Sialate O-acetylesterase SIAE Q.9HB40 Retinoid-inducible serine carboxypeptidase SCPEP1 Q.9HB63 Netrin-4 NTN4 Q.9HBJ0 Placenta-specific protein 1 PLAC1 Q.9HC23 Prokineticin-2 PROK2 Q.9HC57 WAP four-disulfide core domain protein 1 WFDC1 Q.9HC73 Cytokine receptor-like factor 2 CRLF2 Q.9HC84 Mucin-5B MUC5B Q.9HCB6 Spondin-1 SPON1 Q.9HCQ.7 Neuropeptide NPSF NPVF Q.9HCT0 Fibroblast growth factor 22 FGF22 Q.9HD89 Resistin RETN Q.9NNX1 Tuftelin TUFT1 Q.9NNX6 CD209 antigen CD209 Q.9NP55 BPI fold-containing family A member 1 BPIFA1 Q.9NP70 Ameloblastin AMBN 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.9NP95 Fibroblast growth factor 20 FGF20 Q.9NP99 Triggering receptor expressed on myeloid cells 1 TREM1 Q.9NPA2 Matrix metalloproteinase-25 MMP25 Q.9NPE2 Neugrin NGRN Q.9NPH0 Lysophosphatidic acid phosphatase type 6 ACP6 Q.9NPH6 Odorant-binding protein 2b OBP2B Q.9NQ.30 Endothelial cell-specific molecule 1 ESMI Q.9NQ.36 Signal peptide, CUB and EGF-like domaincontaining protein 2 SCUBE2 Q.9NQ.38 Serine protease inhibitor Kazal-type 5 SPINK5 Q.9NQ.76 Matrix extracellular phosphoglycoprotein MEPE Q.9NQ.79 Cartilage acidic protein 1 CRTAC1 Q.9NR16 Scavenger receptor cysteine-rich type 1 protein M160 CD163L1 Q.9NR23 Growth / differentiation factor 3 GDF3 Q.9NR71 Neutral ceramidase AS AH 2 Q.9NR99 Matrix-remodeling-associated protein 5 MXRA5 Q.9NRA1 Platelet-derived growth factor C PDGFC Q.9NRC9 Otoraplin OTOR Q.9NRE1 Matrix metalloproteinase-26 MMP26 Q.9NRJ3 C-C motif chemokine 28 CCL28 Q.9NRM1 Enamelin ENAM Q.9NRN5 Olfactomedin-like protein 3 OLFML3 Q.9NRR1 Cytokine-like protein 1 CYTL1 Q.9NS15 Latent-transforming growth factor betabinding protein 3 LTBP3 Q.9NS62 Thrombospondin type-1 domain-containing protein 1 THSD1 Q.9NS71 Gastrokine-1 GKN1 Q.9NS98 Semaphorin-3G SEMA3G Q.9NSA1 Fibroblast growth factor 21 FGF21 Q.9NT22 EMILIN-3 EMILIN3 Q.9NTU7 Cerebellin-4 CBLN4 Q.9NVR0 Kelch-like protein 11 KLHL11 Q.9NWH7 Spermatogenesis-associated protein 6 SPATA6 Q.9NXC2 Glucose-fructose oxidoreductase domaincontaining protein 1 GFOD1 Q.9NY56 Odorant-binding protein 2a OBP2A Q.9NY84 Vascular non-inflammatory molecule 3 VNN3 Q.9NZ20 Group 3 secretory phospholipase A2 PLA2G3 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.9NZC2 Triggering receptor expressed on myeloid cells 2 TREM2 Q.9NZK5 Adenosine deaminase CECR1 CECR1 Q.9NZK7 Group HE secretory phospholipase A2 PLA2G2E Q.9NZP8 Complement Clr subcomponent-like protein C1RL Q.9NZV1 Cysteine-rich motor neuron 1 protein CRIM1 Q.9NZW4 Dentin sialoprotein DSPP Q.9P0G3 Kallikrein-14 KLK14 Q.9P0W0 Interferon kappa IFNK Q.9P218 Collagen alpha-l(XX) chain COL20A1 Q.9P2C4 Transmembrane protein 181 TMEM181 Q.9P2K2 Thioredoxin domain-containing protein 16 TXNDC16 Q.9P2N4 A disintegrin and metalloproteinase with thrombospondin motifs 9 ADAMTS9 Q.9UBC7 Galanin-like peptide GALP Q.9UBD3 Cytokine SCM-1 beta XCL2 Q.9UBD9 Cardiotrophin-like cytokine factor 1 CLCF1 Q.9UBM4 Opticin OPTC Q.9UBP4 Dickkopf-related protein 3 DKK3 Q9UBQ6 Exostosin-like 2 EXTL2 Q.9UBR5 Chemokine-like factor CKLF Q.9UBS5 Gamma-aminobutyric acid type B receptor subunit 1 GABBR1 Q.9UBT3 Dickkopf-related protein 4 short form DKK4 Q.9UBU2 Dickkopf-related protein 2 DKK2 Q.9UBU3 Ghrelin-28 GHRL Q.9UBV4 Protein Wnt-16 WNT16 Q.9UBX5 Fibulin-5 FBLN5 Q.9UBX7 Kallikrein-11 KLK11 Q.9UEF7 Klotho KL Q.9UFP1 Protein FAM198A FAM198A Q.9UGM3 Deleted in malignant brain tumors 1 protein DMBT1 Q.9UGM5 Fetuin-B FETUB Q.9UGP8 Translocation protein SEC63 homolog SEC63 Q.9UHF0 Neurokinin-B TAC3 Q.9UHF1 Epidermal growth factor-like protein 7 EGFL7 Q.9UHG2 ProSAAS PCSK1N Q.9UHI8 A disintegrin and metalloproteinase with thrombospondin motifs 1 ADAMTS1 Q.9UHL4 Dipeptidyl peptidase 2 DPP7 Q.9UI42 Carboxypeptidase A4 CPA4 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.9UIG4 Psoriasis susceptibility 1 candidate gene 2 protein PSORS1C2 Q.9UIK5 Tomoregulin-2 TMEFF2 Q.9UIQ.6 Leucyl-cystinyl aminopeptidase, pregnancy serum form LNPEP Q.9UJA9 Ectonucleotide pyrophosphatase / phosphodiesterase family member 5 ENPP5 Q.9UJH8 Meteorin METRN Q.9UJJ9 N-acetylglucosamine-l-phosphotransferase subunit gamma GNPTG Q.9UJW2 Tubulointerstitial nephritis antigen TINAG Q.9UK05 Growth / differentiation factor 2 GDF2 Q.9UK55 Protein Z-dependent protease inhibitor SERPINA10 Q.9UK85 Dickkopf-like protein 1 DKKL1 Q.9UKJ1 Paired immunoglobulin-like type 2 receptor alpha PILRA Q.9UKP4 A disintegrin and metalloproteinase with thrombospondin motifs 7 ADAMTS7 Q.9UKP5 A disintegrin and metalloproteinase with thrombospondin motifs 6 ADAMTS6 Q.9UKQ.2 Disintegrin and metalloproteinase domaincontaining protein 28 ADAM28 Q.9UKQ.9 Kallikrein-9 KLK9 Q.9UKR0 Kallikrein-12 KLK12 Q.9UKR3 Kallikrein-13 KLK13 Q.9UKU9 Angiopoietin-related protein 2 ANGPTL2 Q.9UKZ9 Procollagen C-endopeptidase enhancer 2 PCOLCE2 Q.9UL52 Transmembrane protease serine HE non-catalytic chain TMPRSS11E Q.9ULC0 Endomucin EMCN Q.9ULI3 Protein HEG homolog 1 HEG1 Q.9ULZ1 Apelin-13 APLN Q.9ULZ9 Matrix metalloproteinase-17 MMP17 Q.9UM21 Alpha-l,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A soluble form MGAT4A Q.9UM22 Mammalian ependymin-related protein 1 EPDR1 Q.9UM73 ALK tyrosine kinase receptor ALK Q.9UMD9 97 kDa linear IgA disease antigen COL17A1 Q.9UMX5 Neudesin NENF Q.9UN73 Protocadherin alpha-6 PCDHA6 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.9UNA0 A disintegrin and metalloproteinase with thrombospondin motifs 5 ADAMTS5 Q9UNI1 Chymotrypsin-like elastase family member 1 CELA1 Q.9UNK4 Group HD secretory phospholipase A2 PLA2G2D Q.9UP79 A disintegrin and metalloproteinase with thrombospondin motifs 8 ADAMTS8 Q.9UPZ6 Thrombospondin type-1 domain-containing protein 7A THSD7A Q.9UQ.72 Pregnancy-specific beta-l-glycoprotein 11 PSG11 Q.9UQ.74 Pregnancy-specific beta-l-glycoprotein 8 PSG8 Q.9UQ.C9 Calcium-activated chloride channel regulator 2 CLCA2 Q.9UQ.E7 Structural maintenance of chromosomes protein 3 SMC3 Q.9UQ.P3 Tenascin-N TNN Q.9Y223 UDP-N-acetylglucosamine 2-epimerase GNE Q.9Y240 C-type lectin domain family 11 member A CLEC11A Q.9Y251 Heparanase 8 kDa subunit HPSE Q.9Y258 C-C motif chemokine 26 CCL26 Q.9Y264 Angiopoietin-4 ANGPT4 Q.9Y275 Tumor necrosis factor ligand superfamily member 13b, membrane form TNFSF13B Q.9Y287 BRI2 intracellular domain ITM2B Q.9Y2E5 Epididymis-specific alpha-mannosidase MAN2B2 Q.9Y334 von Willebrand factor A domain-containing protein 7 VWA7 Q.9Y337 Kallikrein-5 KLK5 Q.9Y3B3 Transmembrane emp24 domain-containing protein 7 TMED7 Q.9Y3E2 BolA-like protein 1 BOLA1 Q.9Y426 C2 domain-containing protein 2 C2CD2 Q.9Y4K0 Lysyl oxidase homolog 2 LOXL2 Q.9Y4X3 C-C motif chemokine T1 CCL27 Q.9Y5C1 Angiopoietin-related protein 3 ANGPTL3 Q.9Y5I2 Protocadherin alpha-10 PCDHA10 Q.9Y5I3 Protocadherin alpha-1 PCDHA1 Q.9Y5K2 Kallikrein-4 KLK4 Q.9Y5L2 Hypoxia-inducible lipid droplet-associated protein HILPDA Q.9Y5Q.5 Atrial natriuretic peptide-converting enzyme CORIN Q.9Y5R2 Matrix metalloproteinase-24 MMP24 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name Q.9Y5U5 Tumor necrosis factor receptor superfamily member 18 TNFRSF18 Q.9Y5W5 Wnt inhibitory factor 1 WIFI Q.9Y5X9 Endothelial lipase LIPG Q.9Y625 Secreted glypican-6 GPC6 Q.9Y646 Carboxypeptidase Q. CPQ. Q.9Y6C2 EMILIN-1 EMILIN1 Q.9Y6F9 Protein Wnt-6 WNT6 Q.9Y6I9 Testis-expressed sequence 264 protein TEX264 Q.9Y6L7 Tolloid-like protein 2 TLL2 Q.9Y6N3 Calcium-activated chloride channel regulator family member 3 CLCA3P Q.9Y6N6 Laminin subunit gamma-3 LAMC3 Q.9Y6R7 IgGFc-binding protein FCGBP Q.9Y6Y9 Lymphocyte antigen 96 LY96 Q.9Y6Z7 Collectin-10 COLEC10

