Particulate Compositions Comprising Polysarcosine Lipid Conjugates

Abstract

The present disclosure features particle compositions, such as liposomes and lipid nanoparticles, comprising polysarcosine-lipid conjugates, as well as methods for making and using the same. The present disclosure features particle compositions, such as liposomes and lipid nanoparticles, comprising polysarcosine-lipid conjugates, as well as methods for making and using the same. In one embodiment, the particle composition further comprises a therapeutic payload, such as an oligonucleotide (e.g., mRNA or DNA) or a protein (e.g., an antibody or enzyme). In one embodiment, the particle composition comprises particles comprising (i) a polymer described herein and one or more of (ii) a phospholipid, (iii) a steroid, (iv) a payload (e.g., an oligonucleotide or protein), and (v) an additional lipid component.

Description

[Technical Field]

[0001] Priority claims This application claims priority to U.S. Application No. 63 / 424,617, filed November 11, 2022. The entire contents of the foregoing application are incorporated herein by reference in their entirety. [Background technology]

[0002] Biological drugs (biopharmaceuticals) are generally large, complex molecules produced through biotechnology techniques in living systems such as microorganisms, plant cells, or animal cells. Biopharmaceuticals can be more difficult to deliver to target cells or subjects than small molecule drugs. Particle formulations, including lipid nanoparticles, have recently been used as a delivery method for therapeutic payloads. However, these formulations must be fine-tuned across several parameters to ensure performance, including stability and specific and efficient payload delivery. Therefore, it would be desirable to develop particle formulations with improved performance. Summary of the Invention [Means for solving the problem]

[0003] The present disclosure features particle compositions, such as liposomes and lipid nanoparticles, comprising polysarcosine-lipid conjugates, as well as methods for making and using the same. In one embodiment, the particle composition further comprises a therapeutic payload, such as an oligonucleotide (e.g., mRNA or DNA) or a protein (e.g., an antibody or enzyme). In one embodiment, the particle composition comprises particles comprising (i) a polymer described herein and one or more of: (ii) a phospholipid; (iii) a steroid; (iv) a payload (e.g., an oligonucleotide or protein); and (v) an additional lipid component. In one embodiment, the polymer has the structure of formula (Id): [ka] or a pharmaceutically acceptable salt thereof, wherein R 6, R 7 , and R 8 each is independently hydrogen, heteroalkyl, alkyl, alkenyl, or alkynyl; R 9a , R 9b , R 10a , and R 10b are independently hydrogen, alkyl, or halo, and each of x and y is independently an integer from 1 to 20, and z is an integer from 5 to 90. In one embodiment, the particle further comprises (ii). In one embodiment, the particle further comprises (iii). In one embodiment, the particle further comprises (iv). In one embodiment, the particle further comprises (v). In one embodiment, the particle further comprises (vi). Features of particle compositions comprising polysarcosine-lipid conjugates, as well as methods of making and using the same, are described in further detail herein. [Brief explanation of the drawings]

[0004] [Figure 1] 1 is a flow diagram of the synthesis of lipid nanoparticle formulations. DETAILED DESCRIPTION OF THE INVENTION

[0005] Described herein are particulate compositions, such as liposomes and lipid nanoparticles, that contain polysarcosine-lipid conjugates, as well as methods for making and using the same. In one embodiment, the particulate composition further comprises a therapeutic payload, such as an oligonucleotide (e.g., mRNA or DNA) or a protein (e.g., an antibody or enzyme). Features of particulate compositions that contain polysarcosine-lipid conjugates are described in further detail herein.

[0006] definition In order that the present disclosure may be more readily understood, certain technical and scientific terms used herein are specifically defined below. Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0007] As used in this specification, including the appended claims, singular words such as "a," "an," and "the" include their corresponding plural references unless the context clearly dictates otherwise.

[0008] "About," when used herein to modify a numerically defined parameter (e.g., a physical property of a particle, such as diameter, or the amount of polysarcosine-lipid complex in a particle), means that the parameter may vary by up to 15% above and below the numerical value stated for that parameter. In some embodiments, "about" means that the parameter may vary by up to 10% above and below the numerical value stated for that parameter.

[0009] "Obtain" or "obtaining," as used herein, refers to obtaining a possession of a value, e.g., a numerical value, or an image, or a physical entity (e.g., a sample), by "directly obtaining" or "indirectly obtaining" the value or physical entity. "Directly obtaining" means performing a process (e.g., performing an analytical method or protocol) to obtain the value or physical entity. "Indirectly obtaining" refers to receiving the value or physical entity from another party or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Directly obtaining a value or physical entity includes performing a process that involves a physical change of the physical entity or performing a process that involves the use of a machine or device. An example of directly obtaining a value is obtaining a sample from a human subject. Directly obtaining a value includes performing a process to obtain fluorescence microscopy data using a machine or device, such as a fluorescence microscope.

[0010] "Administer," "administering," or "administration," as used herein, refers to providing, absorbing, ingesting, injecting, or otherwise introducing or providing to a subject an entity described herein or a composition comprising said particle.

[0011] The term "subject," as used herein, means a mammal and includes animal subjects such as humans and domestic animals (e.g., horses, dogs, cats, etc.).

[0012] The term "parenteral" or "parenterally" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques for administration. Preferably, the composition is administered intraperitoneally or intravenously. Sterile injectable forms of the compositions of the present disclosure may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (e.g., as a solution in 1,3-butanediol). Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution.

[0013] As used herein, the term "effective amount" refers to the amount of a particle composition (e.g., particle composition) or particle component (e.g., protein or nucleic acid). In some embodiments, the term "effective amount" refers to the amount of a particle component, e.g., the concentration or identity of a therapeutic agent on or within the particle. As will be appreciated by those skilled in the art, an effective amount can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the therapeutic agent, composition, or particle, the condition being treated, the method of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatments.

[0014] As used herein, the term "in solution," when used in reference to a protein, refers to a liquid medium in which the protein is continuously distributed to form a homogeneous mixture.

[0015] As used herein, the terms "treatment," "treat," and "treating," as described herein, refer to partially or completely alleviating, inhibiting, delaying onset, slowing progression, ameliorating, and / or alleviating a disease or disorder, or one or more symptoms of the disease or disorder. In some embodiments, treatment may be administered after one or more symptoms have developed. In some embodiments, the term "treating" encompasses preventing, slowing, or halting the progression of a disease or disorder. In some embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account the history of symptoms and / or taking into account genetic or other susceptibility factors). Treatment may be continued after symptoms have been cured to, for example, prevent or delay their recurrence. Thus, in some embodiments, the term "treating" includes preventing the recurrence or recurrence of a disease or disorder.

[0016] Selected Chemical Definitions The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. (back cover), and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry and specific functional sites and reactivities are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. Abbreviations used herein have their usual meanings within the relevant chemical and biological fields. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0017] When a range of values ​​is recited, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C5-C6, C4-C5, and C5-C6. The following terms are intended to have the meanings set forth below and are useful in describing and understanding the intended scope of the present invention.

[0018] As used herein, "alkyl" refers to the radical of a straight- or branched-chain saturated hydrocarbon group having from 1 to 24 carbon atoms ("C1-C 24 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C 12 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C1), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each example of an alkyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C1 to C8 10 Alkyl (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C1-C6 alkyl.

[0019] As used herein, "alkenyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 24 carbon atoms and one or more carbon-carbon double bonds and no triple bonds ("C2-C24 alkenyl"). In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C2-C10 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each instance of an alkenyl group independently may be optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C1-C10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-C6 alkenyl.

[0020] As used herein, the term "alkynyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 24 carbon atoms and one or more carbon-carbon triple bonds ("C2-C24 alkenyl"). In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C2-C10 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-C8 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-C6 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Each instance of an alkynyl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, an alkynyl group is a substituted C2-6 alkynyl. "Amino," as used herein, refers to the radical -NR70R71, where R70 and R71 are each independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, C4-C10 heterocyclyl, C6-C10 aryl, and C5-C10 heteroaryl. In some embodiments, amino refers to NH2.

[0021] As used herein, "cyano" refers to the group --CN.

[0022] As used herein, "halo," or "halogen," independently or as part of another substituent, means, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.

[0023] As used herein, "hydroxy" refers to the radical --OH.

[0024] As used herein, "oxo" refers to carbonyl, i.e., --C(O)--.

[0025] As used herein, the term "haloalkyl" refers to an acyclic, stable, straight or branched chain, or combination thereof, containing at least one carbon atom and at least one halogen selected from the group consisting of F, C, Br, and I. The halogen(s) F, C, Br, and I can be located at any position of the haloalkyl group. Exemplary haloalkyl groups include, but are not limited to, -CF, -CC, -CH-CF, -CH-CC, -CH-CBr, -CH-Cl, -CH-CH-CH(CF)-CH, -CH-CH-CH(Br)-CH, and -CH-CH=CH-CH-CF. Each instance of haloalkyl can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted haloalkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted haloalkyl"). As used herein, the term "heteroalkyl" refers to a stable acyclic straight or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatom(s) O, N, P, S, and Si can be placed at any position of the heteroalkyl group. Exemplary heteroalkyl groups include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.When "heteroalkyl" is described followed by a specific heteroalkyl group, such as -CHO, -NRCRD, etc., it will be understood that the term heteroalkyl and -CHO or -NRCRD are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is described to provide clarity. Thus, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups, e.g., -CHO, -NRCRD, etc. Each instance of a heteroalkyl group independently can be optionally substituted, i.e., unsubstituted (an "unsubstituted heteroalkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted heteroalkyl").

[0026] As used herein, "aryl" refers to the radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared by the cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided to the aromatic ring system ("C6-C14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C10 aryl", e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C14 aryl", e.g., anthracyl). An aryl group may be described, for example, as a C6-C10 membered aryl, where the term "membered" refers to a non-hydrogen ring atom within the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is unsubstituted C6-C14 aryl. In certain embodiments, the aryl group is substituted C6-C14 aryl.

[0027] As used herein, "heteroaryl" refers to a radical of a 5-10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared by the cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided to the aromatic ring system ("5-10-membered heteroaryl"), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, with the point of attachment being on either the aryl or heteroaryl ring; in such instances, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring bearing the heteroatom (e.g., 2-indolyl) or on the ring that does not contain the heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described, for example, as 6- to 10-membered heteroaryl, where the term "member" refers to a non-hydrogen ring atom within the moiety. Each instance of heteroaryl may independently be optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted heteroaryl"). Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl.Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0028] As used herein, "cycloalkyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms in the non-aromatic ring system ("C3-C10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C10 cycloalkyl"). A cycloalkyl group can be described, for example, as a C4-C7 membered cycloalkyl, where the term "member" refers to a non-hydrogen ring atom in the moiety. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C10 cycloalkyl groups include, but are not limited to, the aforementioned C3-C8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.

[0029] As the foregoing examples illustrate, in certain embodiments, a cycloalkyl group is monocyclic ("monocyclic cycloalkyl") or includes fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring, as defined above, is fused to one or more aryl groups (where the point of attachment is on the cycloalkyl ring). In such instances, the number of carbons still refers to the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group independently may be optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C3-C10 cycloalkyl. In certain embodiments, a cycloalkyl group is a substituted C3-C10 cycloalkyl. As used herein, "heterocyclyl" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, as valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more cycloalkyl groups (the point of attachment is on either the cycloalkyl ring or the heterocyclyl ring), or in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups (the point of attachment is on the heterocyclyl ring), in which case the number of ring members still refers to the number of ring members in the heterocyclyl ring system.A heterocyclyl group may be described, for example, as a 3- to 7-membered heterocyclyl, where the term "member" refers to the non-hydrogen ring atoms within the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each instance of heterocyclyl may independently be optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 10-membered heterocyclyl. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridin-2-onyl), and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, and dioxanyl.Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclyl ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5-bicyclic heterocyclyl ring) include, but are not limited to, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 4,6-membered heterocyclyl rings) fused to a heterocyclyl ring include, but are not limited to, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclyl rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,7-bicyclic heterocyclyl rings) fused to a cycloalkyl ring include, but are not limited to, azabicyclooctanyl (e.g., (1,5)-8-azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,8-bicyclic heterocyclyl rings) fused to a cycloalkyl ring include, but are not limited to, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl).

[0030] The terms "alkylene," "alkenylene," "alkynylene," "haloalkylene," "heteroalkylene," "cycloalkylene," or "heterocyclylene," by themselves or as part of another substituent, mean, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, alkynyl, haloalkylene, heteroalkylene, cycloalkyl, or heterocyclyl, respectively. For example, the term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. An alkylene, alkenylene, alkynylene, haloalkylene, heteroalkylene, cycloalkylene, or heterocyclylene group may be described, for example, as C-C-membered alkylene, C-C-membered alkenylene, C-C-membered alkynylene, C-C-membered haloalkylene, C-C-membered heteroalkylene, C-C-membered cycloalkylene, or C-C-membered heterocyclylene, where the term "member" refers to a non-hydrogen atom within the moiety. For heteroalkylene and heterocyclylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).

[0031] Furthermore, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- can represent both -C(O)R'- and -R'C(O)-. As used herein, the term "cyano" or "-CN" refers to a substituent in which a carbon atom is attached to a nitrogen atom by a triple bond (e.g., C≡N). As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine. As used herein, the term "hydroxy" refers to -OH. As used herein, the term "nitro" refers to a substituent having two oxygen atoms attached to a nitrogen atom (e.g., -NO).

[0032] Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted. In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent (e.g., a substituent that, upon substitution, results in a stable compound (e.g., a compound that does not spontaneously transform by rearrangement, cyclization, elimination, or other reaction)). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when multiple positions in any particular structure are substituted, the substituents are either the same or different at each position. The term "substituted" is intended to encompass substitution with all permissible substituents of organic compounds (e.g., any of the substituents described herein that result in the formation of a stable compound). The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and form a stable moiety. Two or more substituents may optionally be connected to form an aryl, heteroaryl, cycloalkyl, or heterocyclyl group. It is understood that such so-called ring-forming substituents are typically, but not necessarily, attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure form a spiro ring structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.As used herein, the terms "aliphatic" or "aliphatic group" refer to a hydrocarbon moiety that may be linear (i.e., unbranched), branched, or cyclic (including fused polycyclic, bridged polycyclic, and spiro-fused polycyclic), fully saturated, or may contain one or more units of unsaturation, but is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. In some embodiments, aliphatic groups contain 8-20 carbon atoms. In other embodiments, aliphatic groups contain 12-20 carbon atoms. In still other embodiments, aliphatic groups contain 14-20 carbon atoms, and in still other embodiments, aliphatic groups contain 16-20 carbon atoms. The number of carbon atoms present in an aliphatic group may also be defined prior to the recitation of the aliphatic group above. For example, the term (C8-C20)aliphatic refers to an aliphatic group, as defined herein, containing 8-20 carbon atoms. The present disclosure specifically intends to include every individual subcombination of such range members. In particular, the term (C1-C6) aliphatic is intended to include C1 aliphatic (e.g., methyl), C2 aliphatic (e.g., ethyl, ethylene, or ethylyne), C3 aliphatic, C4 aliphatic, C5 aliphatic, and C6 aliphatic. Aliphatic groups include, but are not limited to, straight-chain or branched alkyl, alkenyl, and alkynyl groups, as well as hybrids thereof (such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl). Exemplary aliphatic groups include, but are not limited to, C24 aliphatic (e.g., didodecyl), C20 aliphatic (e.g., dodecyl), C18 aliphatic (e.g., oleyl, octadecyl), C16 aliphatic (e.g., hexadecyl, dioctyl), C14 aliphatic (e.g., tetradecyl), C12 aliphatic (e.g., dodecyl, dihexyl), and C10 aliphatic (e.g., decyl).

[0033] As used herein, the term "hydrophobic aliphatic group" or "hydrophobic aliphatic" refers to a moiety containing six or more carbon atoms and having overall hydrophobic properties. Hydrophobic aliphatic groups may be characterized by properties including, but not limited to, a static water contact angle θ > 90°. The number of carbon atoms present in the hydrophobic aliphatic group may also be defined prior to the enumeration of the hydrophobic aliphatic group above. For example, the term (C6-C20) hydrophobic aliphatic group refers to an aliphatic group, as defined herein, containing 6 to 20 carbon atoms. Exemplary hydrophobic aliphatic groups include oleyl (i.e., CH3(CH2)7CH=CH(CH2)7CH2-), tetradecyl (i.e., CH3(CH2) 12 CH2-), hexadecyl (i.e. CH3(CH2) 14 CH2-), octadecyl (i.e. CH3(CH2) 16 CH2-), dodecyl (i.e., (CH3(CH2)8CH2)2-), and didodecyl (i.e., (CH3(CH2) 10 Examples include, but are not limited to, alkyl groups such as aryl, aryl, aryl- ...

