PARTICULATE COMPOSITIONS COMPRISING POLYsarcosine LIPID CONJUGATES

Abstract

The present disclosure relates to particulate compositions, such as liposomes and lipid nanoparticles, comprising polysarcosine-lipid conjugates, as well as methods of making and using the same.

Description

[0001] Priority claim

[0002] This application claims priority to U.S. Application No. 63 / 424,617, filed on November 11, 2022. The entire contents of the aforementioned application are incorporated herein by reference in their entirety. Background Art

[0003] Biopharmaceuticals (biologics) are large, complex molecules typically produced by biotechnology in biological systems such as microorganisms, plant cells, or animal cells. Compared to small molecule drugs, biologics are more difficult to deliver to target cells or subjects. In recent years, particulate formulations, including lipid nanoparticles, have been used as a method for delivering therapeutic payloads; however, these formulations must be finely tuned across multiple parameters to ensure performance, including stability and effective and efficient payload delivery. Therefore, there is a need to develop particulate formulations with improved properties. Summary of the Invention

[0004] The present disclosure features particle compositions comprising polysarcosine lipid conjugates, such as liposomes and lipid nanoparticles, and methods of preparing 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 as described herein; and one or more of the following: (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):

[0005] or a pharmaceutically acceptable salt thereof, wherein R 6 、R 7 and R 8 are each independently hydrogen, heteroalkyl, alkyl, alkenyl or alkynyl; R 9a 、R 9b 、R 10a and R 10b Each is independently hydrogen, alkyl, or halogen; x and y are each independently an integer between 1 and 20; and z is an integer between 5 and 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). The characteristics of the particle composition comprising a polysarcosine lipid conjugate, as well as methods of making and using the particle composition, are described in more detail herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figure 1 Synthesis flow chart of lipid nanoparticle formulations. DETAILED DESCRIPTION

[0007] Described herein are particle compositions, such as liposomes and lipid nanoparticles, comprising polysarcosine lipid conjugates, and methods for their preparation and use. 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). The features of the particle composition comprising polysarcosine lipid conjugates will be described in more detail herein.

[0008] definition

[0009] In order to make the present disclosure more easily understood, certain technical and scientific terms used herein are specifically defined as follows. Unless otherwise specifically defined in this document, all other technical and scientific terms used herein have the meaning commonly understood by ordinary technicians in the field to which the present disclosure belongs.

[0010] As used herein, the singular forms of "a," "an," "the," etc. include the plural forms unless the context clearly requires otherwise.

[0011] As used herein, "about" when used to modify a numerically defined parameter (e.g., a physical description of a particle, such as diameter, or the amount of polysarcosine lipid conjugate in the particle) indicates that the parameter may vary by up to 15% above or below the stated value. In certain embodiments, "about" indicates that the parameter may vary by up to 10% above or below the stated value.

[0012] As used herein, "acquisition" or "obtaining" refers to obtaining a numerical value, such as a number, an image, or a physical entity (such as a sample) by directly or indirectly acquiring it to obtain its ownership. "Direct acquisition" means performing a process (e.g., performing an analytical method or protocol) to obtain the numerical value or physical entity. "Indirect acquisition" refers to receiving the numerical value or physical entity from another party or source (e.g., a third-party laboratory that directly acquires the physical entity or numerical value). Directly acquiring the numerical value or physical entity includes performing a process that causes a physical change in a physical substance or using a machine or device. Examples of directly acquiring the numerical value include obtaining a sample from a human subject. Directly acquiring the numerical value includes performing a process using a machine or device, such as using a fluorescence microscope to acquire fluorescence microscopy data.

[0013] As used herein, "administering," "administering," or "dosing" means providing, absorbing, ingesting, injecting, or otherwise introducing, or providing an entity described herein or a composition comprising the particles to a subject.

[0014] As used herein, the term "subject" refers to mammals, including humans and animal subjects, such as domestic animals (eg, horses, dogs, cats, etc.).

[0015] As used herein, the term "parenteral administration" or "by a non-intestinal route" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intraspinal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered by peritoneal or intravenous injection. The sterile injectable form of the disclosed composition can be an aqueous or oily suspension. These suspensions can be formulated using dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenteral acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable excipients and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution.

[0016] As used herein, the term "effective amount" refers to the amount of a particle composition (e.g., a particle composition) or a particle component (e.g., a protein or nucleic acid). In some embodiments, the term "effective amount" refers to the amount of a particle component, such as the concentration or characteristics of the therapeutic agent on or within the particle. As will be understood by one of ordinary skill in the art, the 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 mode of administration, and the age and health of the subject. An effective amount includes both therapeutic and prophylactic treatments.