[0651] In some embodiments, the compositions and methods of the invention provide for the delivery of one or more mRNAs encoding one or more additional exemplary proteins listed in Table 2; thus, compositions of the invention may comprise an mRNA encoding a protein listed in Table 2 (or a homolog thereof) along with other components set out herein, and methods of the invention may comprise preparing and / or administering a composition comprising an mRNA encoding a protein chosen from the proteins listed in Table 2 (or a homolog thereof) along with other components set out herein. Table 2. Additional Exemplary Proteins Uniprot ID Protein Name Gene Name A6NGW2 Putative stereocilin-like protein STRCP1 A6NIE9 Putative serine protease 29 PRSS29P A6NJ16 Putative V-set and immunoglobulin domain-containing-like protein IGHV4OR15-8 IGHV4OR15-8 A6NJS3 Putative V-set and immunoglobulin domain-containing-like protein IGHV1OR21-1 IGHV1OR21-1 A6NMY6 Putative annexin A2-like protein ANXA2P2 A8MT79 Putative zinc-alpha-2-glycoprotein-like 1 A8MWS1 Putative killer cell immunoglobulin-like receptor like protein KIR3DP1 KIR3DP1 A8MXU0 Putative beta-defensin 108A DEFB108P1 2026204802   22 Jun 2026 Uniprot ID Protein Name Gene Name C9JUS6 Putative adrenomedullin-5-like protein ADM5 P0C7V7 Putative signal peptidase complex catalytic subunit SEC11B SEC11B P0C854 Putative cat eye syndrome critical region protein 9 CECR9 Q.13046 Putative pregnancy-specific beta-1-glycoprotein 7 PSG7 Q.16609 Putative apolipoprotein(a)-like protein 2 LPAL2 Q.2TV78 Putative macrophage-stimulating protein MSTP9 MST1P9 Q.5JQ.D4 Putative peptide YY-3 PYY3 Q.5R387 Putative inactive group IIC secretory phospholipase A2 PLA2G2C Q.5VSP4 Putative lipocalin 1-like protein 1 LCN1P1 Q.5W188 Putative cystatin-9-like protein CST9LP1 CST9LP1 Q.6UXR4 Putative serpin A13 SERPINA13P Q.86SH4 Putative testis-specific prion protein PRNT Q.86YQ.2 Putative latherin LATH Q.8IVG9 Putative humanin peptide MT-RNR2 Q.8NHM4 Putative trypsin-6 TRY6 Q.8NHW4 C-C motif chemokine 4-1 ike CCL4L2 Q.9H7L2 Putative killer cell immunoglobulin-like receptor-like protein KIR3DX1 KIR3DX1 Q.9NRI6 Putative peptide YY-2 PYY2 Q.9UF72 Putative TP73 antisense gene protein 1 TP73-AS1 Q.9UKY3 Putative inactive carboxylesterase 4 CES1P1