[0034] Protected hydroxyl groups are well known in the art and are described in Wuts, PGMP Protecting Groups in Organic Synthesis, 5 thEd., New York, John Wiley & Sons, 2014 (the entirety of which is incorporated herein by reference). Examples of suitable protected hydroxyl groups further include, but are not limited to, esters, carbonates, sulfonates, allyl ethers, ethers, silyl ethers, alkyl ethers, aryl alkyl ethers, and alkoxy alkyl ethers. Examples of suitable esters include formates, acetates, proprionates, pentanoates, crotonates, and benzoates. Specific examples of suitable esters include formate, benzoylformate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetate), crotonate, 4-methoxycrotonate, benzoate, p-benylbenzoate, and 2,4,6-trimethylbenzoate. Examples of carbonates include 9-fluorenylmethyl carbonate, ethyl carbonate, 2,2,2-trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, 2-(phenylsulfonyl)ethyl carbonate, vinyl carbonate, allyl carbonate, and p-nitrobenzyl carbonate. Examples of silyl ethers include trimethylsilyl ether, triethylsilyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether, triisopropylsilyl ether, and other trialkylsilyl ethers. Examples of alkyl ethers include methyl ether, benzyl ether, p-methoxybenzyl ether, 3,4-dimethoxybenzyl ether, trityl ether, t-butyl ether, and allyl ether, or derivatives thereof.Alkoxyalkyl ethers include acetals such as methoxymethyl ether, methylthiomethyl ether, (2-methoxyethoxy)methyl ether, benzyloxymethyl ether, β-(trimethylsilyl)ethoxymethyl ether, and tetrahydropyran-2-yl ether. Examples of arylalkyl ethers include benzyl ether, p-methoxybenzyl (MPM) ether, 3,4-dimethoxybenzyl ether, O-nitrobenzyl ether, p-nitrobenzyl ether, p-halobenzyl ether, 2,6-dichlorobenzyl ether, p-cyanobenzyl ether, 2-picolyl ether, and 4-picolyl ether.

[0035] Protected amines are well known in the art and are described in Wuts, P.G.M. Greene's Protective Groups in Organic Synthesis, 5 thEd., New Jersey, J. John Wiley & Sons, 2014. Mono-protected amines further include, but are not limited to, aralkylamines, carbamates, allylamines, amides, and the like. Examples of mono-protected amino moieties include t-butyloxycarbonylamino (-NHBOC), ethyloxycarbonylamino, methyloxycarbonylamino, trichloroethyloxycarbonylamino, allyloxycarbonylamino (-NHAlloc), benzyloxocarbonylamino (-NHCBZ), allylamino, benzylamino (-NHBn), fluorenylmethylcarbonyl (-NHFmoc), formamide, acetamide, chloroacetamide, dichloroacetamide, trichloroacetamide, phenylacetamide, trifluoroacetamide, benzamide, t-butyldiphenylsilyl, and the like. Di-protected amines include amines substituted with two substituents independently selected from those described above as mono-protected amines, and further include cyclic imides (such as phthalimide, maleimide, succinimide, and the like). Di-protected amines also include pyrrole and the like, 2,2,5,5-tetramethyl-[1,2,5]azadisilolidine and the like, and azides.

[0036] Protected aldehydes are well known in the art and include those described in detail in Wuts (2014). Protected aldehydes further include, but are not limited to, acyclic acetals, cyclic acetals, hydrazones, imines, and the like. Examples of such groups include dimethyl acetal, diethyl acetal, diisopropyl acetal, dibenzyl acetal, bis(2-nitrobenzyl) acetal, 1,3-dioxane, 1,3-dioxolane, semicarbazones, and derivatives thereof.

[0037] Protected carboxylic acids are well known in the art and include those described in detail in Wuts (2014). Protected carboxylic acids include optionally substituted C 1-20 Further examples include, but are not limited to, aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides, and the like. Examples of such ester groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl esters, each of which is optionally substituted. Additional protected carboxylic acids include oxazolines and orthoesters.

[0038] Protected thiols are well known in the art and include those described in detail in Wuts (2014). Protected thiols further include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates, and the like. Examples of such groups include, but are not limited to, alkyl thioethers, benzyl and substituted benzyl thioethers, triphenylmethyl thioethers, and trichloroethoxycarbonyl thioesters, to name a few.

[0039] As used herein, "CBP-1," "oleyl-NH-poly(Sar 15 )," "Oleylamine-Sar 15 ", "Oleyl-Sar15", and "CH3(CH2)7CH=CH(CH2)7CH2NH-Poly(sarcosine) 15 " all refer to the same compound having the structure: [ka] can be used interchangeably.

[0040] As used herein, "CBP-2," "oleyl-NH-poly(Sar 30 )," "Oleylamine-Sar30 ", "Oleyl-Sar30", "CH3(CH2)7CH=CH(CH2)7CH2NH-Poly(sarcosine) 30 and a polymer having the structure: [ka] All refer to the same compound and can be used interchangeably.

[0041] As used herein, "CBP-3," "dodecyl-NH-poly(Sar 20 ) and "Dodecylamine-Sar 20 ", "Dodecyl-Sar20", "CH3(CH2) 10 CH2NH-poly(sarcosine) 20 and a polymer having the structure: [ka] All refer to the same compound and can be used interchangeably.

[0042] As used herein, "CBP-4," "tetradecyl-NH-poly(Sar 15 )," "Tetradecylamine-Sar 15 ", "Tetradecyl-Sar15", "CH3(CH2) 12 CH2NH-poly(sarcosine) 15 and a polymer having the structure: [ka] All refer to the same compound and can be used interchangeably.

[0043] As used herein, "CBP-5," "tetradecyl-NH-poly(Sar 20 )," "Tetradecylamine-Sar 20 ", "Tetradecyl-Sar20", "CH3(CH2) 12 CH2NH-poly(sarcosine) 20and a polymer having the structure: [ka] All refer to the same compound and can be used interchangeably.

[0044] As used herein, "CBP-6," "hexadecyl-NH-poly(Sar 30 ) and "Hexadecylamine-Sar 30 ", "Hexadecyl-Sar30", "CH3(CH2) 14 CH2NH-poly(sarcosine) 30 and a polymer having the structure: [ka] All refer to the same compound and can be used interchangeably.

[0045] As used herein, "CBP-7," "octadecyl-NH-poly(Sar 30 )," "Octadecylamine-Sar 30 ", "Octadecyl-Sar30", "CH3(CH2) 16 CH2NH-poly(sarcosine) 30 and a polymer having the structure: [ka] All refer to the same compound and can be used interchangeably.

[0046] As used herein, "CBP-8," "didecyl-N-poly(Sar 30 ) and "Didecylamine-Sar 30 ", "Didecyl-Sar30", "(CH3(CH2)8CH2)2-N-Poly(sarcosine) 30 and a polymer having the structure: [ka] All refer to the same compound and can be used interchangeably.

[0047] As used herein, "CBP-9," "didodecyl-N-poly(Sar 30 )," "Didodecylamine-Sar 30 ", "Didodecyl-Sar30", "(CH3(CH2) 10 CH2)2-N-Poly(sarcosine) 30 and a polymer having the structure: [ka] All refer to the same compound and can be used interchangeably.

[0048] As used herein, "CBP-10," "oleyl-NH-poly(Sar 10 )," "Oleylamine-Sar 10 ", "Oleyl-Sar10", "CH3(CH2)7CH=CH(CH2)7CH2NH-Poly(sarcosine) 10 and a polymer having the structure: [ka] All refer to the same compound and can be used interchangeably.

[0049] As used herein, "CBP-11," "tetradecyl-NH-poly(Sar 23 )," "Tetradecylamine-Sar 23 ", "Tetradecyl-Sar23", "CH3(CH2) 12 CH2NH-poly(sarcosine) 23 and a polymer having the structure: [ka] All refer to the same compound and can be used interchangeably.

[0050] As used herein, the monomer repeat units described above are numbers that represent the average number of monomer units that make up a polymer chain. For example, (A) 10 A polymer represented by corresponds to a polymer consisting of 10 "A" monomer units linked together. One skilled in the art will recognize that the number 10, in this case, would represent a distribution with an average number of 10. The width of this distribution is represented by the polydispersity index (PDI). A PDI of 1.0 represents a polymer (e.g., a protein) in which each chain is exactly the same length. A PDI of 2.0 represents a polymer with a Gaussian distribution of chain lengths. Polymers of the present disclosure typically possess a PDI of less than 1.10. In some embodiments, the polymers of the present disclosure have a PDI of about 1.01, about 1.02, about 1.03, about 1.04, about 1.05, about 1.06, about 1.07, about 1.08, about 1.09, about 1.10, about 1.11, about 1.12, about 1.13, about 1.14, about 1.15, about 1.16, about 1.17, about 1.18, about 1.19, or about 1.2.

[0051] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomers of the disclosed compounds are within the scope of the disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14Compounds having this structure except for the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure. Such compounds are useful as analytical tools or probes in biological assays, for example, as in neutron scattering experiments.

[0052] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that is capable of being detected (e.g., primary labels and secondary labels). A "detectable moiety" or "label" is the radical of a compound that is detectable.

[0053] "Primary" labels include radioisotope-containing moieties, e.g. 32 P, 33 P, 35 S, or 14 C-containing moieties), mass tags, and fluorescent labels are signal-generating reporter groups that can be detected without further modification.

[0054] "Secondary" labels include moieties (such as biotin or protein antigens) that require the presence of a second compound to produce a detectable signal. For example, in the case of a biotin label, the second compound may include a streptavidin-enzyme conjugate. In the case of an antigen label, the second compound may include an antibody-enzyme conjugate. Additionally, certain fluorescent groups can act as secondary labels by transferring energy to another compound or group in the process of non-radioactive fluorescence resonance energy transfer (FRET), causing the second compound or group to generate a signal that is then detected.

[0055] The terms "fluorescent label," "fluorescent group," "fluorescent compound," "fluorochrome," and "fluorophore," as used herein, refer to a compound or moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent compounds include Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine Dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-Dimethoxy-Fluorescein, DM-NERF, Eosin, Erythrosine, Fluorescein, FAM, Hydroxycoumarin, IRDye (IRD40, IRD700, IRD800), JOE, Lissamine, Rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

[0056] The term "substrate" as used herein refers to any material or polymer composite to which a polymer can be bonded. Examples of commonly used substrates include, but are not limited to, glass surfaces, silica surfaces, plastic surfaces, metal surfaces, surfaces containing metal or chemical coatings, membranes (e.g., nylon, polysulfone, silica), microbeads (e.g., latex, polystyrene, or other polymers), porous polymer matrices (e.g., polyacrylamide gels, polysaccharides, polymethacrylates), and polymer composites (e.g., proteins, polysaccharides).

[0057] The term "as received" when referring to the use of solvents, reagents, resins, or other components used in chemical reactions or isolations refers to use in the state provided by the manufacturer without any additional isolation and / or purification.

[0058] As used herein, the term "protein" or "polypeptide" refers to a polymer of one or more amino acids joined through peptide bonds. Proteins generally contain more than 20 such amino acids. The term encompasses a single polypeptide chain or multiple polypeptide chains complexed together or covalently linked together (e.g., via disulfide bonds).

[0059] As used herein, the terms "drug," "therapeutic," "pharmaceutical," "medicine," and derivatives thereof, are used interchangeably and refer to a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. A drug or therapeutic agent can be a peptide, protein, nucleic acid, small molecule, lipid, cell, or other agent. In one embodiment, the drug or therapeutic agent is encapsulated by a particle described herein.

[0060] As used herein, "unit dosage form" or "unit dose form" refers to a physically discrete unit of formulation appropriate for the subject to be treated. However, it will be understood that the total daily usage amount of the compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend on various factors, including the disorder being treated and the severity of the disorder, the activity of the specific active agent used, the specific composition used, the age, weight, general health, sex, and diet of the subject, the administration time and excretion rate of the specific active agent used, the duration of treatment, drugs and / or additional therapies used in combination with or simultaneously with the specific compound(s) used, and similar factors well known in the medical field.

[0061] As used herein, the term "lipid" or "lipid component" refers to a group of organic compounds that contain esters of fatty acids and are generally poorly soluble in water but soluble in many organic solvents. They are typically divided into at least three classes: (1) "simple lipids," which include fats, oils, and waxes; (2) "complex lipids," which include phospholipids and glycolipids; and (3) "derived lipids," such as steroids. Lipids or lipid components include any lipid known in the art, such as phospholipids, PEGylated lipids, steroids, cationic lipids, anionic lipids, or fatty acids.

[0062] As used herein, the term "lipid nanoparticle" refers to a particle comprising multiple lipid molecules physically associated with each other by intermolecular forces. Preferably, the lipid nanoparticle is formulated to deliver a payload to one or more target cells. Examples of suitable lipids include, for example, lipids of formula (I) to (Ie). The lipid nanoparticle can be, for example, a liposome / niosome, a nanostructured lipid carrier, a microsphere, the dispersed phase in an emulsion, a micelle, or the internal phase in a suspension.

[0063] As used herein, the term "liposome" refers to a closed multilamellar structure formed by an outer lipid bilayer surrounding an aqueous interior compartment.

[0064] As used herein, the term "phospholipid" refers to any lipid containing a phosphate group or phosphate ion. In some embodiments, "phospholipid" may refer to a triester of glycerol having two aliphatic chains and one alkyl chain containing a phosphate ion. Exemplary phospholipids include naturally occurring phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol, as well as synthetic phospholipids such as diacylglycerol, phosphatidic acid, phosphocholine, phosphoethanolamine, and phosphoglycerol.

[0065] As used herein, the term "enclose" means to surround, enclose, or encase.

[0066] As used herein, " ionizable " refers to a molecule that can be protonated in response to changes in pH. For example, an ionizable lipid is a lipid that is neutral at physiological pH but is protonated at lower pH values.

[0067] Polysarcosine lipid complex The present disclosure relates to polymers comprising hydrophilic poly(sarcosine) chains and hydrophobic aliphatic groups. In some embodiments, the present disclosure relates to polymers of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , and R 2 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be one or more R 3 optionally substituted with R 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, heteroalkyl, or OR C and z is 5 to 250. In one embodiment, R 1a and R 1b At least one of is independently alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0068] In some embodiments, the present disclosure relates to a polymer of formula (I), wherein R 1a , R 1b , and R 2 wherein one or more of R is alkyl, alkenyl, or alkynyl, and the resulting polymer has overall hydrophobic properties. In some embodiments, the present disclosure relates to a polymer of formula (I), wherein R 1a is alkyl, alkenyl, or alkynyl, and the resulting polymer has overall hydrophobic properties. In some embodiments, the present disclosure relates to a polymer of formula (I), wherein R 1b is alkyl, alkenyl, or alkynyl, and the resulting polymer has overall hydrophobic properties. In some embodiments, the present disclosure relates to a polymer of formula (I), wherein R 2 is alkyl, alkenyl, or alkynyl, and the resulting polymer has overall hydrophobic properties.

[0069] As mentioned above, the present disclosure relates to polymers in which the hydrophilic chain comprises a polymer of N-methylglycine (i.e., poly(sarcosine)). The present disclosure further contemplates other N-alkylglycines that can be used to generate water-soluble chains (see Robinson, J. Wet al. Macromolecules 2013, 46(3), 580). In some embodiments, the present disclosure encompasses polymers in which the hydrophilic chain is poly(N-methylglycine), poly(N-ethylglycine), poly(N-{n-propyl})glycine, poly(N-isopropyl)glycine, or poly(N-allyl)glycine. In some aspects, the present disclosure also encompasses mixtures of two or more N-alkylglycines used to construct water-soluble chains, such as a mixture of N-methylglycine and N-ethylglycine.

[0070] Also, as noted above, in some embodiments, R in the polymer of Formula (I) 1a , R 1b , and R 2 are optionally and independently substituted. For example, in some embodiments, such optional and independent substitutions contemplated by the present disclosure include, but are not limited to, an optionally substituted benzyl group, an optionally substituted alkyl, alkenyl, alkynyl, or heteroalkyl group, an optionally substituted silyl group, a poly(amino acid) polymer, a poly(ethylene glycol) polymer, a poly(N-isopropylacrylamide) polymer, a poly(acrylamide) polymer, a poly(2-oxazoline) polymer, a poly(ethyleneimine), a poly(acrylic acid) polymer, a poly(methacrylate) polymer, a poly(vinyl alcohol) polymer, a poly(vinylpyrrolidone) polymer, and their corresponding amine salts.

[0071] In some embodiments of Formula (I), R 1a is alkyl, alkenyl, alkynyl, or cycloalkyl, and R 1b and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a is alkyl, and R1b and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a is alkenyl and R 1b and R 2 is hydrogen and z is 5 to 30. In some embodiments, R 1a is alkynyl and R 1b and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a is a C10-C20 alkyl, and R 1b and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a is C10-C20 alkenyl, and R 1b and R 2 is hydrogen and z is 5 to 30. In some embodiments, R 1a is C10-C20 alkynyl, and R 1b and R 2 is hydrogen and z is 5-30.

[0072] In some embodiments of Formula (I), R 1a is one or more R 3 and R is alkyl optionally substituted with 1b and R 2 is hydrogen, z is 5 to 30, and R 3 is halo, hydroxy, cyano, nitro, oxo, or aryl. In some embodiments of Formula (I), R 1a is one or more R 3 and R is an alkenyl optionally substituted with 1b and R 2 is hydrogen, z is 5 to 30, and R 3 is halo, hydroxy, cyano, nitro, oxo, or aryl. In some embodiments of Formula (I), R 1a is one or more R 3 alkynyl optionally substituted with R 1b and R 2 is hydrogen, z is 5 to 30, and R 3is halo, hydroxy, cyano, nitro, oxo or aryl.