[0017] As used herein, the term "in solution" when referring to a protein refers to a liquid medium in which the protein is continuously distributed to form a homogeneous mixture.

[0018] As used herein, the terms "treat," "treating," and "the act of treating" refer to partially or completely alleviating, inhibiting, delaying the onset of a disease or condition, slowing its development, improving and / or alleviating a disease or condition, or one or more symptoms of a disease or condition. In some embodiments, treatment may be performed after the onset of one or more symptoms. In some embodiments, the term "the act of treating" includes preventing, slowing, or stopping the development of a disease or disorder. In some embodiments, treatment may be performed in the absence of symptoms. For example, a susceptible individual may be treated before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also be continued after the symptoms disappear, for example to prevent or delay their recurrence. Therefore, in some embodiments, the term "the act of treating" includes preventing the recurrence or recurrence of a disease or condition.

[0019] Specific chemical definitions

[0020] 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 in the Handbook of Chemistry and Physics, 75th edition, CAS version. Specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry as well as specific functional groups and reactivities are described in the following references: 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. The abbreviations used herein have their conventional meanings in the chemical and biological sciences. The chemical structures and formulas presented herein are constructed according to standard chemical valence rules known in the chemical art.

[0021] When a numerical range is listed, it is intended that each value and subrange within the range be included. For example, "C1-C6 alkyl" refers to 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 defined below and to aid in understanding the description and intended scope of the present invention.

[0022] As used herein, "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 24 carbon atoms ("C1-C 24 In some embodiments, an alkyl group has 1-12 carbon atoms ("C1-C 12In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). In some embodiments, the 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), Examples of alkyl groups include isobutyl (C4), n-pentyl (C5), 3-pentenyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each instance of alkyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents; for example, 1-5 substituents, 1-3 substituents, or 1 substituent. In certain embodiments, alkyl is unsubstituted C1-C 10 Alkyl (eg, -CH3). In certain embodiments, the alkyl group is a substituted C1-C6 alkyl group.

[0023] As used herein, "alkenyl" refers to a straight or branched hydrocarbon radical having 2-24 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-C24 alkenyl"). In some embodiments, the alkenyl radical has 2-10 carbon atoms ("C2-C10 alkenyl"). In some embodiments, the alkenyl radical has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, the alkenyl radical has 2-6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, the alkenyl radical has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds may be internal (as in 2-butenyl) or terminal (as in 1-butenyl). Examples of C2-C4 alkenyl radicals 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 above-mentioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6) and the like. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octatrienyl (C8) and the like. Each example of an alkenyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl group") or substituted with one or more substituents (a "substituted alkenyl group"), e.g., 1-5 substituents, 1-3 substituents, or 1 substituent. In certain embodiments, an alkenyl group is an unsubstituted C1-C10 alkenyl group. In certain embodiments, an alkenyl group is a substituted C2-C6 alkenyl group.

[0024] As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon group having 2-24 carbon atoms and one or more carbon-carbon triple bonds ("C2-C24 alkenyl"). In some embodiments, the alkynyl group has 2-10 carbon atoms ("C2-C10 alkynyl"). In some embodiments, the alkynyl group has 2-8 carbon atoms ("C2-C8 alkynyl"). In some embodiments, the alkynyl group has 2-6 carbon atoms ("C2-C6 alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as 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 example of an alkynyl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"), e.g., 1-5 substituents, 1-3 substituents, or 1 substituent. In certain embodiments, an alkynyl group is an unsubstituted C2-C10 alkynyl group. In certain embodiments, an alkynyl group is a substituted C2-C6 alkynyl group. As used herein, "amino" refers to the group NR70R71, wherein 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.

[0025] As used herein, "cyano" refers to the group -CN.

[0026]

[0046] As used herein, "halo" or "halogen," by themselves or as part of another substituent, means, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.

[0027] As used herein, "hydroxy" refers to the group -OH.

[0028] As used herein, "oxo" refers to a carbonyl group, ie, -C(O)-.