[0652] The Uniprot IDs set forth in Table 1 and Table 2 refer to the human versions the listed proteins and the sequences of each are available from the Uniprot database. Sequences of the listed proteins are also generally available for various animals, including various mammals and animals of veterinary or industrial interest. Accordingly, in some embodiments, compositions and methods of the invention provide for the delivery of one or more mRNAs encoding one or more proteins chosen from mammalian homologs or homologs from an animal of veterinary or industrial interest of the secreted proteins listed in Table 1 and Table 2; thus, compositions of the invention may comprise an mRNA encoding a protein chosen from mammalian homologs or homologs from an animal of veterinary or industrial interest of a protein listed in Table 1 and Table 2 along with other components set out herein, and methods of the invention may comprise preparing and / or administering a composition comprising an mRNA encoding a protein 2026204802   22 Jun 2026 chosen from mammalian homologs or homologs from an animal of veterinary or industrial interest of a protein listed in Table 1 and Table 2 along with other components set out herein. In some embodiments, mammalian homologs are chosen from mouse, rat, hamster, gerbil, horse, pig, cow, llama, alpaca, mink, dog, cat, ferret, sheep, goat, or camel homologs. In some embodiments, the animal of veterinary or industrial interest is chosen from the mammals listed above and / or chicken, duck, turkey, salmon, catfish, or tilapia.