[0073] In some embodiments of Formula (I), R 1b is alkyl, alkenyl, alkynyl, or cycloalkyl, and R 1a and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1b is alkyl, and R 1a and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1b is alkenyl and R 1a and R 2 is hydrogen and z is 5 to 30. In some embodiments, R 1b is alkynyl and R 1a and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1b is one or more R 3 and R is an alkenyl optionally substituted with 1a and R 2 is hydrogen, z is 5 to 30, and R 3 is halo, hydroxy, cyano, nitro, oxo or aryl.

[0074] In some embodiments of Formula (I), R 1a and R 1b are each alkyl, and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a and R 1b are each C5 to C11 alkyl, and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a and R 1b are each alkenyl, and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a and R 1b are each C5-C11 alkenyl, and R 2is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a and R 1b are each alkynyl, and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a and R 1b are each C5-C11 alkynyl, and R 2 is hydrogen and z is 5-30.

[0075] In some embodiments of Formula (I), R 1a is alkyl, and R 1b is alkenyl and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a is a C5-11 alkyl, and R 1b is C5-C11 alkenyl, and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a is alkenyl and R 1b is alkyl, and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a is C5-11 alkenyl, and R 1b is a C5-C11 alkyl, and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a is alkyl, and R 1b is alkynyl and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a is a C5-11 alkyl, and R 1b is C5-C11 alkynyl, and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a is alkynyl and R 1b is alkyl, and R 2 is hydrogen and z is 5 to 30. In some embodiments of Formula (I), R 1a is C5-11 alkynyl, and R1b is a C5-C11 alkyl, and R 2 is hydrogen and z is 5 to 30.

[0076] In some embodiments, the present disclosure provides a polymer of formula (I) 1a , R 1b , and R 2 Substitutions at R are contemplated, which may add a non-normally present functional group, including, but not limited to, a detectable moiety, a fluorescent label, or a substrate. Those skilled in the art will recognize that isotopically enriched materials may be useful probes in biological assays, such as quantitative whole-body autoradiography (QWBA) assays, which are useful for determining the distribution of compositions in animals. In certain embodiments, R 1a , R 1b , or R 2 is isotopically enriched. In some embodiments, R 1aは , 14 C contains isotopically enriched hydrocarbons. In some embodiments, R 2 teeth 14 Contains C isotope-enriched hydrocarbons.

[0077] In some embodiments, the polymer of Formula (I) has Formula (Ia): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is alkyl, alkenyl, alkynyl, or heteroalkyl, each of which is one or more R 3 optionally substituted with R 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, heteroalkyl, or ORC and z is 5 to 250.

[0078] In some embodiments of Formula (Ia), R 1 is alkyl and Z is 10 to 30. In some embodiments of Formula (Ia), R 1 is C11-19 alkyl and z is 10 to 30. In some embodiments of Formula (Ia), R 1 is alkenyl and Z is 10 to 30. In some embodiments of Formula (Ia), R 1 is C alkenyl and z is 10 to 30. In some embodiments of Formula (Ia), R 1 is alkynyl and Z is 10 to 30. In some embodiments of Formula (Ia), R 1 is C11-19 alkynyl, and z is 10-30.

[0079] In some embodiments, the polymer of Formula (I) is a polymer of Formula (Ib): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b each of which is (C6-C12) alkyl, (C6-C12) alkenyl, or (C6-C12) alkynyl, and each of which is one or more R 3 optionally substituted with R 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, heteroalkyl, or OR C and z is 5 to 50.

[0080] In some embodiments, the present disclosure provides a polymer of formula (Ic): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b each of which is hydrogen, (C-C) alkyl, (C-C) alkenyl, or (C-C) alkynyl, and each of which is one or more R 3 optionally substituted with R 5 is one or more R 3 is (C11-C19) alkyl, (C11-C19) alkenyl, or (C11-C19) alkynyl optionally substituted with 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, heteroalkyl, or OR C and z is 5 to 50.

[0081] In some embodiments of Formula (Ic), R 2 is (C11-C18) alkyl. In some embodiments of Formula (Ic), R 2 is (C11-C18) alkenyl. In some embodiments of Formula (Ic), R 2 is (C11-C18)alkynyl. In some embodiments of Formula (Ic), R 2 is a C17 alkenyl.

[0082] In some embodiments, the present disclosure provides a polymer of formula (I) of formula (Id): [ka] or a pharmaceutically acceptable salt thereof, wherein R6 , R 7 , and R 8 each is independently hydrogen, heteroalkyl, alkyl, alkenyl, or alkynyl; R 9a , R 9b , R 10a , and R 10b are each independently hydrogen, alkyl, or halo; x and y are each independently an integer of 1 to 20; and z is an integer of 5 to 90.

[0083] In some embodiments of Formula (Id), R 6 , R 7 , and R 8 is hydrogen, each of x and y is independently 1 to 10, and z is 5 to 30. In some embodiments of Formula (Id), R 6 , R 7 , and R 8 is hydrogen, x is 8, y is 8, and z is 5 to 30. In some embodiments of Formula (Id), R 6 , R 7 , and R 8 is hydrogen, x is 8, y is 8, and z is 5. In some embodiments of Formula (Id), R 6 , R 7 , and R 8 is hydrogen, x is 8, y is 8, and z is 10. In some embodiments of Formula (Id), R 6 , R 7 , and R 8 is hydrogen, x is 8, y is 8, and z is 15. In some embodiments of Formula (Id), R 6 , R 7 , and R 8 is hydrogen, x is 8, y is 8, and z is 20. In some embodiments of Formula (Id), R 6 , R 7 , and R 8 is hydrogen, x is 8, y is 8, and z is 5 to 25. In some embodiments of Formula (Id), R 6 , R 7 , and R 8is hydrogen, x is 8, y is 8, and z is 30.

[0084] In some embodiments, the present disclosure provides a polymer of formula (I) of formula (Ie): [ka] or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , and R 8 each is independently hydrogen, heteroalkyl, alkyl, alkenyl, or alkynyl; R 9a , R 9b , R 10a , and R 10b are each independently hydrogen, alkyl, or halo; x and y are each independently an integer of 1 to 20; and z is an integer of 5 to 90.

[0085] In some embodiments of Formula (Ie), R 6 , R 7 , and R 8 is hydrogen, each of x and y is independently 1 to 10, and z is 5 to 30. In some embodiments of Formula (Ie), R 6 , R 7 , and R 8 is hydrogen, x is 8, y is 8, and z is 5 to 30. In some embodiments of Formula (Ie), R 6 , R 7 , and R 8 is hydrogen, x is 8, y is 8, and z is 5. In some embodiments of Formula (Ie), R 6 , R 7 , and R 8 is hydrogen, x is 8, y is 8, and z is 10. In some embodiments of Formula (Ie), R 6 , R 7 , and R 8 is hydrogen, x is 8, y is 8, and z is 15. In some embodiments of Formula (Ie), R 6 , R 7 , and R 8is hydrogen, x is 8, y is 8, and z is 20. In some embodiments of Formula (Ie), R 6 , R 7 , and R 8 is hydrogen, x is 8, y is 8, and z is 5 to 25. In some embodiments of Formula (Ie), R 6 , R 7 , and R 8 is hydrogen, x is 8, y is 8, and z is 30.

[0086] In some embodiments, the present disclosure provides a polymer of formula (If): [ka] or a pharmaceutically acceptable salt thereof, wherein z is 5 to 90.

[0087] In some such embodiments of Formula (If), z is 10. In some such embodiments, z is 11. In some such embodiments, z is 12. In some such embodiments, z is 13. In some such embodiments, z is 14. In some such embodiments, z is 15. In some such embodiments, z is 16. In some such embodiments, z is 17. In some such embodiments, z is 18. In some such embodiments, z is 19. In some such embodiments, x is 20. In some such embodiments, z is 21. In some such embodiments, z is 22. In some such embodiments, z is 23. In some such embodiments, z is 24. In some such embodiments, z is 25. In some such embodiments, z is 26. In some such embodiments, z is 27. In some such embodiments, z is 28. In some such embodiments, z is 29. In some such embodiments, x is 30. In some such embodiments, x is 35. In some such embodiments, x is 40. In some such embodiments, x is 45.

[0088] In some embodiments, the present disclosure provides a polymer of formula (Ig): [ka] or a pharmaceutically acceptable salt thereof, wherein z is 5 to 90.

[0089] In some such embodiments of Formula (Ig), z is 10. In some such embodiments, z is 11. In some such embodiments, z is 12. In some such embodiments, z is 13. In some such embodiments, z is 14. In some such embodiments, z is 15. In some such embodiments, z is 16. In some such embodiments, z is 17. In some such embodiments, z is 18. In some such embodiments, z is 19. In some such embodiments, x is 20. In some such embodiments, z is 21. In some such embodiments, z is 22. In some such embodiments, z is 23. In some such embodiments, z is 24. In some such embodiments, z is 25. In some such embodiments, z is 26. In some such embodiments, z is 27. In some such embodiments, z is 28. In some such embodiments, z is 29. In some such embodiments, x is 30. In some such embodiments, x is 35. In some such embodiments, x is 40. In some such embodiments, x is 45.

[0090] In some embodiments, the present disclosure provides particles comprising a polymer of any of the following structures for use in accordance with the present invention: [ka] [ka] [ka]

[0091] In some embodiments, the present disclosure provides a polymer of the following structure: [ka]

[0092] In some embodiments, the present disclosure provides a polymer of the following structure: [ka]

[0093] In some embodiments, the present disclosure provides a polymer of the following structure: [ka]

[0094] In some embodiments, the present disclosure provides a polymer of the following structure: [ka]

[0095] Lipids and lipid components The present disclosure provides particle compositions (e.g., lipid nanoparticles, e.g., liposomes) comprising a lipid or lipid component, such as a phospholipid, a PEGylated lipid, or a steroid. In one embodiment, the lipid or lipid component is a phospholipid. In some embodiments, the phospholipid is one of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol, or derivatives thereof. In some embodiments, the phospholipid is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein each R 9 and R 10 independently, one or more R 3 is alkyl, alkenyl, or alkynyl optionally substituted with R 11 is one or more R 12 is alkyl, alkenyl, alkynyl, or heteroalkyl optionally substituted with R 3 is one or more R 4hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, heteroalkyl, or OR C and R 12 is alkyl, alkenyl, alkynyl, -NR D R E , oxo, or hydroxy, and R D and R E Each of is independently hydrogen or alkyl.

[0096] In some embodiments, the phospholipid is a phosphatidylcholine. In some embodiments, the phospholipid of Formula (II) is a compound of Formula (II-a): [ka] or a pharmaceutically acceptable salt thereof, wherein each R 9 and R 10 independently, one or more R 3 is (C1-C25) alkyl, (C2-C25) alkenyl, or (C2-C25) alkynyl optionally substituted with 13 , R 14 , and R 15 each independently represents one or more R 12 is alkyl, alkenyl, alkynyl, or heteroalkyl optionally substituted with R 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, heteroalkyl, or OR Cand R 12 is alkyl, alkenyl, alkynyl, oxo, or hydroxy.

[0097] In some embodiments of Formula (II-a), R 9 , R 10 , R 13 , R 14 , and R 15 Each of is alkyl. In some embodiments of Formula (II-a), R 9 and R 10 each of R is alkenyl; 13 , R 14 , and R 15 is alkyl. In some embodiments of Formula (II-a), R 9 and R 10 Each of R is a C6 alkyl; 13 , R 14 , and R 15 Each of is C alkyl. In some embodiments of Formula (II-a), R 9 and R 10 Each of R is a C7 alkyl; 13 , R 14 , and R 15 Each of is C alkyl. In some embodiments of Formula (II-a), R 9 and R 10 Each of R is a C8 alkyl; 13 , R 14 , and R 15 Each of is a C1 alkyl.

[0098] In some embodiments, the phospholipid is phosphatidylserine. In some embodiments, the phospholipid of Formula (II) is a compound of Formula (II-b): [ka] or a pharmaceutically acceptable salt thereof, wherein each R 9 and R 10 independently, one or more R 3is (C1-C25) alkyl, (C2-C25) alkenyl, or (C2-C25) alkynyl optionally substituted with 16 and R 17 each independently represents one or more R 12 is alkyl, alkenyl, alkynyl, or heteroalkyl optionally substituted with R 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, heteroalkyl, or OR C and R 12 is alkyl, alkenyl, alkynyl, -NR D R E , oxo, or hydroxy, and R D and R E Each of is independently hydrogen or alkyl.

[0099] In some embodiments of Formula (II-b), R 9 and R 10 each of which is alkyl and R 16 Ha-NR D R E and R 17 is hydroxy and R D and R E are hydrogen atoms.

[0100] In some embodiments, the phospholipid is phosphatidylglycerol. In some embodiments, the phospholipid of Formula (II) is a compound of Formula (II-c): [ka] or a pharmaceutically acceptable salt thereof, wherein each R 9 and R 10 independently, one or more R 3is (C1-C25) alkyl, (C2-C25) alkenyl, or (C2-C25) alkynyl optionally substituted with 18 and R 19 each independently represents one or more R 12 is alkyl, alkenyl, alkynyl, or heteroalkyl optionally substituted with R 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, heteroalkyl, or OR C and R 12 is alkyl, alkenyl, alkynyl, -NR D R E , oxo, or hydroxy, and R D and R E Each of is independently hydrogen or alkyl.

[0101] In some embodiments, the phospholipid is phosphatidylethanolamine. In some embodiments, the phospholipid is a compound of formula (II-d): [ka] or a pharmaceutically acceptable salt thereof, wherein each R 9 and R 10 independently, one or more R 3 is (C1-C25) alkyl, (C2-C25) alkenyl, or (C2-C25) alkynyl optionally substituted with 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R Cis hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, heteroalkyl, or OR C and R 12 is alkyl, alkenyl, alkynyl, -NR D R E , oxo, or hydroxy, and R D and R E Each of is independently hydrogen or alkyl.

[0102] In some embodiments, the phospholipid is 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-di Undecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 diether PC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME16).0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoyloleoylphosphatidylethanolamine (POPE), distearoyl-phosphatidylethanolamine (DSP) E), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), 1-stearoyl-2-oleoyl-phosphatidylethanolamine (SOPE), 1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC), sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloleoylphosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine (LPE), decyl (2-(dioctylammonio)ethyl)phosphate, ethylphosphatidylcholine (ePC), or a salt thereof.

[0103] In some embodiments, the lipid is a polyethylene glycol-modified (PEGylated) lipid or a derivative thereof. In one embodiment, the PEGylated lipid is selected from the group consisting of methoxypolyethylene-glycoloxy(2000)-N,N-ditetradecylacetamide (ALC-0159), 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000), 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-5000 (DMG-PEG 5000), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DOPE-PEG 2000), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-5000] (DOPE-PEG 5000), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG 2000), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-5000] (DSPE-PEG 5000), distearoyl-rac-glycerol-PEG2K (DSG-PEG 2000), and distearoyl-rac-glycerol-PEG5K (DSG-PEG 5000).

[0104] In some embodiments, the phospholipid is a combination of one or more phospholipids of formula (II)-(II-d) described herein.

[0105] In another aspect, the present disclosure provides a particle composition (e.g., lipid nanoparticle, e.g., liposome) comprising a steroid. In some embodiments, the steroid is cholesterol or a derivative thereof. In some embodiments, the steroid is a compound of formula (III): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein each of ring positions 1-17 is selected from the group consisting of one or more R3 optionally substituted with R 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, alkenyl, alkynyl, heteroalkyl, or OR C and R 12 is alkyl, alkenyl, alkynyl, -NR D R E , oxo, or hydroxy, and R D and R E are independently hydrogen or alkyl, and the dotted line "---" represents a single or double bond as determined by the rules of chemical valence.

[0106] In some embodiments of Formula (III), ring positions 3, 10, 13, and 17 each contain one R 3 and the bond between ring positions 5 and 6 is a double bond. In some embodiments, the compound of Formula (III) is a gonane or a derivative thereof. In some embodiments, the compound of Formula (III) is a sterol or a derivative thereof. In some embodiments, the compound of Formula (III) is cholesterol or a derivative thereof.

[0107] In some embodiments, the steroid of formula (III) is a compound of formula (III-a): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , and R 27 each independently represents one or more R3 is hydrogen, oxo, hydroxy, halo, alkyl, alkenyl, alkynyl, or heteroalkyl optionally substituted with R 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, alkenyl, alkynyl, heteroalkyl, or OR C and R 12 is alkyl, alkenyl, alkynyl, -NR D R E , oxo, or hydroxy, and R D and R E Each of is independently hydrogen or alkyl.

[0108] In some embodiments of Formula (III-a), R 21 is OR C and R 24 and R 25 is alkyl (e.g., methyl), and R 26 There are two R 3 and R is alkyl (e.g., heptyl) substituted with 22 , R 23 , and R 27 is hydrogen and R 3 is alkyl (e.g., methyl). In some embodiments of Formula (III-a), the compound of Formula (III-a) is a gonane or a derivative thereof. In some embodiments, the compound of Formula (III-a) is a sterol or a derivative thereof. In some embodiments, the compound of Formula (III-a) is cholesterol or a derivative thereof.

[0109] In some embodiments, the steroid of formula (III) is a compound of formula (III-b): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 each independently represents one or more R 3 is hydrogen, oxo, hydroxy, halo, alkyl, alkenyl, alkynyl, or heteroalkyl optionally substituted with R 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, alkenyl, alkynyl, heteroalkyl, or OR C and R 12 is alkyl, alkenyl, alkynyl, -NR D R E , oxo, or hydroxy, and R D and R E Each of is independently hydrogen or alkyl.