[0029] As used herein, the term "haloalkyl" refers to a non-cyclic stable straight or branched chain, or a combination thereof, comprising at least one carbon atom and at least one halogen selected from F, Cl, Br and I. The halogens F, Cl, Br and I may be located at any position of the haloalkyl group. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CCl3, -CH2-CF3, -CH2-CCl3, -CH2-CBr3, -CH2-CI3, -CH2-CH2-CH(CF3)CH3, -CH2-CH2-CH(Br)-CH3 and -CH2-CH=CH-CH2-CF3. Each example of a haloalkyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted haloalkyl") or substituted ("substituted haloalkyl") with one or more substituents, such as 1-5 substituents, 1-3 substituents or 1 substituent. As used herein, the term "heteroalkyl" refers to a non-cyclic stable straight or branched chain, or a combination thereof, comprising at least one carbon atom and at least one heteroatom selected from O, N, P, Si, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, P, S, and Si may be located 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 can be consecutive, for example, -CH2-NH-OCH3 and -CH2-OSi(CH3)3. When referring to "heteroalkyl" followed by reference to a specific heteroalkyl group, for example, -CHO, -NRCRD, etc., it should be understood that the terms heteroalkyl and -CHO or -NRCRD are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are listed for clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups, for example, -CHO, -NRCRD, etc. Each example of a heteroalkyl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted heteroalkyl") or substituted ("substituted heteroalkyl") with one or more substituents, for example, 1-5 substituents, 1-3 substituents, or 1 substituent.

[0030] As used herein, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in the ring array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-C14 aryl"). In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms ("C14 aryl"; e.g., anthracenyl). Aryl groups can be described as, for example, C6-C10-aryl rings, where the term "aryl ring" refers to the non-hydrogen ring atoms within the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each example of an aryl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted aryl group") or substituted (a "substituted aryl group") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C6-C14 aryl group. In certain embodiments, an aryl group is a substituted C6-C14 aryl group.

[0031] As used herein, "heteroaryl" refers to a group consisting of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having 6 or 10 shared π electrons in the cyclic array), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom if 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 to one or more aryl groups, wherein the point of attachment is on the aryl ring or the heteroaryl ring, in which case the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl, wherein one ring does not contain heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on any ring, i.e., a ring with heteroatoms (e.g., 2-indolyl) or a ring without heteroatoms (e.g., 5-indolyl). Heteroaryl can be described as, for example, 6-10 yuan heteroaryl, wherein the term "yuan" refers to the non-hydrogen ring atoms within the portion. Each example of heteroaryl can be independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents, such as 1-5 substituents, 1-3 substituents, or 1 substituent. Exemplary 5-yuan heteroaryl containing one heteroatom includes, but is not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-yuan heteroaryl containing two heteroatoms includes, but is 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, aza Oxalic acid thia Exemplary 5,6-fused bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0032] As used herein, "cycloalkyl" refers to a group of non-aromatic cyclic hydrocarbon groups having 3-10 carbon atoms ("C3-C10 cycloalkyl") and no heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group has 3-8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3-6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 3-6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5-10 ring carbon atoms ("C5-C10 cycloalkyl"). A cycloalkyl group may be described, for example, as a C4-C7 membered cycloalkyl group, where the term "membered" refers to the non-hydrogen ring atoms in the partial structure. 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), etc. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the above-mentioned 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]pentyl (C5), bicyclo[2.2.2]octyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), etc. 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), decahydronaphthyl (C10), spiro[4.5]decyl (C10), and the like.

[0033] As shown in the foregoing examples, in certain embodiments, cycloalkyl is a monocyclic ring ("monocyclic cycloalkyl"), or comprises a fused, bridged or spirocyclic ring system, such as a bicyclic ring system ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. "Cycloalkyl" also includes a ring system in which a cycloalkyl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the cycloalkyl ring, in which case the number of carbon atoms still represents the number of carbon atoms in the cycloalkyl ring system. Each example of cycloalkyl can independently be optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, cycloalkyl is an unsubstituted C3-C10 cycloalkyl. In certain embodiments, cycloalkyl is a substituted C3-C10 cycloalkyl. As used herein, heterocyclyl refers to a group of a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, if valence permits. A heterocyclyl group may be a monocyclic ring ("monocyclic heterocyclyl") or a fused, bridged, or spirocyclic ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. In heterocyclyl bicyclic ring systems, one or both rings may contain one or more heteroatoms. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more cycloalkyl groups, where the point of attachment is on the cycloalkyl or heterocyclyl ring; or a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the ring system on the heterocyclyl ring; in this 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 3-7 membered heterocyclyl group, where the term "membered" refers to the non-hydrogen ring atoms in that portion of the structure, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each example of a heterocyclyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl group. In certain embodiments, a heterocyclyl group is a substituted 3-10 membered heterocyclyl group. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiirane. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thiirane. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrole-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiirane, dithiirane, and oxazolidin-2-one.Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridonyl (e.g., -1-methylpyridin-2-onyl), and thiopyranyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithiopyranyl, and dioxane. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxacyclooctyl, and thiocanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 5-membered heterocyclic groups fused to a heterocyclic ring (also referred to herein as 5,5-bicyclic heterocyclic rings) include, but are not limited to, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclic groups fused to a heterocyclic ring (also referred to as 4,6-membered heterocyclic rings) include, but are not limited to, diazaspirononyl (e.g., 2,7-diazaspiro[3.5]nonyl). Exemplary 6-membered heterocyclyls fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyls fused to a cycloalkyl ring (also referred to herein as 6,7-bicyclic heterocyclyl rings) include, but are not limited to, azabicyclooctanyl (e.g., (1,5)-8-azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyls fused to a cycloalkyl ring (also referred to herein as 6,8-bicyclic heterocyclyl) include, but are not limited to, azabicyclononyl (e.g., 9-azabicyclo[3.3.1]nonyl).