[0653] In embodiments, the compositions and methods of the invention provide for the delivery of mRNA encoding a lysosomal protein chosen from Table 3. In some embodiments, the compositions and methods of the invention provide for the delivery of one or more mRNAs encoding one or more lysosomal and / or related proteins listed in Table 3; thus, compositions of the invention may comprise an mRNA encoding a protein listed in Table 3 (or a homolog thereof) along with other components set out herein, and methods of the invention may comprise preparing and / or administering a composition comprising an mRNA encoding a protein chosen from the proteins listed in Table 3 (or a homolog thereof) along with other components set out herein. Table 3. Lysosomal and Related Proteins a-fucosidase a-galactosidase a-glucosidase a-lduronidase a-mannosidase a-N-acetylgalactosaminidase (a-galactosidase B) P-galactosidase P-glucuronidase P-hexosaminidase P-mannosidase 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase 3-methylcrotonyl-CoA carboxylase 3-O-sulfogalactosyl cerebroside sulfatase (arylsulfatase A) acetyl-CoA transferase acid alpha-glucosidase acid ceramidase acid lipase acid phosphatase acid sphingomyelinase alpha-galactosidase A 2026204802   22 Jun 2026 arylsulfatase A beta-galactosidase beta-glucocerebrosidase beta-hexosaminidase Biotinidase cathepsin A cathepsin K CLN3 CLN5 CLN6 CLN8 CLN9 cystine transporter (cystinosin) cytosolic protein beta3A subunit of the adaptor protein-3 complex, AP3 formyl-Glycine generating enzyme (FGE) Galactocerebrosidase galactose-1-phosphate uridyltransferase (GALT) galactose 6-sulfate sulfatase (also known as N-acetylgalactosamine-6-sulfatase) Glucocerebrosidase glucuronate sulfatase glucuronidase glycoprotein cleaving enzymes glycosaminoglycan cleaving enzymes glycosylasparaginase (aspartylglucosaminidase) GM2-AP Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT, TMEM76) Heparan sulfatase hexosaminidase A lysosomal proteases methylmalonyl-CoA mutase Hyaluronidase Iduronate sulfatase LAMP-2 lysosomal a-mannosidase Lysosomal p40 (C2orfl8) Major facilitator superfamily domain containing 8 protein (MFSD8 or CLN7) N-acetylgalactosamine 4-sulfatase N-acetyl glucosamine 6-sulfatase N-acetyl glucosaminidase N-acetylglucosamine-l-phosphate transferase NPC1 NPC2 palmitoyl-protein thioesterase palmitoyl-protein thioesterase (CLN1) 2026204802   22 Jun 2026 Saposin A (Sphingolipid activator protein A) Saposin B (Sphingolipid activator protein B) Saposin C (Sphingolipid activator protein C) Saposin D (Sphingolipid activator protein D) sialic acid transporter (sialin) Sialidase Sialin Sulfatase Transmembrane protein 74 (TMEM74) tripeptidyl-peptidase tripeptidyl-peptidase I (CLN2) UDP-N-acetylglucosamine- phosphotransferase