[0110] In some embodiments of Formula (III-b), R 31 is OR A (e.g., hydroxyl, e.g., —OH), and R 32 , R 33 , R 34 , R 35 , and R 36 is alkyl (e.g., methyl).

[0111] In some embodiments, the steroid is cholesterol or a cholesterol derivative. In some embodiments, the cholesterol derivative is cholesta-5,7-dien-3β-ol, cholest-5-en-3-ol, 7β-hydroxycholesterol, cholest-7-en-3β-ol, lanosta-8,24-dien-3-ol, (3S,8S,9S,10R,13R,14S,17R)-17-[(2S,5S)-5-ethyl-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthate. phenanthren-3-ol, (3S)-17-[(5S)-5-ethyl-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol, (3S,8S,9S,10R,13R,14S,17R)-17-[(2R,5S)-5-ethyl-6-methylhept-3-en-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol 17-[(5R)-5,6-dimethylheptan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3-ol, cholesteryl isopropyl ether, stigmast-5-en-3-ol, 10-(iodomethyl)-17-(6-methylheptan-2-yl)-1,2,3,4,7,8,9,11,12,13,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3-ol Phenanthrene-3-ol, (3S,5S,10S,13R,17R)-3-hydroxy-10,13-dimethyl-17-(6-methylheptan-2-yl)-1,2,3,4,5,6,7,9,11,12,16,17-dodecahydrocyclopenta[a]phenanthrene-15-one, 25-hydroxycholesterol, lathosterol, 3-methoxycholest-5-ene, 17-(5-ethyl-6-methylhept-6-en-2-yl)-4,10,13-trimethyl-2,3,4,5,6,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol, 17-(5,6-dimethylheptan-2-yl)-10,13-dimethyl-2,3,4,5,6,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol, (7R,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro- 1H-Cyclopenta[a]phenanthrene-3,7-diol, 24-methylenecholesterol, zymosterol, BHEM-cholesterol, 2-(((((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)-N,N-bis(2-hydroxyethyl) (N-methylethane-1-aminium bromide), DC-cholesterol, 3β-[N-(N',N'-dimethylaminoethane)carbamoyl]cholesterol, dihydrocholesterol, ent-cholesterol, epi-cholesterol, desmosterol, cholestanol, cholestanone, cholestenone, cholesteryl-2'-hydroxyethyl ether, cholesteryl-4'-hydroxybutyl ether, 3β-[N-(N'N'-dimethylaminoethyl)carbamoylcholesterol (DC-Chol), 24(S)-hydroxycholesterol, 25-hydroxycholesterol, 25(R)-27-hydroxycholesterol, 22-oxacholesterol, 23-oxacholesterol, 24-oxacholesterol, cycloartenol, 22-ketosterol, 20-hydroxysterol, 7-hydroxycholesterol, 19-hydroxycholesterol, 22-hydroxycholesterol, 25-hydroxycholesterol, 7-dehydrocholesterol, 5α-cholest-7-en-3β-ol, 3,6,9-trioxaoctan-1-ol-cholesteryl-3e-ol, dehydroergosterol, dehydroepiandrosterone, lanosterol, dihydrolanosterol, lanostenol, lumisterol, cytocalciferol, calcipotriol, coprostanol, cholecalciferol, lupeol, ergocalciferol, 22-dihydroegocalciferol, ergosterol, brassicasterol, tomatidine, tomatine, ursolic acid, cholic acid, chenodeoxycholic acid, zymosterol, diosgenin, fucosterol, fecosterol, or fecosterol, or a salt, stereoisomer, or tautomer thereof.

[0112] In some embodiments, the lipid is a cationic lipid or an ionizable lipid (i.e., a lipid that can be protonated at low pH). In some embodiments, the lipid (e.g., a cationic lipid or an ionizable lipid) is a compound of formula (IV): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 41 , R 42 , R 43 , R 44 , R 45 , and R 46 each independently represents one or more R 3 and each of W, X, Y, and Z is independently —N(R 3 )-, -N(R 3 )(R3')-, or C(R 3 )(R 3 ')- and R 3 and R 3 ' is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and RC is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, alkenyl, alkynyl, heteroalkyl, or OR C and R 12 is alkyl, alkenyl, alkynyl, -NR D R E , oxo, or hydroxy, and R D and R E Each of is independently hydrogen or alkyl.

[0113] In some embodiments, the lipid is a compound of formula (IV-a): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein each R 47 , R 48 , and R 49 independently, one or more R 3 is hydrogen, oxo, hydroxy, halo, alkyl, alkenyl, alkynyl, or heteroalkyl optionally substituted with R 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, alkenyl, alkynyl, heteroalkyl, or OR C and R 12 is alkyl, alkenyl, alkynyl, -NR D R E , oxo, or hydroxy, and R D and R E Each of is independently hydrogen or alkyl.

[0114] In some embodiments, the lipid is a compound of formula (II-b): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , and R 58 independently, one or more R 3 is hydrogen, oxo, hydroxy, halo, alkyl, alkenyl, alkynyl, or heteroalkyl optionally substituted with R 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, alkenyl, alkynyl, heteroalkyl, or OR C and R 12 is alkyl, alkenyl, alkynyl, -NR D R E , oxo, or hydroxy, and R D and R E Each of is independently hydrogen or alkyl.

[0115] In some embodiments, the lipids (e.g., cationic lipids or ionizable lipids) are selected from the group consisting of lipids described in International Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, and WO2012054365. , WO2012044638, WO2010080724, WO201021865, and WO2008103276, U.S. Patent Nos. 7,893,302, 7,404,969, and 8,283,333, and U.S. Patent Publication Nos. US20100036115 and US20120202871.

[0116] In some embodiments, the lipid (e.g., any lipid, cationic lipid, or ionizable lipid) is didecyldimethylammonium bromide, 1,2-dioleoyloxy-3-(trimethylammonium)propane, dioctiadecylamine, trimethyl[2,3-(dioleoyloxy)propyl]ammonium, N-tert-butyl-N'-tetradecyl-3-(tetradecylamino)propanimidamide, cetrimonium, tridodecylamine, dimethyldioctadecylammonium, stearyltrimethylammonium, amine, N,N-dimethyltetradecylamine, trioctylamine, cetrimide, dihexadecyldimethylammonium, dimethyldipalmitylammonium, hexadecyldimethylamine, methyltrioctylammonium, dipalmitylamine, dimyristylamine, 1,2-di(oleoyloxy)-3-(dimethylamino)propane, or 2,5-bis(3-aminopropylamino)-N-[2-[di(heptadecyl)amino]-2-oxoethyl]pentanamide, ([(4-hydroxybutyl)azanediyl]di(hexane- 6,1-diyl)bis(2-hexyldecanoate) (ALC-0315), 9-heptadecanyl 8-{(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino}octanoate (SM-102), N,N-dimethyl-2,3-dioleyloxypropylamine (DODMA), N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(l-(2,3-dioleoyloxy)propyl)-N,N ,N-trimethylammonium chloride (DOTAP), N-(l-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[l,3]-dioxolane (DLin-KC2-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA), or a pharmaceutically acceptable salt thereof.

[0117] particle composition The present disclosure features particles (e.g., lipid nanoparticles) and related compositions comprising the polysarcosine lipid conjugates described herein (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig)). Exemplary lipid nanoparticles include liposomes / niosomes, nanostructured lipid carriers, cationic lipid-nucleic acid complexes, and solid lipid nanoparticles. Details regarding each of the foregoing particles are provided in more detail below.

[0118] lipid nanoparticles Described herein are lipid nanoparticle compositions comprising polysarcosine lipid complexes, e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), as described herein. In some embodiments, the present disclosure provides particles comprising: (i) polysarcosine lipid complexes (e.g., polymers of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig)); (ii) phospholipids (e.g., compounds of Formulas (II)-(II-e)); (iii) steroids (e.g., compounds of Formulas (III)-(III-b)); (iv) a payload (e.g., a nucleic acid or a drug); and (v) an additional lipid component (e.g., a cationic lipid, e.g., an ionizable lipid, e.g., a compound of Formulas (IV)-(IV-e)), wherein each of components (i)-(iv) is as described herein.

[0119] Exemplary lipid nanoparticle compositions are disclosed in International Patent Publication No. WO2010005721, U.S. Pat. No. 10,703,789, US20200254086, U.S. Pat. No. 11,406,706, and US20200345641, each of which is incorporated by reference herein in its entirety.

[0120] In some embodiments, the lipid nanoparticles contain a polysarcosine lipid conjugate (e.g., a polymer of any of Formulas (I)-(Ig) described herein) in an amount of 0.1 to 50 mol%, 0.1 to 45 mol%, 0.1 to 40 mol%, 0.1 to 35 mol%, 0.1 to 30 mol%, 0.1 to 20 mol%, 0.25 to 20 mol%, 0.5 to 20 mol%, 1 to 20 mol%, 1.5 to 20%, 0.1 to 15 mol%, 0.25 to 15 mol%, 0.5 to 15 mol%, 1 to 15 mol%, 1.5 to 15 mol%, 2 to 15 mol%, 2.5 to 15 mol%, 0.1 to 12. 5 mol%, 0.25 to 12.5 mol%, 0.5 to 12.5 mol%, 1 to 12.5 mol%, 1.5 to 12.5 mol%, 2 to 12.5 mol%, 2.5 to 12.5 mol%, 0.1 to 10 mol%, 0.25 to 10 mol%, 0.5 to 10 mol%, 1 to 10 mol%, 1.5 to 10 mol%, 2 to 10 mol%, 2.5 to 10 mol%, 0.1 to 7.5 mol%, 0.25 to 7.5 mol%, 0.5 to 7.5 mol%, 1 to 7.5 mol%, 1.5 to 7.5 mol%, 2 to 7.5 mol%, 2.5 to 7.5 mol%, 0.1 to 5 mol%, 0.25 to 5 mol%, 0.5 to 5 mol% , 1 to 5 mol%, 1.5 to 5 mol%, 2 to 5 mol%, 2.5 to 5 mol%, 0.1 to 3 mol%, 0.25 to 3 mol%, 0.5 to 3 mol%, 1 to 3 mol%, 1.5 to 3 mol%, 2 to 3 mol%, 2.5 to 3 mol%, 0.1 to 2.5 mol%, 0.25 to 2.5 mol%, 0.5 to 2.5 mol%, 1 to 2.5 mol%, 1.5 to 2.5 mol%, 2 to 2.5 mol%, 0.1 to 4.5 mol%, 0.25 to 4.5 mol%, 0.5 to 4.5 mol%, 1 to 4.5 mol%, 1.5 to 4.5 mol%, 2 to 4.5 mol%, 2.5 to 4.5 mol%, 0.1 to 4 mol%, 0.2 The amount may be 5 to 4 mol%, 0.5 to 4 mol%, 1 to 4 mol%, 1.5 to 4 mol%, 2 to 4 mol%, 2.5 to 4 mol%, 0.1 to 3.5 mol%, 0.25 to 3.5 mol%, 0.5 to 3.5 mol%, 1 to 3.5 mol%, 1.5 to 3.5 mol%, 2 to 3.5 mol%, 2.5 to 3.5 mol%, 0.1 to 2.0 mol%, 0.1 to 1.5 mol%, 0.1 to 1.0 mol%, 0.5 to 2.0 mol%, 0.5 to 1.5 mol%, 0.5 to 1.0 mol%, 1.0 to 2.0 mol%, 1.0 to 1.5 mol%, 1.5 to 2.0 mol%, 1.0 mol%, or 1.5 mol%.

[0121] In some embodiments, the lipid nanoparticles comprise polysarcosine lipid conjugates (e.g., polymers of any of Formulas (I)-(Ig) described herein) in an amount greater than 70 mol%, greater than 65 mol%, greater than 60 mol%, greater than 55 mol%, greater than 50 mol%, greater than 45 mol%, greater than 40 mol%, greater than 35 mol%, greater than 30 mol%, greater than 25 mol%, greater than 20 mol%, greater than 15 mol%, greater than 10 mol%, greater than 5 mol%, greater than 1 mol%, or greater than 0.1 mol%. In some embodiments, the lipid nanoparticles comprise polysarcosine lipid conjugates (e.g., polymers of any of Formulas (I)-(Ig) described herein) in an amount of less than 70 mol%, less than 65 mol%, less than 60 mol%, less than 55 mol%, less than 50 mol%, less than 45 mol%, less than 40 mol%, less than 35 mol%, less than 30 mol%, less than 25 mol%, less than 20 mol%, less than 15 mol%, less than 10 mol%, less than 5 mol%, less than 1 mol%, or less than 0.1 mol%.

[0122] In some embodiments, the lipid nanoparticles contain phospholipids (e.g., compounds of Formula (II) to (II-e) described herein) at 1 to 75 mol%, 5 to 7 mol%, 10 to 75 mol%, 20 to 75 mol%, 35 to 75 mol%, 1 to 60 mol%, 5 to 60 mol%, 10 to 60 mol%, 20 to 60 mol%, 30 to 60 mol%, 1 to 50 mol%, 5 to 50 mol%, %, 5 to 40 mol%, 5 to 30 mol%, 5 to 25 mol%, 5 to 20 mol%, 5 to 15 mol%, 5 to 13 mol%, 5 to 10 mol%, 10 to 30 mol%, 10 to 25 mol%, 10 to 20 mol%, 10 to 15 mol%, 10 to 13 mol%, 15 to 30 mol%, 15 to 25 mol%, 15 to 20 mol%, 20 to 30 mol%, or 20 to 25 mol%.

[0123] In some embodiments, the lipid nanoparticles comprise phospholipids (e.g., a compound of any of Formulas (II)-(II-e) described herein) in an amount greater than 85 mol%, greater than 80 mol%, greater than 75 mol%, greater than 65 mol%, greater than 60 mol%, greater than 55 mol%, greater than 50 mol%, greater than 45 mol%, greater than 40 mol%, greater than 35 mol%, greater than 30 mol%, greater than 25 mol%, greater than 20 mol%, greater than 15 mol%, greater than 10 mol%, greater than 5 mol%, greater than 1 mol%, or greater than 0.1 mol%. In some embodiments, the lipid nanoparticles comprise phospholipids (e.g., a compound of any of Formulas (II) to (II-e) described herein) in an amount of less than 80 mol%, less than 75 mol%, less than 70 mol%, less than 65 mol%, less than 60 mol%, less than 55 mol%, less than 50 mol%, less than 45 mol%, less than 40 mol%, less than 35 mol%, less than 30 mol%, less than 25 mol%, less than 20 mol%, less than 15 mol%, less than 10 mol%, less than 5 mol%, less than 1 mol%, or less than 0.1 mol%.

[0124] In some embodiments, the lipid nanoparticles contain a steroid (e.g., cholesterol, e.g., a cholesterol derivative, e.g., a compound of Formula (III)-(III-b) described herein) at 10-60 mol%, 20-60 mol%, 30-60 mol%, 30-55 mol%, 30-52.5 mol%, 30-52 mol%, 30-51 mol%, 30-50 mol%, 30-47 mol%, 30-45 mol%, 30-44 mol%, 30-43 mol%, 30-43 mol%, 30-41 mol%, 30-4 ... 0 to 39 mol%, 35 to 60 mol%, 35 to 55 mol%, 35 to 52.5 mol%, 35 to 52 mol%, 35 to 51 mol%, 35 to 50 mol%, 35 to 47.5 mol%, 35 to 45 mol%, 35 to 44 mol%, 35 to 43.5 mol%, 35 to 43 mol%, 35 to 41.5 mol%, 35 to 40 mol%, 35 to 39 mol%, 37 to 60 mol%, 37 to 55 mol%, 37 to 52. mol%, 37 to 52 mol%, 37 to 51 mol%, 37 to 50 mol%, 37.5 to 47 mol%, 37 to 45 mol%, 37 to 44 mol% , 37-43 mol%, 37-43 mol%, 37.5-41 mol%, 37.5-40 mol%, 37.5-39.5 mol%, 39.5-60 mol%, 39.5-55 mol%, 39.5-52 mol%, 39-52 mol%, 39-51 mol%, 39-50 mol%, 39-47 mol%, 39-45 mol%, 39-44 mol%, 39-43 mol%, 39-43 mol%, 3-4 mol%, 39-40 mol%, 40-60 mol%, 40-55 mol%, 40-52 mol%, 40-52 mol%, 40-51 mol%, 40-5 0 mol%, 40-47 mol%, 40-45 mol%, 40-44 mol%, 40-43 mol%, 40-43 mol%, 40-41.5 mol%, 41-60 mol%, 41.5-55 mol%, 41.5-52 mol%, 41-52 mol%, 41-51 mol%, 41-50 mol%, 41-47 mol%, 41-45 mol%, 41-44 mol%, 41-43 mol%, 41-43 mol%, 43-60 mol%, 43-55 mol%, 43-52 mol%, 43-52 mol%, 43-51 mol%, 43-50 mol%, 43-47.5 mol%, 43-45 mol%, 43-44 mol%, 43-43 mol%, 43-60 mol%, 43-55 mol%, 43-52 mol%, 43-52 mol%, 43-51 mol%, 43-50 mol%, 43-47 mol%, 43-45 mol%, 43-44 mol%, 45-60 mol%, 45-55 mol%, 45-52 mol%, 45-52 mol%, 45-51 mol%, 45-50 mol%, 45-47 mol%, 47-60 mol%, 47 51 to 52 mol%, 51 to 55 mol%, 47.5 to 52 mol%, 47 to 52 mol%, 47 to 51 mol%, 47 to 50 mol%, 50 to 60 mol%, 50 to 55 mol%, 50 to 52 mol%, 50 to 52 mol%, 50 to 52 mol%, 50 to 51 mol%, 51 to 60 mol%, 51 to 55 mol%, 51 to 52.5 mol%, or 51 to 52 mol%, 51 to 60 mol%, 51 to 55 mol%, 51 to 52.5 mol%, or 51 to 52 mol%.