[0034] Unless otherwise indicated, the terms "alkylene," "alkenylene," "alkynylene," "haloalkylene," "heteroalkylene," "cycloalkylene," or "heterocyclylene," by themselves or as part of another substituent, refer to a divalent radical derived from an alkyl, alkenyl, alkynyl, haloalkylene, heteroalkylene, cycloalkyl, or heterocyclyl, respectively. For example, unless otherwise indicated, the term "alkenylene," by itself or as part of another substituent, refers to a divalent radical derived from an alkene. An alkylene, alkenylene, alkynylene, haloalkylene, heteroalkylene, cycloalkylene, or heterocyclylene radical may be described, for example, as a C1-C6-membered alkylene, a C2-C6-membered alkenylene, a C2-C6-membered alkynylene, a C1-C6-membered haloalkylene, a C1-C6-membered heteroalkylene, a C3-C8-membered cycloalkylene, or a C3-C8-membered heterocyclylene radical, where the term "member" refers to a non-hydrogen atom in the partial structure. For heteroalkylene and heterocyclylene groups, heteroatoms can also occupy either or both of the chain termini (eg, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).

[0035] Furthermore, the direction in which the formula of a linking group is written does not imply the orientation of the linking group. For example, the formula -C(O)2R'- can represent both -C(O)2R'- and -R'C(O)2-. As used herein, the term "cyano" or "-CN" refers to a substituent in which a carbon atom is triple-bonded to a nitrogen atom, e.g., C≡N. As used herein, the term "hydroxy" refers to -OH. As used herein, the term "nitro" refers to a substituent in which two oxygen atoms are bonded to a nitrogen atom, e.g., -NO2.

[0036] As defined herein, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted. Generally, the term "substituted," whether or not preceded by the term "optionally," means that at least one hydrogen atom present on a 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, i.e., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when multiple positions are substituted in any given structure, the substituents at each position may be the same or different. The term "substituted" encompasses substitutions with all permissible substituents of an organic compound, e.g., any of the substituents described herein that can form stable compounds. This disclosure contemplates all such combinations to provide stable compounds. For purposes of the present 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 group. Two or more substituents can be optionally connected to form aryl, heteroaryl, cycloalkyl or heterocyclic groups. Such so-called ring-forming substituents are usually (but not necessarily) connected to the cyclic base structure. In one embodiment, the ring-forming substituent is connected to the adjacent members of the base structure. For example, two ring-forming substituents connected to the adjacent members of the cyclic base structure produce a fused ring structure. In another embodiment, the ring-forming substituent is connected to a single member of the base structure. For example, two ring-forming substituents connected to a single member of the cyclic base structure can form a spiro ring structure. In another embodiment, the ring-forming substituent is connected to the non-adjacent members of the base structure. As used herein, the term "aliphatic" or "aliphatic group" is a hydrocarbon group of a straight chain (i.e., non-branched), branched or cyclic (including fused, bridged and spirofused polycyclic) chain, which can be fully saturated or can contain one or more unsaturated units, but does not have aromaticity. Unless otherwise stated, an aliphatic group contains 1-20 carbon atoms. In some embodiments, an aliphatic group contains 8-20 carbon atoms. In another embodiment, an aliphatic group contains 12-20 carbon atoms. In other embodiments, aliphatic groups comprise 14-20 carbon atoms, and in other embodiments, aliphatic groups comprise 16-20 carbon atoms. The number of carbon atoms present in an aliphatic group can also be defined before stating the aliphatic group. For example, the term (C8-C20) aliphatic refers to an aliphatic group comprising 8-20 carbon atoms as defined herein. Specifically, the disclosure includes each individual subcombination of this range member. In particular, the term (C1-C6) aliphatic is intended to include C1 aliphatic (e.g., methyl), C2 aliphatic (e.g., ethyl, ethylene, or acetylene), C3 aliphatic, C4 aliphatic, C5 aliphatic, and C6 aliphatic.Aliphatic groups include, but are not limited to, straight or branched chain alkyl, alkenyl, and alkynyl, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. Exemplary aliphatic groups include, but are not limited to, C24 aliphatic (e.g., dodecyl), 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).