[0654] Information regarding lysosomal proteins is available from Lubke et al., "Proteomics of the Lysosome," Biochim Biophys Acta. (2009) 1793: 625-635. In some embodiments, the protein listed in Table 3 and encoded by mRNA in the compositions and methods of the invention is a human protein. Sequences of the listed proteins are ...

Claims

1. A cationic lipid having a structure according to Formula (A):zx1AX1BIR1(A),or a pharmaceutically acceptable salt thereof, whereineach n is independently 0 or 1;X1A is independently O or NR1A;R1A is H or Ci-Cg alkyl;X1B is a covalent bond, C(O), CH2CO2, or CH2C(O);one of X2A and X2B is O and the other is a covalent bond;one of X3A and X3B is O and the other is a covalent bond;one of X4A and X4B is O and the other is a covalent bond;R1 is independently L^B1, Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl;R2 is independently L2-B2, Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl;R3 is independently L3-B3, Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl;R4 is independently L4-B4, Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl;L1, L2, L3, and L4 are each independently C1-C30 alkylene; C2-C30 alkenylene; or C2-C30 alkynylene;each of B1, B2, B3, and B4 is independently an ionizable nitrogen-containing group, andwherein the cationic lipid comprises at least one ionizable nitrogen-containing group.2026204802   22 Jun 20262. The cationic lipid of claim 1, having a structure according to Formula (I),or a pharmaceutically acceptable salt thereof, whereineach of R2, R3, and R4 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; and L1 is C1-C10 alkylene.

3. The cationic lipid of claim 1, having a structure according to Formula (II),or a pharmaceutically acceptable salt thereof, whereineach of R2, R3, and R4 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; andL1 is Ci-Cio alkylene.

4. The cationic lipid of claim 1, having a structure according to Formula (Al),or a pharmaceutically acceptable salt thereof, wherein2026204802   22 Jun 2026L1 is Ci-Cio alkylene;each R6A is independently H or Ci-Cg alkyl; and each R6b is independently H or Ci-Cg alkyl.

5. The cationic lipid of claim 4, wherein R6A is methyl and R6B is methyl.

6. The cationic lipid of claim 1 or 4, having a structure according to Formula (All),or a pharmaceutically acceptable salt thereof.

7. The cationic lipid of any one of claims 1, or 3-6 having a structure according toFormula (Alli),(Alli),or a pharmaceutically acceptable salt thereof, whereinR1A is H.

8. A cationic lipid having a structure according to Formula (Ila),2026204802   22 Jun 2026or a pharmaceutically acceptable salt thereof, whereinB1 is an ionizable nitrogen-containing group;R1A is H or C(O)-R7;each of R2, R3, R4, and R7 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl; and L1 is Ci-Cio alkylene.

9. The cationic lipid of claim 8, having a structure according to Formula (lib),or a pharmaceutically acceptable salt thereof.

10. The cationic lipid of claim 8 or 9, having a structure according to Formula (He),(He),or a pharmaceutically acceptable salt thereof.2026204802   22 Jun 2026The cationic lipid of claim 8 or 9, having a structure according to Formula (lid),or a pharmaceutically acceptable salt thereof.