[0125] In some embodiments, the lipid nanoparticles comprise a steroid (e.g., cholesterol, e.g., a cholesterol derivative, e.g., a compound of Formula (III)-(III-b) described herein) in an amount greater than 70 mol%, greater than 65 mol%, greater than 60 mol%, greater than 55 mol%, greater than 50 mol%, greater than 45 mol%, greater than 40 mol%, greater than 35 mol%, greater than 30 mol%, greater than 25 mol%, greater than 20 mol%, greater than 15 mol%, greater than 10 mol%, greater than 5 mol%, greater than 1 mol%, or greater than 0.1 mol%. In some embodiments, the lipid nanoparticles comprise a steroid (e.g., cholesterol, e.g., a cholesterol derivative, e.g., a compound of Formula (III)-(III-b) described herein) in an amount of less than 70 mol%, less than 65 mol%, less than 60 mol%, less than 55 mol%, less than 50 mol%, less than 45 mol%, less than 40 mol%, less than 35 mol%, less than 30 mol%, less than 25 mol%, less than 20 mol%, less than 15 mol%, less than 10 mol%, less than 5 mol%, less than 1 mol%, or less than 0.1 mol%.

[0126] In some embodiments, the lipid nanoparticles include an additional lipid component (e.g., a cationic lipid, e.g., an ionizable lipid, e.g., a compound of Formula (IV)-(IV-c) described herein) in an amount equal to (100-((molar percentage of polysarcosine lipid complex)+(molar percentage of steroid)+(molar percentage of phospholipid))). According to one example, the cationic lipid or ionizable lipid may be present in the lipid nanoparticles at 10-70 mol%, 10-60 mol%, 10-55 mol%, 10-50 mol%, 10-45 mol%, 10-42.5 mol%, 10-40 mol%, 10-35 mol%, 10-30 mol%, 10-26.5 mol%, 10-25 mol%, 10-20 mol%, 15-60 mol%, 15-55 mol%, 15-50 mol%, 15-45 mol%, 10-50 mol%, 10-60 mol%, 10-70 mol%, 10-80 mol%, 10-85 mol%, 10-90 mol%, 10-95 mol%, 10-100 mol%, 10-120 mol%, 10-140 mol%, 10-160 mol%, 10-18 ... 5 to 42.5 mol%, 15 to 40 mol%, 15 to 35 mol%, 15 to 30 mol%, 15 to 26.5 mol%, 15 to 25 mol%, 15 to 20 mol%, 20 to 60 mol%, 20 to 55 mol%, 20 to 50 mol%, 20 to 45 mol%, 20 to 42.5 mol%, 20 to 40 mol%, 20 to 35 mol%, 20 to 30 mol%, 20 to 26.5 mol%, 20 to 25 mol%, 25 to 60 mol%, 25 to 55 mol%, 25 to 50 mol%, 25 to 45 mol%, 25 to 42.5 mol%, 25 to 40 mol%, 25 to 35 mol%, 25 to 30 mol%, 25 to 26.5 mol%, 26.5 to 60 mol%, 26.5 to 55 mol%, 26.5 to 50 mol%, 26.5 to 45 mol%, 26.5 to 42.5 mol%, 26.5 to 40 mol%, 26.5 to 35 mol%, 26.5 to 30 mol%, 30 to 60 mol%, 30 to 55 mol%, 30 to 50 mol%, 30 to 45 mol%, 30 It may be contained in an amount of 42.5 mol%, 30 to 40 mol%, 30 to 35 mol%, 35 to 60 mol%, 35 to 55 mol%, 35 to 50 mol%, 35 to 45 mol%, 35 to 42.5 mol%, 35 to 40 mol%, 40 to 60 mol%, 40 to 55 mol%, 40 to 50 mol%, 40 to 45 mol%, 40 to 42.5 mol%, 42.5 to 60 mol%, 42.5 to 55 mol%, 42.5 to 50 mol%, or 42.5 to 45 mol%.

[0127] In some embodiments, the lipid nanoparticles comprise an additional lipid component (e.g., a cationic lipid, e.g., an ionizable lipid, e.g., a compound of Formula (IV)-(IV-c) described herein) in an amount greater than 70 mol%, greater than 65 mol%, greater than 60 mol%, greater than 55 mol%, greater than 50 mol%, greater than 45 mol%, greater than 40 mol%, greater than 35 mol%, greater than 30 mol%, greater than 25 mol%, greater than 20 mol%, greater than 15 mol%, greater than 10 mol%, greater than 5 mol%, greater than 1 mol%, or greater than 0.1 mol%. In some embodiments, the lipid nanoparticles comprise an additional lipid component (e.g., a cationic lipid, e.g., an ionizable lipid, e.g., a compound of Formula (IV)-(IV-c) described herein) in an amount of less than 70 mol%, less than 65 mol%, less than 60 mol%, less than 55 mol%, less than 50 mol%, less than 45 mol%, less than 40 mol%, less than 35 mol%, less than 30 mol%, less than 25 mol%, less than 20 mol%, less than 15 mol%, less than 10 mol%, less than 5 mol%, less than 1 mol%, or less than 0.1 mol%.

[0128] In some embodiments, the lipid nanoparticles are about 20 nm to about 150 nm, about 30 nm to about 150 nm, about 40 nm to about 150 nm, about 50 nm to about 150 nm, about 60 nm to about 130 nm, about 70 nm to about 110 nm, about 70 nm to about 100 nm, about 80 nm to about 100 nm, about 90 nm to about 100 nm, about 70 nm to about 90 nm, about 80 nm to about 90 nm, about 70 nm to about 80 nm, or or about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, or more, and are substantially non-toxic to human subjects.

[0129] In some embodiments, the average diameter of lipid nanoparticles is determined by dynamic light scattering. In some embodiments, the average diameter of lipid nanoparticles is determined by optical microscopy. In some embodiments, the average diameter of lipid nanoparticles is determined by wide-field microscopy or confocal microscopy. In some embodiments, the average diameter is determined by size exclusion chromatography (SEC) or nuclear magnetic resonance (NMR) spectroscopy.

[0130] In some embodiments, the particles have a net charge or are neutral. In some embodiments, the particles have a net positive charge or a net negative charge. In preferred embodiments, the particles have a net positive charge. In some embodiments, the charge is determined by zeta potential measurement.

[0131] Liposomes Another exemplary particle composition comprising the polysarcosine lipid complexes described herein is a liposome. Liposomes are lipid vesicles composed of a lipid bilayer (e.g., a phospholipid bilayer), often with an additional lipid component (e.g., cholesterol). Liposomes can be made from several different types of lipids, including commonly found phospholipids. Exemplary liposome formulations are disclosed in U.S. Patent No. 10,722,508, U.S. Patent No. 10,220,095, and U.S. Patent No. 11,071,713, each of which is incorporated herein by reference in its entirety.

[0132] The method for preparing multilamellar vesicle lipids is known in the art (see, for example, U.S. Patent No. 6,693,086, the teaching of which is incorporated herein by reference).Vesicle formation can occur spontaneously when lipid membranes are mixed with aqueous solution, but can also be promoted by applying force in the form of shaking using a homogenizer, sonicator, or extrusion device (for example, for a review, see Spuch and Navarro, Journal of Drug Delivery, vol. 2011, Article ID 469679, 12 pages, 2011. doi: 10.1155 / 2011 / 469679).Extruded lipids can be prepared by extruding through a size-reducing filter, as described in Templeton et al., Nature Biotech, 15: 647652, 1997, the teaching of which is incorporated herein by reference for the preparation of extruded lipids.

[0133] Other particles Nanostructured lipid carriers (NLCs) are modified solid lipid nanoparticles (SLNs) that retain the properties of solid lipid nanoparticles (SLNs), improve drug stability and loading capacity, and prevent drug leakage. Polymer nanoparticles (PNPs) are an important component of drug delivery. These nanoparticles can effectively target drug delivery and improve drug stability and controlled drug release. Lipid-polymer nanoparticles (PLNs), a new type of carrier that combines liposomes and polymers, may also be used. These nanoparticles possess the complementary advantages of PNPs and liposomes. PLNs have a core-shell structure, with the polymer core providing a stable structure and the phospholipid shell providing good biocompatibility. In this way, the two components improve drug encapsulation efficiency, promote surface modification, and prevent leakage of water-soluble drugs. For a review, see, for example, Li et al. 2017, Nanomaterials 7, 122; doi:10.3390 / nano7060122.

[0134] payload The present disclosure further provides particle compositions (e.g., lipid nanoparticles, e.g., liposomes, e.g., nanostructured lipid carriers) comprising polysarcosine-lipid conjugates that further comprise a payload. Exemplary payloads include proteins (e.g., enzymes, antibodies, lipoproteins), natural or synthetic peptides, or peptides containing unnatural amino acids, nucleic acids (e.g., DNA or mRNA), or small molecule drugs. In one embodiment, the payload is a therapeutic agent, e.g., an agent useful for treating a disease, disorder, or condition.

[0135] In one embodiment, the payload is a protein. Exemplary proteins include hormones, enzymes, antibodies, cytokines, receptors, or variants and fragments thereof. For example, the payload may be tumor necrosis factor (TNF) alpha or beta, renin, colchicine, prolactin, adrenocorticotropic hormone, vasopressin, somatostatin, lypressin, pancreozymin, leuprolide, alpha-1-antitrypsin, clotting factors (such as factor VIIIC, factor IX, tissue factor, and von Willebrand factor), anticoagulants such as protein C, atrial natriuretic factor, pulmonary surfactant, plasminogen activators other than tissue-type plasminogen activator (t-PA), bombesin, thrombin, hematopoietic growth factors, enkephalinase, RANTES (regulated upon activation and normally expressed and secreted by T cells), human macrophage inflammatory protein (MIP-1-alpha), serum albumin such as human serum albumin, Müllerian inhibitory substance, relaxin A chain, relaxin B chain, proline, or the like. microbial proteins such as laxin, mouse gonadotropin-related peptide, chorionic gonadotropin, β-lactamase, DNase, inhibin, activin, hormone or growth factor receptors, integrins, protein A or D, rheumatoid factor, platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factors (TGFs) such as TGF-α and TGF-β (including TGF-β1, TGF-β2, TGF-β3, TGF-β4, or TGF-β5), insulin-like growth factors I and II (IGF-I and IGF-II), des(1-3)-IGF-I (brain IGF-I), insulin-like growth factor binding proteins, CD proteins (such as CD-3, CD-4, CD-8, and CD-19), erythropoietin, bone morphogenetic factors, immunotoxins, interferons (e.g., interferon-α (e.g., interferon-α)).2A), interferon-β, interferon-γ, interferon-λ, and consensus interferon, colony-stimulating factors (CSFs) (e.g., M-CSF, GM-CSF, and G-CSF), interleukins (ILs) (e.g., IL-1 to IL-10), superoxide dismutase, T cell receptors, surface membrane proteins, decay-accelerating factors, transport proteins, homing receptors, addressins, fertilization inhibitors such as prostaglandins, fertilization enhancers, regulatory proteins, antibodies (including fragments thereof), and chimeric proteins (e.g., immunoadhesins), precursors, derivatives, prodrugs, and analogs of these compounds, as well as pharmaceutically acceptable salts of these compounds or their precursors, derivatives, prodrugs, and analogs. Suitable proteins or peptides may be natural or recombinant and include, for example, fusion proteins.

[0136] Among these are CCL1, CCL2(MCP-1), CCL3(MIP-1α), CCL4(MIP-1β), and CCL5 (RANTES) CCL6, CCL7, CCL8, CCL9(CCL10), CCL11, CCL12, CCL13, CCL14, CC L15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL2 5 CCL26, CCL27, CCL28, CXCL1(KC), CXCL2(SDF1a), CXCL3, CXCL4, CXCL5C XCL6, CXCL7, CXCL8(IL8), CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14 CXCL15, CXCL16, CXCL17, CX3CL1, XCL1, XCL2, TNFA, TNFB(LTA), TNFC(LTB). )、TNFSF4、TNFSF5(CD40LG)、TNFSF6、TNFSF7、TNFSF8、TNFSF9、TNFSF10、TN FSF11, TNFSF13B, EDA, IL2, IL15, IL4, IL13, IL7, IL9, IL21, IL3, IL5, IL6, I L11, IL27, IL30, IL31, OSM, LIF, CNTF, CTF1, IL12a, IL12b, IL23, IL27, IL3 5, IL14, IL16, IL32, IL34, IL10, IL22, IL19, IL20, IL24, IL26, IL29, IFNL1 IFNL2, IFNL3, IL28, IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IF NA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA21, IFNB1, IFNK, IFNW1, IFNG, I L1A(IL1F1),IL1B(IL1F2),IL1Ra(IL1F3),IL1F5(IL36RN),IL1F6(IL36A) IL1F7(IL37), IL1F8(IL36B), IL1F9(IL36G), IL1F10(IL38), IL33(IL1F1). 1) IL18(IL1G), IL17, KITLG, IL25(IL17E), CSF1(M-CSF), CSF2(GM-CSF); CSF3(G-CSF), SPP1, TGFB1, TGFB2, TGFB3, CCL3L1, CCL3L2, CCL3L3, CCL4L1CCL4L2, IL17B, IL17C, IL17D, IL17F, AIMP1(SCYE1), MIF, Areg, BC096441, Bmp1, Bmp10, Bmp15, Bmp2, Bmp3, Bmp4, Bmp5, Bmp6, Bmp7, Bmp8a, Bmp8b, C1q tnf4, Ccl21a, Ccl27a, Cd70, Cer1, Cklf, Clcf1, Cmtm2a, Cmtm2b, Cmtm3, Cmtm4, Cmtm5, Cmtm6, Cmtm7, Cmtm8, Crlf1, Ctf2, Ebi3, Edn1, Fam3b, Fasl, Fgf 2, Flt3l, Gdf10, Gdf11, Gdf15, Gdf2, Gdf3, Gdf5, Gdf6, Gdf7, Gdf9, Gm1259 7, Gm13271, Gm13275, Gm13276, Gm13280, Gm13283, Gm2564, Gpi1, Grem1, Gre m2, Grn, Hmgb1, Ifna11, Ifna12, Ifna9, Ifnab, Ifne, Il17a, Il23a, Il25, Il31, Iltifb, Inhba, Lefty1, Lefty2, Mstn, Nampt, Ndp, Nodal, Pf4, Pglyrp1 , Prl7d1, Scg2, Scgb3a1, Slurp1, Spp1, Thpo, Tnfsf10, Tnfsf11, Tnfsf12, Tnfsf13, nfsf13b, Tnfsf14, Tnfsf15, Tnfsf18, Tnfsf4, Tnfsf8, Tnfsf9, Tslp, Vegfa, Wnt1, Wnt2, Wnt5a, Wnt7a, Xcl1, epinephrine, melatonin, triiodothyronine, thyroxine, prostaglandins, leukotrienes, prostacyclin, thromboxane, islet amyloid polypeptide, Müllerian inhibitory factor, or or hormones, adiponectin, adrenocorticotropic hormone, angiotensin, vasopressin, arginine vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholecystokinin, cortistatin, enkephalin, endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastric inhibitory polypeptide, gastrin, ghrelin, glucagon, glucagon-like peptide-1, gonadotropin-releasing hormone, growth hormone-releasing hormone, hepcidin, human chorionic gonadotropin, human placental lactogen, growth hormone, inhibin,Also included are insulin, somatomedin, leptin, lipotropin, luteinizing hormone, melanocyte-stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, pituitary adenylate cyclase-activating peptide, prolactin, prolactin-releasing hormone, relaxin, renin, secretin, somatostatin, thrombopoietin, thyroid-stimulating hormone, thyrotropin-releasing hormone, vasoactive intestinal peptide, androgens, acid maltase (α-glucosidase), glycogen phosphorylase, glycogen debranching enzyme, phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, carnitine palmitoyltransferase, carnitine, and myoadenylate deaminase.