[0037] As used herein, the term "hydrophobic aliphatic group" or "hydrophobic aliphatic" refers to a group comprising 6 or more carbon atoms, the group having overall hydrophobic properties as a whole. The characteristics of a hydrophobic aliphatic group can have a variety of characteristics, including but not limited to a static water contact angle θ> 90°. The number of carbon atoms present in a hydrophobic aliphatic group can also be expressed as a function of the number of carbon atoms present in the hydrophobic aliphatic group. For example, the term "(C6-C20) hydrophobic aliphatic group" refers to an aliphatic group comprising 6-20 carbon atoms as defined herein. Exemplary hydrophobic aliphatic groups include but are not limited to 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 behenyl (i.e. (CH3(CH2) 10 CH2)2-).

[0038] In the field of organic synthesis, protected hydroxyl groups are well known. For a detailed introduction, see Wuts, PGM Protecting Groups in Organic Synthesis, 5 thEd., New York, John Wiley & Sons, 2014, the book is incorporated herein by reference in its entirety. The example of suitable protected hydroxyl also includes, but is not limited to, ester, carbonate, sulfonate, allyl ether, ether, silyl ether, alkyl ether, aryl alkyl ether and alkoxyalkyl ether. The example of suitable ester includes formates, acetate, propionate, valerate, crotonate and benzoate. The specific example of suitable ester includes formates, benzoylformate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionic acid ester, 4-oxopentanoate, 4,4-(ethylenedithio) valerate, pivalate (trimethyl acetate), crotonate, 4-methoxycrotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate. The example of carbonate includes 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. The example of silyl ether includes trimethylsilyl ether, triethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, triisopropylsilyl ether and other trialkylsilyl ethers. The example of alkyl ether includes methyl ether, benzyl ether, p-methoxybenzyl ether, 3,4-dimethoxybenzyl ether, trityl ether, tert-butyl ether and allyl ether, or its derivatives. Alkoxyalkyl ether includes acetal, 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 ether (MPM), 3,4-dimethoxybenzyl ether, o-nitrobenzyl ether, p-nitrobenzyl ether, p-halobenzyl ether, 2,6-dichlorobenzyl ether, p-cyanobenzyl ether, 2- and 4-picolyl ether.

[0039] Protected amines are well known in the art and are described in Wuts, PGM Greene's Protective Groups in Organic Synthesis, 5 thEd., New Jersey, J. John Wiley & Sons, 2014. are described in detail. Mono-protected amines further include, but are not limited to, arylalkylamines, carbamates, allylamines, amides and the like. Examples of mono-protected amino groups include tert-butyloxycarbonylamino (-NHBOC), ethoxycarbonylamino, methoxycarbonylamino, trichloroethoxycarbonylamino, allyloxycarbonylamino (-NHAlloc), benzyloxycarbonylamino (-NHCBZ), allylamino, benzylamino (-NHBn), fluorenylmethylcarbonyl (-NHFmoc), formamide, acetamide, chloroacetamide, dichloroacetamide, trichloroacetamide, phenylacetamide, trifluoroacetamide, benzamide, tert-butyldiphenylsilyl and the like. Di-protected amines include amines substituted with two substituents, the two substituents being independently selected from the substituents described above for the mono-protected amines, and also include cyclic imides such as phthalimide, maleimide, succinimide and the like. Doubly protected amines also include pyrroles, 2,2,5,5-tetramethyl-[1,2,5]azadisilidine and other analogs, and azides.

[0040] Protected aldehydes are well known in the art and are described in detail in Wuts (2014). Protected aldehydes also 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-dioxazolidine, semicarbazone, and their derivatives.

[0041] Protected carboxylic acids are well known in the art and are described in detail in Wuts (2014). Protected carboxylic acids further include, but are not limited to, optionally substituted C1-20 aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides and the like. Examples of such ester groups include methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, benzyl esters and phenyl esters, each of which is optionally substituted. Other protected carboxylic acids include oxazolines and orthoesters.

[0042] Protected thiols are well known in the art and are described in detail in Wuts (2014). Protected thiols further include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates. Examples of such groups include, but are not limited to, alkyl thioethers, benzyl and substituted benzyl thioethers, triphenylmethyl thioether, and trichloroethoxycarbonyl thioester, to name a few.