12. The cationic lipid of any one of claims 1 and 4-6, wherein X1A is NR1A.

13. The cationic lipid of any one of claims 1, 3-9 and 12, wherein R1A is H.

14. The cationic lipid of any one of claims 1, 4-6 and 12-13, wherein X1B is a covalentbond.

15. The cationic lipid of any one of claims 1, 4-6 and 7-13, wherein X1B is CH2CO2.

16. The cationic lipid of any one of claims 1-15, wherein L1 is unsubstituted C1-C10alkylene.

17. The cationic lipid of claim 16, wherein L1 is (6(-)2)2, (6-)2)3, (6-)2)4, or (6-)2)5.

18. The cationic lipid of claim 17, wherein L1 is (6-)2)219.     The cationic lipid of claim 17, wherein L1 is (6-)2)320.    The cationic lipid of any one of claims 1-3, and 8-19, wherein B1 is independentlyNH2, guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered nitrogen-containing heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl.2026204802   22 Jun 2026H. t Me21. The cationic lipid of claim 20, wherein B1 is independently H , MeMe . Et .ZN-I ,N 522. The cationic lipid of claim 21, wherein B1 is independently Me , Et , HOorCH23. The cationic lipid of any one of claims 1-22, wherein each of R2, R3, and R4 is independently unsubstituted linear C6-C22 alkyl, unsubstituted linear C6-C22 alkenyl, unsubstituted linear C6-C22 alkynyl, unsubstituted branched C6-C22 alkyl, unsubstituted branched C6-C22 alkenyl, or unsubstituted branched C6-C22 alkynyl.

24. The cationic lipid of any one of claims 1-23, wherein each of R2, R3, and R4 is unsubstituted C6-C22 alkyl.

25. The cationic lipid of any one of claims 1-22, wherein each of R2, R3, and R4 is independently C6-C12 alkyl substituted by -O(CO)R5 or -C(O)OR5, wherein R5 is unsubstituted Cg-Ci4 alkyl.

26. The cationic lipid of any one of claims 1-23, wherein each of R2, R3, and R4 is unsubstituted C6-C22 alkenyl.

27. The cationic lipid of claim 26, wherein said C6-C22 alkenyl is a monoalkenyl, a dienyl, or a trienyl.

28. The cationic lipid of any one of claims 1-22, wherein each of R2, R3, and R4 is2026204802   22 Jun 202629. The cationic lipid of any one of claims 1-22, wherein each of R2, R3, R4 and R7 isindependently2026204802   22 Jun 202630. The cationic lipid of any one of claims 1-22, wherein each of R2, R3, and R4isindependently31. The cationic lipid of any one of claims 1-22, wherein each of R2, R3, R4 and R7 isindependently2026204802   22 Jun 202632. The cationic lipid of any one of claims 1-22, wherein each of R2, R3, R4 and R7 is independently CsHi7, C10H21, C12H25, C14H29, C16H33, C16H31, C16H29 and C16H32.

33. The cationic lipid of any one of claims 1-22, wherein each of R2, R3, R4 and R7 is independently C6-C22 alkyl, C6-C22 alkenyl, or C6-C22 alkynyl.

34. The cationic lipid of any one of claims 1-22, wherein each of R2, R3, R4 and R7 is independently C6-C22 alkyl, or C6-C22 alkenyl.

35. The cationic lipid of any one of claims 1-22, wherein each of R2, R3, R4 and R7 is independently unsubstituted linear C6-C22 alkyl, or unsubstituted linear C6-C22 alkenyl.

36. The cationic lipid of claim 1, wherein R1 is independently CsHi7, C10H21, C12H25,C14H29, C16H33, C16H31, C16H29 and C16H32.

37. The cationic lipid of claim 1, wherein R1 is independently unsubstituted linear C6-C22 alkyl, unsubstituted linear C6-C22 alkenyl, or unsubstituted linear C6-C22 alkynyl.

38. The cationic lipid of claim 1, having a structure according to Formula (III),or a pharmaceutically acceptable salt thereof, whereinR1 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.2026204802   22 Jun 202639. The cationic lipid of claim 1, having a structure according to Formula (IV),or a pharmaceutically acceptable salt thereof, whereinR1 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

40. The cationic lipid of claim 39, wherein RA is H.

41. The cationic lipid of claim 1, having a structure according to Formula (V),or a pharmaceutically acceptable salt thereof, whereinR1 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

42. The cationic lipid of claim 1, having a structure according to Formula (VI),2026204802   22 Jun 2026or a pharmaceutically acceptable salt thereof, whereinR1 is independently Cg-Cao alkyl, Cg-Cao alkenyl, or Cg-Cao alkynyl.