[0137] The protein payload may further comprise hormones such as antidiuretic hormone (ADH), which is produced by the posterior pituitary gland and targets the kidneys, affecting water balance and blood pressure; oxytocin, which is produced by the posterior pituitary gland and targets the uterus and breast, stimulating uterine contractions and milk production; growth hormone (GH), which is produced by the anterior pituitary gland and targets somatic cells, bone, and muscle, affecting growth and development; prolactin, which is produced by the anterior pituitary gland and targets the breast, maintaining milk production; and growth hormone releasing hormone, which is a GH-releasing hormone produced in the arcuate nucleus of the hypothalamus. Thyroid-stimulating hormone (GHRH), produced by the anterior pituitary gland, targets the thyroid gland and regulates thyroid hormones; thyrotropin-releasing hormone (TSH), produced by the hypothalamus, stimulates the release of TSH and prolactin from the anterior pituitary gland; adrenocorticotropic hormone (ACTH), produced by the anterior pituitary gland, targets the adrenal cortex and regulates adrenal cortical hormones; follicle-stimulating hormone (FSH), produced by the anterior pituitary gland, targets the ovaries / testes and stimulates egg and sperm production; and thyroid-stimulating hormone (THR), produced by the anterior pituitary gland, targets the ovaries / testes and stimulates egg and sperm production. Luteinizing hormone (LH), which targets the foetus and stimulates ovulation and sex hormone secretion; luteinizing hormone-releasing hormone (LHRH), also known as gonadotropin-releasing hormone (GnRH), a trophic peptide hormone synthesized and released from GnRH neurons in the hypothalamus and responsible for the release of FSH and LH; thyroxine, produced by the thyroid gland, which targets somatic cells and regulates metabolism; calcitonin, produced by the thyroid gland, which targets the adrenal cortex and lowers blood calcium; and parathyroid gland, which targets the bone matrix and increases blood calcium. Thyroid hormones, aldosterone, produced by the adrenal cortex, targeted to the kidneys and regulating water balance; cortisol, produced by the adrenal cortex, targeted to body cells and dampening the immune system and stress response; epinephrine, produced by the adrenal medulla, targeted to the heart, lungs, liver, and body cells and affecting the primary "fight or flight" response; glucagon, produced by the pancreas, targeted to the liver and increasing blood glucose levels; insulin, produced by the pancreas, targeted to body cells and decreasing blood glucose levels; and thyroid hormones, produced by the ovaries and targeted to the reproductive system and affecting puberty, menstruation, andThese may be estrogen, which is produced by the ovaries and targets the reproductive system, influencing puberty, the menstrual cycle, and gonadal development; progesterone, which is produced by the adrenal glands and testes, targets the reproductive system, and influences puberty, gonadal development, and sperm.

[0138] In one embodiment, the protein payload is a growth hormone (such as human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth hormone, methionine-human growth hormone, des-phenylalanine-human growth hormone, and porcine growth hormone), insulin, insulin A chain, insulin B chain, and proinsulin, or a growth factor (such as vascular endothelial growth factor (VEGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor (TGF), and insulin-like growth factor I and II (IGF-I and IGF-II)).

[0139] In one embodiment, the protein payload is a vaccine component, such as an antigen. Antigens can include any protein or peptide that is foreign to the subject's organism. Preferred antigens can be presented on the surface of the subject's antigen-presenting cells (APCs) for surveillance by immune effector cells, such as CD4 receptor-expressing white blood cells (CD4 T cells) and natural killer (NK) cells. Typically, antigens are derived from viruses, bacteria, protozoa, fungi, or animals. In some embodiments, the antigen is a cancer antigen. Cancer antigens can be antigens that are expressed only on tumor cells and / or that are required for tumor cell survival.

[0140] Certain antigens are recognized by those skilled in the art as immunostimulatory (i.e., stimulating effective immune recognition) and provide effective immunity against the organism or molecule from which they are derived. Antigens can be peptides, proteins, polysaccharides, sugars, lipids, nucleic acids, or combinations thereof. Antigens can be derived from viruses, bacteria, parasites, plants, protozoa, fungi, tissues, or transformed cells such as cancer cells or leukemia cells, and can also be whole cells or their immunogenic components (e.g., their cell wall components or molecular components). Suitable antigens are well known in the art and are available from commercial, government, and scientific sources. Antigens can be purified or partially purified polypeptides derived from tumors or viral or bacterial sources. Antigens can also be recombinant polypeptides produced by expressing DNA encoding the polypeptide antigen in a heterologous expression system. Antigens can also be DNA encoding all or part of the antigen protein. Antigens can be provided as single antigens or in combination. Antigens can also be provided as complex mixtures of polypeptides or nucleic acids.

[0141] Exemplary antigens can be isolated from any virus, including, but not limited to, viruses from any of the following viral families: Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, Badnavirus, Barnaviridae, Birnaviridae, Bromoviridae, Bunyaviridae, Caliciviridae, Capillovirus, Carlavirus, Caulimovirus, Circoviridae, Closterovirus, Comoviridae, Coronaviridae (e.g., coronaviruses such as severe acute respiratory syndrome (SARS) virus), Corticoviridae, Cystoviridae, Deltavirus, Dianthovirus, Enamovirus, Filoviridae (e.g., Marburg virus and Ebola virus (e.g., Zaire, Reston, Ivory Coast, or Sudan strains)), Flaviviridae ae (e.g., hepatitis C virus, dengue virus 1, dengue virus 2, dengue virus 3, and dengue virus 4), Hepadnaviridae, Herpesviridae (e.g., human herpesviruses 1, 3, 4, 5, and 6, and cytomegalovirus), Hypoviridae, Iridoviridae, Leviviridae, Lipothrixviridae, Microviridae, Orthomyxoviridae (e.g., influenza viruses A, B, and C), ), Papovaviridae, Paramyxoviridae (e.g., measles virus, mumps virus, and human respiratory syncytial virus), Parvoviridae, Picornaviridae (e.g., poliovirus, rhinovirus, hepatovirus, and aphthovirus), Poxviridae (e.g., vaccinia virus and smallpox virus), Reoviridae (e.g., rotavirus), Retroviridae (e.g., human immunodeficiency virus (HIV) type 1 and HIVLentiviruses such as type 2), Rhabdoviridae (e.g., rabies virus, measles virus, respiratory syncytial virus, etc.), Togaviridae (e.g., rubella virus, dengue virus, etc.), and Totiviridae. Suitable viral antigens also include all or part of dengue protein M, dengue protein E, dengue D1NS1, dengue D1NS2, and dengue D1NS3. Viral antigens may be derived from specific strains of papillomavirus, herpesvirus (i.e., herpes simplex types 1 and 2), hepatitis virus (e.g., hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D delta virus (HDV), hepatitis E virus (HEV), and hepatitis G virus (HGV), tick-borne encephalitis virus, etc.), parainfluenza, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, rotavirus, rhinovirus, adenovirus, coxsackievirus, equine encephalitis, Japanese encephalitis, yellow fever, Rift Valley fever, and lymphocytic choriomeningitis.

[0142] Additional exemplary antigens include Actinomyces, Anabaena, Bacillus, Bacteroides, Bdellovibrio, Bordetella, Borrelia, Campylobacter, Caulobacter, Chlamydia, Chlorobium , Chromatium, Clostridium, Corynebacterium, Cytophaga, Deinococcus, Escherichia, Francisella, Halobacterium, Heliobacter, Haemophilus, Hemophilus influenza type B (HIB), Hyphomicrobium, Legionella, Leptspirosis, Listeria, Meningococcus The bacterial strains may be derived from any bacteria, including, but not limited to, A, B, and C, Methanobacterium, Micrococcus, Myobacterium, Mycoplasma, Myxococcus, Neisseria, Nitrobacter, Oscillatoria, Prochloron, Proteus, Pseudomonas, Phodospirillum, Rickettsia, Salmonella, Shigella, Spirillum, Spirochaeta, Staphylococcus, Streptococcus, Streptomyces, Sulfolobus, Thermoplasma, Thiobacillus, Treponema, Vibrio, and Yersinia. Further exemplary antigens include Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia asteroides, Rickettsia ricketsii, Rickettsia typhi, Mycoplasma pneumoniae, Chlamydial psittaci, Chlamydial trachomatis, Plasmodium falciparum, Trypanosoma brucei, Entamoeba histolytica, These include, but are not limited to, antigens that can be obtained from parasites, such as those from Toxoplasma gondii, Trichomonas vaginalis, and Schistosoma mansoni, including sporozoan antigens, Plasmodium antigens (e.g., all or part of a circumsporozoite protein, a sporozoite surface protein, a liver stage antigen, an apical membrane-associated protein, or a merozoite surface protein).

[0143] Yet another exemplary antigen may be an allergen or environmental antigen (an antigen derived from a naturally occurring allergen such as, but not limited to, pollen allergens (tree, herb, weed, and grass pollen allergens), insect allergens (inhalant allergens, saliva allergens, and venom allergens), animal hair and dung allergens, and food allergens). Important pollen allergens from trees, grasses and herbs are from the taxonomic orders Fagales, Oleales, Pinales and Platanaceae (including, inter alia, birch (Betula), alder (Alnus), hazel (Corylus), hornbeam (Carpinus) and olive (Olea), cedars (Cryptomeria and Juniperus), plane tree (Platanus)), Poales (i.e., including grasses of the genera Lolium, Phleum, Poa, Gynodon, Dactylis, Holcus, Phalaris, Secale and Sorghum), Asterales and Urticales (including herbs of the genera Ambrosia, Artemisia and Parietaria). Other allergen antigens that can be used include allergens from house dust mites of the genera Dermatophagoides and Euroglyphus, storage mites (e.g., Lepidoglyphys, Glycyphagus, and Tyrophagus), cockroaches, midges, and fleas (e.g., Blatella, Periplaneta, Chironomus, and Ctenocephalides), mammals such as cats, dogs, and horses, allergens from birds, and venom allergens from stinging or biting insects (e.g., insects of the order Hymenoptera, which includes bees (superfamily Apidae), hornets (superfamily Vespidea), and ants (superfamily Formicoidae)). Still other allergen antigens that can be used include inhalant allergens from fungi (e.g., the genera Alternaria and Cladosporium).

[0144] Further exemplary antigens include tumor antigens, including tumor-associated or tumor-specific antibodies (e.g., but not limited to, α-actinin-4, Bcr-Abl fusion protein, Casp-8, β-catenin, cdc27, cdk4, cdkn2a, coa-1, dek-can fusion protein, EF2, ETV6-AML1 fusion protein, LDLR-fucosyltransferase AS fusion protein, HLA-A2, HLA-A11, hsp70-2, KIAAO205, Mart2, Mum-1, 2, and 3, neo-PAP, myosin class I, OS-9, pml-RARa fusion protein, PTPRK, K-ras, N-ras, triosephosphate isomerase, Bage-1, Gage, etc.). 3,4,5,6,7, GnTV, Herv-K-mel, Lage-1, Mage-A1,2,3,4,6,10,12, Mage-C2, NA-88, NY-Eso-1 / Lage-2, SP17, SSX-2, TRP2-Int2, MelanA(MART-I), gp100(Pmel 17), tyrosinase, TRP-1, TRP-2, MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, p15(58), CEA, RAGE, NY-ESO (LAGE), SCP-1, Hom / Mel-40, PRAME, p53, H-Ras, HER-2 / neu, BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein-Barr virus antigen, EBNA, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, β-catenin, CDK4, Mum-1, p16, TAGE, PSMA, PSCA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, α-fetoprotein, 13HCG, BCA225, BTAA, CA 125, CA 15-3(CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C-related protein), TAAL6, TAG72, TLP, and TPS.

[0145] In another embodiment, the payload is an antibody. Antibodies are described that function by directly binding to one or more epitopes, other ligands, or accessory molecules on the surface of eukaryotic cells. Typically, antibodies or antigen-binding fragments thereof have affinity for receptors on the surface of specific cell types, such as receptors expressed on the surface of macrophage cells. Various types of antibodies and antibody fragments can be used in the described compositions and methods, including whole immunoglobulins of any class, fragments thereof, and synthetic proteins containing at least the antigen-binding variable domain of an antibody. The antibody can be an IgG antibody, such as IgG1, IgG2, IgG3, or IgG4. The antibody can be in the form of an antigen-binding fragment, including Fab fragments, F(ab')2 fragments, single-chain variable regions, etc. The antibody can be polyclonal or monoclonal (mAb). Monoclonal antibodies include "chimeric" antibodies in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, so long as the antibodies specifically bind to a target antigen and / or exhibit the desired biological activity, as well as fragments of such antibodies (U.S. Patent No. 4,816,567 and Morrison, et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). The described antibodies can also be modified by recombinant means, for example, by deleting, adding, or substituting amino acids, to increase the efficacy of the antibody in mediating the desired function. Substitutions may be conservative. For example, at least one amino acid in the constant region of the antibody can be replaced with a different residue (see, e.g., U.S. Pat. No. 5,624,821, U.S. Pat. No. 6,194,551, WO 9958572, and Angal, et al., Mol. Immunol. 30:105-08 (1993)). In some cases, alterations are made to reduce undesirable activities, such as complement-dependent cytotoxicity. The antibody may be a bispecific antibody, having binding specificities for at least two different antigen epitopes.In one embodiment, the epitopes are from the same antigen. In another embodiment, the epitopes are from two different antigens. Bispecific antibodies can include bispecific antibody fragments (see, e.g., Hollinger, et al., Proc. Natl. Acad. Sci. USA, 90:6444-48 (1993); Gruber, et al., J. Immunol., 152:5368 (1994)).

[0146] Antibodies can be produced by any means known in the art. Exemplary descriptions of antibody generation and production means include Delves, Antibody Production: Essential Techniques (Wiley, 1997); Shephard, et al., Monoclonal Antibodies (Oxford University Press, 2000); Goding, Monoclonal Antibodies: Principles And Practice (Academic Press, 1993); and Current Protocols In Immunology (John Wiley & Sons, latest edition). Fragments of intact Ig molecules can be produced using methods well known in the art, such as enzymatic digestion and recombinant means.

[0147] In some embodiments, the payload is a small molecule drug. In some embodiments, the small molecule drug is a cytotoxic agent, a chemotherapeutic agent, a natural product, an antiviral agent, an antibiotic, or other therapeutic agent. Cytotoxic agents include, for example, SN-38, paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracenedione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, thiazolinone ... Inactive ingredients may include fluticasone, tetracaine, lidocaine, propranolol, puromycin, maytansinoids, rachelmycin, amiodarone, isavuconazonium, delafloxacin, remdesivir, carfilzomib, posaconazole, allopregnanolone, dalbavancin, plerixafor, netupitant, erbulin, letermovir, palonosetron, copanlisib, lurbinectedin, and analogs thereof. Other therapeutic agents may include, for example, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil, and dacarbazine), alkylating agents (e.g., mechlorethamine, thiotepa, chlorambucil, rachelmycin, melphalan, carmustine, lomustine, cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamineplatinum(II) (DDP), and cisplatin), anthracyclines (e.g., daunorubicin and doxorubicin), antibiotics (e.g., dactinomycin, bleomycin, mithramycin, and anthramycin), and antimitotic agents (e.g., vincristine, vinblastine, and maytansinoids).

[0148] In some embodiments, the particle composition (e.g., lipid nanoparticles) comprises a payload selected from the therapeutic agents described in U.S. Patent No. 8,734,846 or U.S. Patent Publication No. US20100087337.

[0149] Exemplary Enumerated Embodiments 1. A particle, (i) a polymer of formula (Id), [ka] or a pharmaceutically acceptable salt thereof (wherein R 6 , R 7 , and R 8 each is independently hydrogen, heteroalkyl, alkyl, alkenyl, or alkynyl; R 9a , R 9b , R 10a , and R 10b each is independently hydrogen, alkyl, or halo, each of x and y is independently an integer from 1 to 20, and z is an integer from 5 to 90; (ii) phospholipids, (iii) steroids, (iv) the payload, and (v) one or more additional lipid components.

[0150] 2. The particle of embodiment 1, comprising (ii).

[0151] 3. The particle of any one of the preceding embodiments, comprising (iii).

[0152] 4. The particle of any one of the preceding embodiments, comprising (iv).

[0153] 5. The particle of any one of the preceding embodiments, comprising (v).

[0154] 6. The particle of any one of the preceding embodiments, including (ii) and (iii).

[0155] 7. The particle of any one of the preceding embodiments, including (ii), (iii), and (iv).

[0156] 8. The particle of any one of the preceding embodiments, including (ii), (iii), (iv), and (v).

[0157] 9. The particle of any one of the preceding embodiments, including (ii), (iii), and (v).

[0158] 10. The particle of any one of the preceding embodiments, including (ii), (iv), and (v).

[0159] 11. A particle according to any one of the preceding embodiments, including (ii) and (iii).

[0160] 12. The particle of any one of the preceding embodiments, which does not include (iii).

[0161] 13. The particle of any one of the preceding embodiments, which does not include (iv).

[0162] 14. The particle of any one of the preceding embodiments, which does not include (v).

[0163] 15.R 6 , R 7 , and R 8

[0023] The particle of any one of the preceding embodiments, wherein each of is independently hydrogen.

[0164] 16.R 6 3. The particle of any one of the preceding embodiments, wherein is hydrogen.

[0165] 17.R 7 3. The particle of any one of the preceding embodiments, wherein is hydrogen.

[0166] 18.R 8 3. The particle of any one of the preceding embodiments, wherein is hydrogen.

[0167] 19.R 9a , R 9b , R 10a , and R 10b

[0023] 5. The particle of any one of the preceding embodiments, wherein each of is independently hydrogen.

[0168] 20.R 9a3. The particle of any one of the preceding embodiments, wherein is hydrogen.

[0169] 21.R 9b 3. The particle of any one of the preceding embodiments, wherein is hydrogen.

[0170] 22.R 10a 3. The particle of any one of the preceding embodiments, wherein is hydrogen.

[0171] 23.R 10b 3. The particle of any one of the preceding embodiments, wherein is hydrogen.