[0043] As used herein, the terms "CBP-1," "oleyl-NH-poly(sarcosine 15 )", "Oleylamine-sarcosine15 ", "Oleyl-sarcosine 15 " and "CH3(CH2)7CH=CH(CH2)7CH2NH-poly(sarcosine) 15 ” refer to the same compound with the following structure and can be used interchangeably:

[0044]

[0045] As used herein, the terms "CBP-2," "oleyl-NH-poly(sarcosine 30 )", "Oleylamine-sarcosine 30 ", "Oleyl-sarcosine 30 ”, “CH3(CH2)7CH=CH(CH2)7CH2NH-poly(sarcosine) 30 ”, and polymers having the following structures all represent the same compound and are used interchangeably:

[0046]

[0047] As used herein, the terms "CBP-3," "dodecyl-NH-poly(sarcosine 20 )", "Laurylamine-sarcosine 20 ", "Lauryl-sarcosine 20 ”, “CH3(CH2) 10 CH2NH-poly(sarcosine) 20 ”, and polymers having the following structures all represent the same compound and are used interchangeably:

[0048]

[0049] As used herein, the terms "CBP-4," "tetradecyl-NH-poly(sarcosine 15 )", "Tetradecylamine-sarcosine 15 ","Tetradecyl-sarcosine 15 ”, “CH3(CH2) 12 CH2NH-poly(sarcosine) 15 ”, and polymers with the following structures all represent the same compound and are used interchangeably:

[0050]

[0051] As used herein, the terms "CBP-5," "tetradecyl-NH-poly(sarcosine 20 )", "Tetradecylamine-sarcosine 20 ","Tetradecyl-sarcosine 20 ”, “CH3(CH2) 12CH2NH-poly(sarcosine) 20 ”, and polymers with the following structures all represent the same compound and are used interchangeably:

[0052]

[0053] As used herein, the terms "CBP-6," "hexadecyl-NH-poly(sarcosine 30 )", "Hexadecylamine-sarcosine 30 ", "Cetyl-sarcosine 30 ”, “CH3(CH2) 14 CH2NH-poly(sarcosine) 30 ”, and polymers with the following structures all represent the same compound and are used interchangeably:

[0054]

[0055] As used herein, the terms "CBP-7," "octadecyl-NH-poly(sarcosine 30 )", "Octadecanamine-sarcosine 30 ", "Octadecanyl-sarcosine 30 ”, “CH3(CH2) 16 CH2NH-poly(sarcosine) 30 ”, and polymers having the following structures all represent the same compound and are used interchangeably:

[0056]

[0057] As used herein, the terms "CBP-8", "didecyl-N-poly(sarcosine 30 )", "Didecylamine-sarcosine 30 )", "Didecyl-sarcosine 30 )", "(CH3(CH2)8CH2)2-N-poly(sarcosine) 30 ”, and polymers having the following structures all represent the same compound and are used interchangeably:

[0058]

[0059] As used herein, the terms "CBP-9," "docosyl-N-poly(sarcosine 30 )", "Docosanine-Sarcosine 30 ", "Docosyl-sarcosine 30 ”, “(CH3(CH2) 10 CH2)2-N-poly(sarcosine) 30 ”, and polymers having the following structures all represent the same compound and are used interchangeably:

[0060]

[0061] As used herein, the terms "CBP-10," "oleyl-NH-poly(sarcosine 10 )", "Oleylamine-sarcosine 10 ", "Oleyl-sarcosine 10 ”, “CH3(CH2)7CH=CH(CH2)7CH2NH-poly(sarcosine) 10 ”, and polymers having the following structures all represent the same compound and are used interchangeably:

[0062]

[0063] As used herein, the terms "CBP-11," "tetradecyl-NH-poly(sarcosine 23 )", "Tetradecylamine-sarcosine 23 ","Tetradecyl-sarcosine 23 ”, “CH3(CH2) 14 CH2NH-poly(sarcosine) 23 ”, and polymers having the following structures all refer to the same compound and are used interchangeably:

[0064]

[0065] As used herein, the above monomer repeating units are numerical values representing the average number of monomer units comprising the polymer chain. For example, 10 The polymer represented corresponds to a polymer formed by ten "A" monomer units connected together. One of ordinary skill in the art will recognize that the number 10 here will represent a numerical distribution with an average value of 10. The breadth of this distribution is represented by the polydispersity index (PDI). When the PDI is 1.0, it means that the length of each chain in the polymer is exactly the same (for example, a protein). When the PDI is 2.0, it means that the length of each chain in the polymer is Gaussian. The PDI of the polymers of the present disclosure is generally less than 1.10. In some embodiments, the PDI of the polymers of the present disclosure is 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.