43. The cationic lipid of claim 42, wherein R1A is H.

44. The cationic lipid of any one of claims 38-43, wherein R1 is independentlyunsubstituted linear Cg-C22 alkyl, unsubstituted linear Cg-C22 alkenyl, unsubstituted linear Cg-C22 alkynyl, unsubstituted branched Cg-C22 alkyl, unsubstituted branched Cg-C22 alkenyl, or unsubstituted branched Cg-C22 alkynyl.

45. The cationic lipid of claim 44, wherein R1 is independently unsubstituted Cg-C22 alkyl.

46. The cationic lipid of any one of claims 38-43, wherein R1 is independently Cg-Ci2 alkylsubstituted by -O(CO)R5 or -C(O)OR5, wherein R5 is unsubstituted Cg-Ci4 alkyl.

47. The cationic lipid of claim 44, wherein R1 is independently unsubstituted Cg-C22 alkenyl.

48. The cationic lipid of claim 47, wherein said Cg-C22 alkenyl is a monoalkenyl, a dienyl, or a trienyl.

49. The cationic lipid of claim 38 or 39, wherein R1 is independently2026204802   22 Jun 202650. The cationic lipid of claim 41 or 42, wherein R1 is independently51. The cationic lipid of any one of claims 38-50, wherein each of L2, L3, and L4 isunsubstituted Ci-Cio alkylene.

52. The cationic lipid of claim 51, wherein each of L2, L3, and L4 is (CH2h, (CH2)s, (CH2)4, or (CH2)5.

53. The cationic lipid of any one of claims 38-52, wherein each of B2, B3, and B4 is independently NH2, guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered nitrogencontaining heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl.2026204802   22 Jun 2026The cationic lipid of claim 53, wherein each of B2, B3, and B4 is independently54.

55. The cationic lipid of claim 54, wherein each of B2, B3, and B4 is independentlyHOMes . Etx .      \___.            __IM—|   N—HO N_|    /   N_|Me Et \___ / S or \___ / 556. A cationic lipid that is any of Compounds 1-264, la-lh, I lb 1-1 Ib4,1 lcl-1 Ic4, 11 la-11 Id, and Va-Vd, or a pharmaceutically acceptable salt thereof.

57. A composition comprising an mRNA encoding a protein, encapsulated within a liposome, wherein the liposome comprises one or more cationic lipids, optionally one or more noncationic lipids, optionally one or more cholesterol-based lipids, and optionally one or more PEG-modified lipids, wherein at least one cationic lipid is of any one of claims 1-56.

58. The composition of claim 57, comprising an mRNA encoding for cystic fibrosis transmembrane conductance regulator (CFTR) protein.

59. The composition of claim 57, comprising an mRNA encoding for ornithine transcarbamylase (OTC) protein.

60. A composition comprising a nucleic acid encapsulated within a liposome, wherein the liposome comprises a cationic lipid of any one of claims 1-56.

61. The composition of claim 60, further comprising one more lipids selected from the group consisting of one or more cationic lipids, one or more non-cationic lipids, and one or more PEG-modified lipids.

62. The composition of claim 60 or 61, wherein the nucleic acid is an mRNA encoding a peptide or polypeptide.2026204802   22 Jun 202663. The composition of any one of claims 60-62, wherein the mRNA encodes a peptide or polypeptide for use in the delivery to or treatment of the lung of a subject or a lung cell.

64. The composition of claim 63, wherein the mRNA encodes cystic fibrosis transmembrane conductance regulator (CFTR) protein.

65. The composition of any one of claims 60-62, wherein the mRNA encodes a peptide or polypeptide for use in the delivery to or treatment of the liver of a subject or a liver cell.

66. The composition of claim 65, wherein the mRNA encodes ornithine transcarbamylase (OTC) protein.

67. The composition of any one of claims 60-62, wherein the mRNA encodes a peptide or polypeptide for use in vaccine.

68. The composition of claim 67, wherein the mRNA encodes an antigen.

69. The composition of claim 68, wherein the antigen is from an infectious agent.

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