[0172] 24. The particle of any one of the preceding embodiments, wherein z is 5 to 50.

[0173] 25. The particle of any one of the preceding embodiments, wherein z is 5-48, 5-45, 5-40, 5-35, 5-30, 5-25, 5-20, 5-18, or 5-15.

[0174] 26. A particle according to any one of the preceding embodiments, wherein z is 15.

[0175] 27. A particle according to any one of the preceding embodiments, wherein z is 25.

[0176] 28. The particle of any one of the preceding embodiments, wherein z is 30.

[0177] 29. A particle according to any one of the preceding embodiments, wherein z is 35.

[0178] 30. The particle of any one of the preceding embodiments, wherein z is 40.

[0179] 31. A particle according to any one of the preceding embodiments, wherein z is 45.

[0180] 32. The particle of any one of the preceding embodiments, wherein x is 5 to 10.

[0181] 33. The particle of any one of the preceding embodiments, wherein z is 6 to 8.

[0182] 34. The particle of any one of the preceding embodiments, wherein x is 5.

[0183] 35. The particle of any one of the preceding embodiments, wherein x is 6.

[0184] 36. The particle of any one of the preceding embodiments, wherein x is 7.

[0185] 37. The particle of any one of the preceding embodiments, wherein x is 8.

[0186] 38. The particle of any one of the preceding embodiments, wherein x is 9.

[0187] 39. The particle of any one of the preceding embodiments, wherein x is 10.

[0188] 40. The particle of any one of the preceding embodiments, wherein y is 5 to 10.

[0189] 41. The particle of any one of the preceding embodiments, wherein y is 6-8.

[0190] 42. The particle of any one of the preceding embodiments, wherein y is 5.

[0191] 43. A particle according to any one of the preceding embodiments, wherein y is 6.

[0192] 44. The particle of any one of the preceding embodiments, wherein y is 7.

[0193] 45. The particle of any one of the preceding embodiments, wherein y is 8.

[0194] 46. ​​The particle of any one of the preceding embodiments, wherein y is 9.

[0195] 47. The particle of any one of the preceding embodiments, wherein y is 10.

[0196] 48. The particle of any one of the preceding embodiments, wherein the polymer of formula (Id) is present in a molar percentage of about 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, 0.5% to 2%, or 0.5% to 1%.

[0197] 49. The particle of any one of the preceding embodiments, wherein the polymer of formula (Id) is present in a molar percentage of about 1% to 60%.

[0198] 50. The particle of any one of the preceding embodiments, wherein the polymer of formula (Id) is present in a molar percentage of about 1% to 20%.

[0199] 51. The particle of any one of the preceding embodiments, wherein the polymer of formula (Id) is present in a molar percentage of about 1% to 10%.

[0200] 52. The particle of any one of the preceding embodiments, wherein the polymer of formula (Id) is present in a molar percentage of about 1% to 5%.

[0201] 53. The particle of any one of the preceding embodiments, wherein the polymer of formula (Id) is present in a molar percentage of about 1% to 4%.

[0202] 54. The particle of any one of the preceding embodiments, wherein the polymer of formula (Id) is present in a molar percentage of about 1% to 3%.

[0203] 55. The particle of any one of the preceding embodiments, wherein the polymer of formula (Id) is present in a molar percentage of about 1% to 2%.

[0204] 56. The particle of any one of the preceding embodiments, wherein the polymer of formula (Id) is present in a molar percentage of about 0.5% to 2%.

[0205] 57. The particle of any one of the preceding embodiments, wherein the polymer of formula (Id) is present in a molar percentage of about 1% to 15%.

[0206] 58. The particle of any one of the preceding embodiments, wherein the polymer of formula (Id) is present in a molar percentage of about 1.5%.

[0207] 59. The particle of any one of the preceding embodiments, wherein the polymer of formula (Id) is present in a molar percentage of about 2.5%.

[0208] 60. The particle of any one of the preceding embodiments, wherein the particle is a liposome, a noosome, or a lipid nanoparticle.

[0209] 61. The particle of any one of the preceding embodiments, wherein the particle is a liposome.

[0210] 62. The particle of any one of the preceding embodiments, wherein the particle is a noisome.

[0211] 63. The particle of any one of the preceding embodiments, wherein the particle is a lipid nanoparticle.

[0212] 64. The particle of any one of the preceding embodiments, wherein the phospholipid is selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol.

[0213] 65. The particle of any one of the preceding embodiments, wherein the phospholipid is a phosphatidylcholine.

[0214] 66. A particle according to any one of the preceding embodiments, wherein the phospholipid is phosphatidylethanolamine.

[0215] 67. The particle of any one of the preceding embodiments, wherein the phospholipid is phosphatidylserine.

[0216] 68. The particle of any one of the preceding embodiments, wherein the phospholipid is phosphatidylglycerol.

[0217] 69. A particle according to any one of the preceding embodiments, wherein the phospholipid is, for example, a compound of any one of formulas (II) to (II-e) described herein.

[0218] 70. The phospholipid is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein each R 9 and R 10 independently, one or more R 3 is alkyl, alkenyl, or alkynyl optionally substituted with R 11 is one or more R 12 is alkyl, alkenyl, alkynyl, or heteroalkyl optionally substituted with R 3 is one or more R 4 hydrogen, halo, oxo, cyano, nitro, -OR optionally substituted with C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and R 4 is halo, alkyl, heteroalkyl, or OR C and R 12 is alkyl, alkenyl, alkynyl, -NR D R E , oxo, or hydroxy, and R D and R E

[0023] The particle of any one of the preceding embodiments, wherein each of is independently hydrogen or alkyl.

[0219] 71. For formula (II), R 9 is alkyl, and R 10 is alkyl, and R 11 71. The particle of embodiment 70, wherein is heteroalkyl.

[0220] 72. For formula (II), R 9 is a C17 alkyl, and R 10 is a C17 alkyl, and R 11 72. The particle of embodiment 70 or 71, wherein is heteroalkyl (e.g., —CH2CH3N(CH3)3).

[0221] 73. The phospholipid of formula (II) [ka] 73. The particle of any one of embodiments 70 to 72, wherein

[0222] 74. A particle according to any one of the preceding embodiments, wherein the phospholipid is a compound of formula (II-a) as described herein.

[0223] 75. For formula (II-a), R 9 is alkyl, and R 10 is alkyl, and R 13 is alkyl, and R 14 is alkyl, and R 15 75. The particle of embodiment 74, wherein is alkyl.

[0224] 76. For formula (II-a), R 9 is a C17 alkyl, and R 10 is a C17 alkyl, and R 13 is C1 alkyl, and R 14 is C1 alkyl, and R 15 is C1 alkyl.

[0225] 77. A particle according to any one of the preceding embodiments, wherein the phospholipid is a compound of formula (II-b) as described herein.

[0226] 78. A particle according to any one of the preceding embodiments, wherein the phospholipid is a compound of formula (II-c) as described herein.

[0227] 79. A particle according to any one of the preceding embodiments, wherein the phospholipid is a compound of formula (II-d) as described herein.

[0228] 80. A particle according to any one of the preceding embodiments, wherein the phospholipid is 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC).

[0229] 81. A particle according to any one of the preceding embodiments, wherein the phospholipid is 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC).

[0230] 82. A particle according to any one of the preceding embodiments, wherein the phospholipid is 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC).

[0231] 83. A particle according to any one of the preceding embodiments, wherein the phospholipid is 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC).

[0232] 84. A particle according to any one of the preceding embodiments, wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

[0233] 85. A particle according to any one of the preceding embodiments, wherein the phospholipid is 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC).

[0234] 86. A particle according to any one of the preceding embodiments, wherein the phospholipid is 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC).

[0235] 87. The particle of any one of the preceding embodiments, wherein the phospholipid further comprises a polyethylene glycol modification.

[0236] 88. The phospholipid containing a polyethylene glycol modification is selected from the group consisting of methoxypolyethylene-glycoloxy(2000)-N,N-ditetradecylacetamide (ALC-0159), 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000), 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-5000 (DMG-PEG 5000), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DOPE-PEG 2000), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-5000] (DOPE-PEG 5000), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG 2000), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-5000] (DSPE-PEG 5000), distearoyl-rac-glycerol-PEG2K (DSG-PEG 2000), and distearoyl-rac-glycerol-PEG5K (DSG-PEG 5000).

[0237] 89. Particles according to embodiment 87 or 88, wherein the phospholipid comprising a polyethylene glycol modification is selected from 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DOPE-PEG 2000), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG 2000), and distearoyl-rac-glycerol-PEG2K (DSG-PEG 2000).

[0238] 90. The particle of embodiment 97 or 88, wherein the phospholipid comprising a polyethylene glycol modification is 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000).

[0239] 91. A particle according to any one of the preceding embodiments, wherein the phospholipid is a combination of one or more phospholipids described herein.

[0240] 92. The particle of any one of the preceding embodiments, wherein the steroid is, for example, a compound of any one of formulas (III) to (III-b) described herein.

[0241] 93. The particle of any one of the preceding embodiments, wherein the steroid is a compound of formula (III) described herein.

[0242] 94. For formula (III), ring positions 3, 10, 13, and 17 each contain one R 3 and the bond between ring positions 5 and 6 is a double bond.

[0243] 95. The particle of any one of the preceding embodiments, wherein the steroid is a compound of formula (III-a) described herein.

[0244] 96. For formula (III-a), R 21 -OR C and R 24 is alkyl, and R 25 is alkyl, and R 26 There are two R 3 is alkyl substituted with R 22 , R 23 , and R 27 96. The particle of embodiment 95, wherein is hydrogen.

[0245] 97. For formula (III-a), R 21 is -OH and R 24 is methyl and R 25 is methyl and R 26 There are two R 3 and R is a heptyl substituted with 22 , R 23 , and R 27 97. The particle of embodiment 95 or 96, wherein is hydrogen.

[0246] 98. The particle of any one of the preceding embodiments, wherein the steroid is a compound of formula (III-b) described herein.

[0247] 99. For formula (III-b), R 31 -OR A and R 32 is alkyl, and R 33 is alkyl, and R 34 is alkyl, and R 35 is alkyl, and R 36 99. The particle of embodiment 98, wherein is alkyl.

[0248] 100. The particle of any one of the preceding embodiments, wherein the steroid is cholesterol or a cholesterol derivative.

[0249] 101. The particle of any one of the preceding embodiments, wherein the steroid is cholesterol.

[0250] 102. The particle of any one of the preceding embodiments, wherein the payload is selected from a protein, an enzyme, a peptide, a nucleic acid, a small molecule, or a lipid.

[0251] 103. The particle of any one of the preceding embodiments, wherein the payload is a protein.

[0252] 104. The particle of any one of the preceding embodiments, wherein the particle is an enzyme or a peptide.

[0253] 105. The particle of any one of the preceding embodiments, wherein the payload is a peptide.

[0254] 106. The particle of any one of the preceding embodiments, wherein the payload is a nucleic acid.

[0255] 107. The particle of any one of the preceding embodiments, wherein the payload is a small molecule.

[0256] 108. The particle of any one of the preceding embodiments, wherein the payload is a lipid.

[0257] 109. The particle of embodiment 102, wherein the nucleic acid is an RNA molecule.

[0258] 110. The particle of embodiment 105, wherein the RNA molecule is selected from mRNA, tRNA, rRNA, and snRNA.

[0259] 111. The particle of embodiment 105 or 106, wherein the RNA molecule is an mRNA molecule.

[0260] 112. The particle of embodiment 102, wherein the payload is a small molecule selected from a cytotoxic agent, a chemotherapeutic agent, a natural product, an antiviral agent, and an antibiotic.

[0261] 113. The particle of embodiment 112, wherein the small molecule is a cytotoxic agent.

[0262] 114. The particle of embodiment 112, wherein the small molecule is a chemotherapeutic agent.

[0263] 115. The particle of embodiment 112, wherein the small molecule is a natural product.

[0264] 116. The particle of embodiment 112, wherein the small molecule is an antiviral agent.

[0265] 117. The particle of embodiment 112, wherein the small molecule is an antibiotic.

[0266] 118. The payload is selected from the group consisting of SN-38, paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracenedione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoid compounds, procaine, tetracaine, lidocaine, propranolol, puromycin, rachelmycin, amiodarone, isavuconazonium, delafloxacin, remdesivir, carfilzomib, posaconazole, allopregnanolone, dalbavancin, plerixafor, netupitant, and entrectin. 10. The particle of any one of the preceding embodiments, wherein the compound is selected from lubricating oil, letermovir, palonosetron, copanlisib, lurbinectedin, methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil, dacarbazine, mechlorethamine, thiotepa, chlorambucil, rachelmycin, melphalan, carmustine, lomustine, cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamineplatinum(II), cisplatin, daunorubicin, doxorubicin, dactinomycin, bleomycin, mithramycin, anthramycin, vincristine, vinblastine, and a maytansinoid.

[0267] 119. The particle of any one of the preceding embodiments, wherein the additional lipid component is a cationic lipid.

[0268] 120. A particle according to any one of the preceding embodiments, wherein the additional lipid component is, for example, a compound of formula (IV) to (IV-b) as described herein.

[0269] 121. A particle according to any one of the preceding embodiments, wherein the additional lipid component is a compound of formula (IV).

[0270] 122. The particle of any one of the preceding embodiments, wherein the additional lipid component is SM-102.

[0271] 123. The particle of any one of the preceding embodiments, wherein the additional lipid component is ALC-0315.

[0272] 124. Lipid nanoparticles, (i) a polymer of formula (Id), [ka] or a pharmaceutically acceptable salt thereof (wherein R 6 , R 7 , and R 8 each is independently hydrogen, heteroalkyl, alkyl, alkenyl, or alkynyl; R 9a , R 9b , R 10a , and R 10b each is independently hydrogen, alkyl, or halo, each of x and y is independently an integer from 1 to 20, and z is an integer from 5 to 90; (ii) phospholipids, (iii) steroids, (iv) the payload, and (v) one or more additional lipid components.

[0273] 125. Lipid nanoparticles, (i) a polymer of formula (Id), [ka] or a pharmaceutically acceptable salt thereof (wherein R 6 , R 7 , and R 8 each is independently hydrogen, heteroalkyl, alkyl, alkenyl, or alkynyl; R 9a , R 9b , R 10a , and R 10b each is independently hydrogen, alkyl, or halo, each of x and y is independently an integer from 1 to 20, and z is an integer from 5 to 90; (ii) a phospholipid; (iii) a steroid; (iv) a payload; and (v) an additional lipid component.

[0274] 126. Lipid nanoparticles, (i) a polymer having the structure: [ka] or a pharmaceutically acceptable salt thereof; (ii) phospholipids, (iii) steroids, (iv) the payload, and (v) one or more additional lipid components.

[0275] 127. Lipid nanoparticles, (i) a polymer having the structure: [ka] or a pharmaceutically acceptable salt thereof; (ii) a phospholipid; (iii) a steroid; (iv) a payload; and (v) an additional lipid component.

[0276] 128. Lipid nanoparticles, (i) a polymer having the structure: [ka] or a pharmaceutically acceptable salt thereof; (ii) a phospholipid; (iii) a steroid; (iv) a payload; and (v) an additional lipid component.

[0277] 129. The particle or lipid nanoparticle of any one of the preceding embodiments, wherein the phospholipid comprises diastearoylphosphatidylcholine (DSPC) or 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (DMG-PEG).

[0278] 130. The particle or lipid nanoparticle of embodiment 129, wherein the DMG-PEG comprises DMG-PEG-2000, DMG-PEG-3000, DMG-PEG-3350, DMG-PEG-4000, DMG-PEG-5000, DMG-PEG-10,000, or DMG-PEG-20,000.

[0279] 131. The particle or lipid nanoparticle of embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-2000.

[0280] 132. The particle or lipid nanoparticle according to embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-3000.

[0281] 133. The particle or lipid nanoparticle of embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-3350.

[0282] 134. The particle or lipid nanoparticle according to embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-4000.

[0283] 135. The particle or lipid nanoparticle of embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-5000.

[0284] 136. The particle or lipid nanoparticle of embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-10,000.

[0285] 137. The particle or lipid nanoparticle of embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-20,000.

[0286] 138. The particle or lipid nanoparticle of any one of the preceding embodiments, wherein the particle or lipid nanoparticle comprises a plurality of phospholipids.

[0287] 139. The particle or lipid nanoparticle of any one of the preceding embodiments, wherein the particle comprises DSPC and DMG-PEG.

[0288] 140. The particle or lipid nanoparticle of embodiment 139, wherein the concentration of DSPC provided in the particle or lipid nanoparticle formulation is 5 to 15%.

[0289] 141. A particle or lipid nanoparticle according to any one of embodiments 139 to 140, wherein the concentration of DMG-PEG provided in the particle or lipid nanoparticle formulation is 0.5 to 5%.

[0290] 142. A particle or lipid nanoparticle described in any one of embodiments 129 to 141, wherein the concentration of DMG-PEG-2,000 provided in the particle or lipid nanoparticle formulation is 0.5 to 5%.

[0291] 143. A particle according to any one of the preceding embodiments, wherein the polymer of formula (Id) is selected from oleyl-pSar10, oleyl-pSar15, and oleyl-pSar30.

[0292] 144. A particle according to any one of the preceding embodiments, wherein the polymer of formula (Id) is oleyl-pSar10.