[0066] Unless otherwise stated, structures depicted herein are also intended to encompass all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational) isomers) of that structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as mixtures of enantiomers, diastereomers, and geometric (or conformational) isomers of the compounds of the invention are within the scope of this disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of this disclosure. In addition, unless otherwise stated, structures depicted herein are also intended to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the invention may have hydrogen replaced by deuterium or tritium, or a carbon replaced by 13 C- or 14 Compounds having the disclosed structures except for C-enriched carbon substitutions are within the scope of the present disclosure. For example, such compounds can be used as analytical tools in neutron scattering experiments, or as probes in biological assays, etc.

[0067] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any group capable of being detected (e.g., primary and secondary labels). A "detectable group" or "label" is a group of a detectable compound.

[0068] "Primary" labels include groups containing radioisotopes (e.g., 32 P. 33 p、 35 S or 14 C groups), mass tags, and fluorescent tags, which are signal-generating reporter groups that can be detected without further modification.

[0069] "Secondary" labels include groups such as biotin or protein antigens, which require the presence of a second compound to produce a detectable signal. For example, for a biotin label, the second compound might include a streptavidin-enzyme conjugate. For an antigen label, the second compound might include an antibody-enzyme conjugate. Furthermore, certain fluorescent groups can function as secondary labels by transferring energy to another compound or group through a non-radiative fluorescence resonance energy transfer (FRET) process, allowing the second compound or group to produce a detectable signal.

[0070] As used herein, the terms "fluorescent label," "fluorescent group," "fluorescent compound," "fluorescent dye," and "fluorophore" refer to a compound or group that absorbs light energy at a specific excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent compounds include, but are not limited to, 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, Dapoxil, Dialkylaminocoumarins, 4,5-dichloro-2,7-dimethoxyfluorescein, DM-NERF, Eosin, Erythrosine, Fluorescein, FAM, Hydroxycoumarins, IRDyes (IRD40, IRD 700, IRD 800), JOE, Lissamine Rhodamine B, Marina Blue, methoxycoumarin, naphthyl fluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, RhodolGreen, 2,4,5,7-tetrabromosulfone fluorescein, tetramethylrhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0071] As used herein, the term "substrate" refers to any material or macromolecular complex to which a polymer can be attached. 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 macromolecular complexes (e.g., proteins, polysaccharides).

[0072] The term "as received" when referring to solvents, reagents, resins, or other components used in a chemical reaction or separation means use as provided by the manufacturer without additional isolation and / or purification.

[0073] As used herein, the term "protein" or "polypeptide" refers to a polymer composed of one or more amino acids linked by peptide bonds. Proteins typically contain more than 20 such amino acids. The term encompasses a single polypeptide chain or multiple polypeptide chains that are complexed together or covalently bound (e.g., by disulfide bonds).

[0074] As used herein, the terms "drug," "therapeutic agent," "medicament," "drug," and their derivatives are used interchangeably to refer to a substance used for the diagnosis, cure, alleviation, treatment, or prevention of disease. The 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 the particles described herein.

[0075] As used herein, "unit dosage form" or "unit dosage form" refers to a physically discrete unit of preparation suitable for the subject to be treated. However, it will be understood that the total daily usage of the compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject or organism will depend on a variety of factors, including the disease being treated and the severity of the disease; the activity of the specific active agent being used; the specific ingredients used; the age, weight, general health, sex, and diet of the subject; the time of administration and the excretion rate of the specific active agent being used; the duration of treatment; drugs and / or additional therapies used in combination or concomitantly with the specific compound being used, and similar factors well known in the medical arts.

[0076] As used herein, the term "lipid" or "lipid component" refers to a group of organic compounds, including fatty acid esters, which are generally characterized by being poorly soluble in water but soluble in many organic solvents. They are generally divided into at least three categories: (1) "simple lipids," which include fats, oils, and waxes; (2) "complex lipids," which include phospholipids and glycolipids; and (3) "derivatized lipids," such as steroids. Lipids or lipid components include any lipid known in the art, including phospholipids, PEGylated lipids, steroids, cationic lipids, anionic lipids, or fatty acids.

[0077] As used herein, the term "lipid nanoparticle" refers to a particle formed by a plurality of lipid molecules physically bound to each other by intermolecular forces. Preferably, the lipid nanoparticle is formulated for delivery of a payload to one or more target cells. Examples of suitable lipids include, for example, lipids of Formula (I)-(Ie). The lipid nanoparticle can be, for example, a liposome / vesicle, a nanostructured lipid carrier, a microsphere, a dispersed phase in an emulsion, a micelle, or an internal phase in a suspension.