[0293] 145. A particle according to any one of the preceding embodiments, wherein the polymer of formula (Id) is oleyl-pSar15.

[0294] 146. A particle according to any one of the preceding embodiments, wherein the polymer of formula (Id) is oleyl-pSar30.

[0295] 147. A particle or lipid nanoparticle according to any one of the preceding embodiments, wherein the concentration of the polymer of formula (Id) is 0.5-5%.

[0296] 148. The particle or lipid nanoparticle of any one of the preceding embodiments, wherein the particle or lipid nanoparticle has a diameter of 50 nm to 1 mm.

[0297] 149. The particle or lipid nanoparticle of any one of the preceding embodiments, wherein the particle or lipid nanoparticle has a diameter of 50 nm to 750 nm.

[0298] 150. The particle or lipid nanoparticle of any one of the preceding embodiments, wherein the particle or lipid nanoparticle has a diameter of between 50 nm and 500 nm.

[0299] 151. The particle or lipid nanoparticle of any one of the preceding embodiments, wherein the particle or lipid nanoparticle has a diameter of 50 nm to 250 nm.

[0300] 152. The particle or lipid nanoparticle of any one of the preceding embodiments, wherein the particle or lipid nanoparticle has a diameter of 50 nm to 200 nm.

[0301] 153. The particle or lipid nanoparticle of any one of the preceding embodiments, wherein the particle or lipid nanoparticle has a diameter of 50 nm to 150 nm.

[0302] 154. The particle or lipid nanoparticle of any one of the preceding embodiments, wherein the polydispersity of the particle or lipid nanoparticle is between 0.05 and 0.5.

[0303] 155. The particle or lipid nanoparticle of any one of the preceding embodiments, wherein the polydispersity of the particle or lipid nanoparticle is between 0.1 and 0.4.

[0304] 156. The particle or lipid nanoparticle of any one of the preceding embodiments, wherein the polydispersity of the particle or lipid nanoparticle is between 0.1 and 0.3.

[0305] 157. The particle or lipid nanoparticle of any one of the preceding embodiments, wherein the polydispersity of the particle or lipid nanoparticle is 0.1 to 0.2.

[0306] 158. A method for delivering a payload to a subject or a cell, comprising: (i) a polymer of formula (Id), [ka] or a pharmaceutically acceptable salt thereof (wherein R 6 , R 7 , and R 8 each is independently hydrogen, heteroalkyl, alkyl, alkenyl, or alkynyl; R 9a , R 9b , R 10a , and R 10b each is independently hydrogen, alkyl, or halo, each of x and y is independently an integer from 1 to 20, and z is an integer from 5 to 90; (ii) phospholipids, (iii) steroids, (iv) the payload, and (v) administering particles comprising one or more additional lipid components.

[0307] 159. The particle of embodiment 158, wherein the particle is a liposome, a noosome, or a lipid nanoparticle.

[0308] 160. The particle according to embodiment 158, wherein the particle is a liposome.

[0309] 161. The particle according to embodiment 158, wherein the particle is a noisome.

[0310] 162. The particle of embodiment 158, wherein the particle is a lipid nanoparticle.

[0311] 163. A particle according to any one of embodiments 158 to 162, wherein the payload is selected from a protein, an enzyme, a peptide, a nucleic acid, a small molecule, or a lipid.

[0312] 164. A particle according to any one of embodiments 158 to 162, wherein the payload is a protein.

[0313] 165. The particle of any one of embodiments 158-162, wherein the particle is an enzyme.

[0314] 166. A particle according to any one of embodiments 158 to 162, wherein the payload is a peptide.

[0315] 167. A particle according to any one of embodiments 158 to 162, wherein the payload is a nucleic acid.

[0316] 168. A particle according to any one of embodiments 158 to 162, wherein the payload is a small molecule.

[0317] 169. A particle according to any one of embodiments 158-162, wherein the payload is a lipid.

[0318] 170. The particle according to any one of embodiments 158 to 162, wherein the particle is mRNA.

[0319] 171. A method of treating a disease, disorder, or condition in a subject, comprising administering to the subject: (i) a polymer of formula (Id), [ka] or a pharmaceutically acceptable salt thereof (wherein R 6 , R 7 , and R 8 each is independently hydrogen, heteroalkyl, alkyl, alkenyl, or alkynyl; R 9a , R 9b , R 10a , and R 10b each is independently hydrogen, alkyl, or halo, each of x and y is independently an integer from 1 to 20, and z is an integer from 5 to 90; (ii) phospholipids, (iii) steroids, (iv) the payload, and (v) administering particles comprising one or more additional lipid components.

[0320] 172. The particle of embodiment 171, wherein the particle is a liposome, a noosome, or a lipid nanoparticle.

[0321] 173. A particle according to any one of embodiments 171-172, wherein the payload is selected from a protein, an enzyme, a peptide, a nucleic acid, a small molecule, or a lipid.

[0322] 174. A particle according to any one of embodiments 171-172, wherein the payload is a protein.

[0323] 175. The particle according to any one of embodiments 171-172, wherein the particle is an enzyme.

[0324] 176. A particle according to any one of embodiments 171-172, wherein the payload is a peptide.

[0325] 177. A particle according to any one of embodiments 171-172, wherein the payload is a nucleic acid.

[0326] 178. A particle according to any one of embodiments 171-172, wherein the payload is a small molecule.

[0327] 179. A particle according to any one of embodiments 171-172, wherein the payload is a lipid. [Example]

[0328] In order that the disclosure set forth herein may be more fully understood, the following examples are set forth: The examples described in this application are provided to illustrate the particles, compositions and methods provided herein, and should not be construed in any way as limiting the scope thereof.

[0329] Example 1. Synthesis of lipid nanoparticles containing polysarcosine lipid conjugates Prepare lipid nanoparticles by mixing the aqueous phase (0.1–0.3 mg / mL mRNA diluted in 0.1 M citrate buffer) with an organic phase containing a mixture of cationic lipid:polysarcosine lipid complex:phospholipid:cholesterol dissolved in ethanol in the ratios shown in Table 1. Dialyze the mixture and then concentrate it using a centrifugal filter with a 30 kDa cutoff. [Table 1-1] [Table 1-2] [Table 1-3]

[0330] Example 2. Lipid nanoparticle formulations containing polysarcosine lipid complexes Lipid nanoparticle (LNP) formulations containing polysarcosine-lipid complexes encapsulating an exemplary cargo (RNA) approximately 2 kDa in size were prepared according to the flow diagram shown in Figure 1. mRNA expressing firefly luciferase (Fluc, approximately 2 kDa) was obtained from CATUG. SM-102, ALC-0315, and ALC-0159 were obtained from SINOPEG. DSPC, cholesterol, and DMG-PEG 2000 (DMG-PEG-2K) were obtained from AVT Pharma. Oleyl-Sar15 was obtained from Curapath. Oleyl-Sar30 and Oleyl-Sar10 were manufactured by Calusa Bio.

[0331] The mixing device used was a NanoAssemblr Ignite from Precision NanoSystems. The volume of the RNA solution before mixing was 4-11 mL, and the density was approximately 1 g / mL. The volume of the lipid, polysarcosine-lipid complex mixture (95:5, volume / volume, ethanol:water) was 1 / 3 (volume / volume) of the RNA solution. Dialysis (10K MWCO) was performed overnight at 2-8 °C with stirring. Centrifugal concentration (30K MWCO) was performed at 2-8 °C and 2000-4000 x g. Filtration was performed using a 0.22 μm PES filter.

[0332] Particle size and polydispersity (PDI) were measured using a Wyatt Dynapro plate reader III. Encapsulation efficiency (EE%) was measured using a fluorescence-based assay (RiboGreen from Thermo Fisher) on a SpectraMax iD5 microplate reader. mRNA content was quantified by HPLC.

[0333] LNP formulations LNP-01 to LNP-04 were prepared and evaluated using the blended product process shown in the flow diagram in Figure 1. The mole percentages of the components and analytical results are shown in Tables 2 and 3 below. [Table 2] [Table 3]

[0334] For example, to evaluate the effect of the polysarcosine chain length of the polysarcosine-lipid conjugate, LNP formulations LNP-03 and LNP-05 to LNP-10 were prepared and evaluated using the mixed product process shown in the flow chart in Figure 1. The molar percentages of the components and analytical results are shown in Tables 4 and 5. [Table 4] [Table 5]

[0335] For example, to evaluate the effect of the dilution buffer and dilution factor used, LNP formulations LNP-11 to LNP-22 were prepared and evaluated using the blended product process shown in the flow diagram in Figure 1. The dilution buffer was either CBS / Tris (citrate buffered saline + 3% 1 M Tris) or 50 mM Tris. The molar percentages of the components and analytical results are shown in Tables 6 and 7. [Table 6] [Table 7]

[0336] A selection of LNP formulations, LNP-11 through LNP-22, were further processed and evaluated in the lipid nanoparticle final product process shown in the flow diagram shown in Figure 1. Analytical results of the formulations are shown in Table 8. [Table 8]

[0337] Equivalents and Scope This application refers to various published patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference in their entirety. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. Also, any particular embodiment of the present disclosure that falls within the prior art may be expressly excluded from any one or more of the claims. Because such embodiments are deemed known to those of ordinary skill in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present disclosure may be excluded from any claim for any reason, whether related to the existence of prior art or not.

[0338] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above specification, drawings, or examples, but is instead as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications can be made to this description without departing from the spirit or scope of the present disclosure, as defined in the following claims. **************************

Claims

1. A particle, (i) a polymer of formula (I-d), 【Chemistry 47】 or a pharmaceutically acceptable salt thereof (wherein R ６ , R ７ , and R ８ each is independently hydrogen, heteroalkyl, alkyl, alkenyl, or alkynyl; R ９ａ , R ９ｂ , R １０ａ , and R １０ｂ each is independently hydrogen, alkyl, or halo; each of x and y is independently an integer from 1 to 20; and z is an integer from 5 to 90; (ii) phospholipids, (iii) steroids, (iv) a payload, and (v) one or more additional lipid components.

2. The particle of claim 1 comprising (ii).

3. The particle of claim 1 comprising (iii).

4. The particle of claim 1 comprising (iv).

5. The particle of claim 1 comprising (v).

6. R ６ , R ７ , R ８ , R ９ａ , R ９ｂ , R １０ａ , and R １０ｂ 10. The particle of claim 1, wherein each of is independently hydrogen.

7. 10. A particle according to any one of the preceding claims, wherein z is from 5 to 50.

8. 2. The particle of claim 1, wherein x is 5 to 10 (e.g., 6 to 8).

9. The particle of claim 1, wherein y is 5 to 10 (e.g., 6 to 8).

10. 10. The particle of claim 1, wherein the polymer of formula (Id) is present in a mole percent of about 1% to 60%.

11. 10. The particle of claim 1, wherein the polymer of formula (Id) is present in a mole percent of about 1% to 20%.

12. 10. The particle of claim 1, wherein the polymer of formula (Id) is present in a mole percent of about 1% to 15%.

13. The particle of claim 1 , wherein the particle is a liposome, a noosome, or a lipid nanoparticle.

14. The particle of claim 1 , wherein the phospholipid is selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol.

15. 2. The particle of claim 1, wherein the phospholipid is, for example, a compound of any one of formulas (II) to (II-e) described herein.

16. 2. The particle of claim 1, wherein the steroid is, for example, a compound of any one of formulas (III) to (III-b) described herein.

17. The particle of claim 1 , wherein the steroid is cholesterol or a cholesterol derivative.

18. The particle of claim 1 , wherein the payload is selected from a protein, an enzyme, a peptide, a nucleic acid, a small molecule, or a lipid.

19. 20. The particle of claim 18, wherein the payload is a nucleic acid.

20. 20. The particle of claim 19, wherein the nucleic acid is an mRNA molecule.

21. The particle of claim 1 , wherein the additional lipid component is a cationic lipid.

22. 2. The particle of claim 1, wherein the additional lipid component is, for example, a compound of formula (IV) to (IV-b) as described herein.

23. A lipid nanoparticle, comprising: (i) a polymer of formula (I-d), 【Chemistry 48】 or a pharmaceutically acceptable salt thereof (wherein R ６ , R ７ , and R ８ each is independently hydrogen, heteroalkyl, alkyl, alkenyl, or alkynyl; R ９ａ , R ９ｂ , R １０ａ , and R １０ｂ each is independently hydrogen, alkyl, or halo; each of x and y is independently an integer from 1 to 20; and z is an integer from 5 to 90; (ii) phospholipids, (iii) steroids, (iv) a payload, and (v) one or more additional lipid components.

24. A lipid nanoparticle, comprising: (i) a polymer of formula (I-d), 【Chemistry 49】 or a pharmaceutically acceptable salt thereof (wherein R ６ , R ７ , and R ８ each is independently hydrogen, heteroalkyl, alkyl, alkenyl, or alkynyl; R ９ａ , R ９ｂ , R １０ａ , and R １０ｂ each is independently hydrogen, alkyl, or halo; each of x and y is independently an integer from 1 to 20; and z is an integer from 5 to 90; (ii) a phospholipid; and (iii) a steroid; and (iv) a payload; and (v) an additional lipid component.

25. A lipid nanoparticle, comprising: (i) a polymer having the structure: [Transformation 50] or a pharmaceutically acceptable salt thereof; (ii) phospholipids, (iii) steroids, (iv) a payload, and (v) one or more additional lipid components.

26. A lipid nanoparticle, comprising: (i) a polymer having the structure: 【Chemistry 51】 or a pharmaceutically acceptable salt thereof; (ii) a phospholipid; and (iii) a steroid; and (iv) a payload; and (v) an additional lipid component.

27. A lipid nanoparticle, comprising: (i) a polymer having the structure: 【Chemistry 52】 or a pharmaceutically acceptable salt thereof; (ii) a phospholipid; and (iii) a steroid; and (iv) a payload; and (v) an additional lipid component.

28. 2. The particle of claim 1, wherein the phospholipid comprises diastearoylphosphatidylcholine (DSPC) or 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (DMG-PEG).

29. 29. The particle of claim 28, wherein the DMG-PEG comprises DMG-PEG-2000, DMG-PEG-3000, DMG-PEG-3350, DMG-PEG-4000, DMG-PEG-5000, DMG-PEG-10,000, or DMG-PEG-20,000.

30. The particle of claim 1, wherein the particle comprises multiple phospholipids (e.g., DSPC and DMG-PEG).

31. The particle of any one of claims 28 to 30, wherein the concentration of DSPC provided in the particle or lipid nanoparticle formulation is 5 to 15%.

32. 2. The particle of claim 1, wherein the concentration of DMG-PEG (e.g., DMG-PEG-2,000) provided in the particle or lipid nanoparticle formulation is 0.5 to 5%.

33. 2. The particle of claim 1, wherein the polymer of formula (Id) is selected from oleyl-pSar10, oleyl-pSar15, and oleyl-pSar30.

34. 2. The particles according to claim 1, wherein the concentration of the polymer of formula (Id) is 0.5 to 5%.

35. 2. The particle of claim 1, wherein the particle or lipid nanoparticle has a diameter of 50 nm to 1 mm (e.g., 50 nm to 750 nm, 50 nm to 500 nm, 50 to 250 nm).

36. The particle of claim 1, wherein the particle or lipid nanoparticle has a diameter of 50 nm to 200 nm (e.g., 50 nm to 150 nm).

37. The particle of claim 1, wherein the polydispersity of the particle or lipid nanoparticle is 0.05 to 0.5 (e.g., 0.1 to 0.4, 0.1 to 0.3, 0.1 to 0.2).

38. 1. A method of delivering a payload to a subject or a cell, comprising administering to said subject or said cell: (i) a polymer of formula (I-d), 【Chemistry 53】 or a pharmaceutically acceptable salt thereof (wherein R ６ , R ７ , and R ８ each is independently hydrogen, heteroalkyl, alkyl, alkenyl, or alkynyl; R ９ａ , R ９ｂ , R １０ａ , and R １０ｂ each is independently hydrogen, alkyl, or halo; each of x and y is independently an integer from 1 to 20; and z is an integer from 5 to 90; (ii) phospholipids, (iii) steroids, (iv) a payload, and (v) administering particles comprising one or more additional lipid components.

39. 39. The particle of claim 38, wherein the particle is a liposome, a noosome, or a lipid nanoparticle.

40. 40. The particle of any one of claims 38 to 39, wherein the payload is selected from a protein, an enzyme, a peptide, a nucleic acid, a small molecule, or a lipid.

41. 1. A method of treating a disease, disorder, or condition in a subject, comprising administering to the subject: (i) a polymer of formula (I-d), 【Chemistry 54】 or a pharmaceutically acceptable salt thereof (wherein R ６ , R ７ , and R ８ each is independently hydrogen, heteroalkyl, alkyl, alkenyl, or alkynyl; R ９ａ , R ９ｂ , R １０ａ , and R １０ｂ each is independently hydrogen, alkyl, or halo; each of x and y is independently an integer from 1 to 20; and z is an integer from 5 to 90; (ii) phospholipids, (iii) steroids, (iv) a payload, and (v) administering particles comprising one or more additional lipid components.

42. 42. The particle of claim 41, wherein the particle is a liposome, a noosome, or a lipid nanoparticle.

43. The particle of claim 1 , wherein the payload is selected from a protein, an enzyme, a peptide, a nucleic acid, a small molecule, or a lipid.

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