[0078] As used herein, the term "liposome" refers to a closed multilamellar structure formed by an outer lipid bilayer enclosing an aqueous interior compartment.

[0079] As used herein, the term "phospholipid" refers to any lipid containing a phosphate group or phosphate ion. In some embodiments, "phospholipid" refers to a triester of glycerol with two fatty chains and one alkyl chain containing a phosphate ion. Exemplary phospholipids include natural phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol, as well as synthetic phospholipids such as diacylglycerol, phosphatidic acid, phosphocholine, phosphoethanolamine, and phosphoglycerol.

[0080] As used herein, the term "encapsulate" means to wrap, surround, or enclose something.

[0081] As used herein, "ionizable" refers to a molecule that is capable of undergoing protonation in response to a change in pH. For example, an ionizable lipid is one that is neutral at physiological pH but undergoes protonation at lower pH values.

[0082] Polysarcosine lipid conjugate

[0083] The present disclosure relates to polymers comprising hydrophilic poly(sarcosine) chains and hydrophobic aliphatic groups. In some embodiments, the present disclosure provides polymers of formula (I):

[0084] or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b and R 2 are each independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted by one or more R 3 Replacement, R 3 is hydrogen, halogen, oxo, cyano, nitro, OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement, R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, heteroalkyl or OR C , z is 5-250. In one embodiment, R 1a and R 1b At least one of the groups is independently alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0085] In some embodiments, the present disclosure relates to polymers of formula (I), wherein R 1a 、R1b and R 2 One or more of is alkyl, alkenyl or alkynyl, and the resulting polymer has overall hydrophobic properties. In some embodiments, the present disclosure relates to polymers of formula (I), wherein R la is an alkyl, alkenyl, or alkynyl group, and the resulting polymer has an overall hydrophobic character. In some embodiments, the present disclosure relates to a polymer of formula (I) wherein R 1b is an alkyl, alkenyl, or alkynyl group, and the resulting polymer has an overall hydrophobic character. In some embodiments, the present disclosure relates to a polymer of formula (I) wherein R 2 is an alkyl, alkenyl or alkynyl group, and the resulting polymer has an overall hydrophobic character.

[0086] As described above, the present invention relates to polymers whose hydrophilic chains are polymerized from N-methylglycine (i.e., polysarcosine). 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 whose hydrophilic chains are 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 includes mixtures of two or more N-alkylglycines used to construct water-soluble chains, such as mixtures of N-methylglycine and N-ethylglycine.

[0087] Also as described above, in some embodiments, one or more R la 、R 1b and R 2 Can be optionally and independently substituted. For example, in some embodiments, the present invention contemplates such optional and independent substitutions including, but not limited to, optionally substituted benzyl, optionally substituted alkyl, alkenyl, alkynyl, or heteroalkyl, optionally substituted silyl, poly(amino acid) polymers, poly(ethylene glycol) polymers, poly(N-isopropylacrylamide) polymers, poly(acrylamide) polymers, poly(2-oxazoline) polymers, poly(ethyleneimine), poly(acrylic acid) polymers, poly(methacrylate) polymers, poly(vinyl alcohol) polymers, poly(vinylpyrrolidone) polymers, and their corresponding amine salts.

[0088] In some embodiments, in Formula (I), R 1a is alkyl, alkenyl, alkynyl or cycloalkyl; R 1b and R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a is an alkyl group; R 1b and R2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a is alkenyl; R 1b and R 2 is hydrogen; z is 5-30. In some embodiments, R 1a is an alkynyl group; R 1b and R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a is a C10-C20 alkyl group; R 1b and R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a is a C10-C20 alkenyl group; R 1b and R 2 is hydrogen; z is 5-30. In some embodiments, R 1a is a C10-C20 alkynyl group; R 1b and R 2 is hydrogen; z is 5-30.

[0089] In some embodiments, in Formula (I), R 1a is optionally replaced by one or more R 3 Substituted alkyl; R 1b and R 2 is hydrogen; z is 5-30; and R 3 is halogen, hydroxy, cyano, nitro, oxo or aryl. In some embodiments, in formula (I), R 1a is optionally replaced by one or more R 3 Substituted alkenyl; R 1b and R 2 is hydrogen; z is 5-30; R 3 is halogen, hydroxy, cyano, nitro, oxo or aryl. In some embodiments, in formula (I), R 1a is optionally replaced by one or more R 3 Substituted alkynyl, R 1 and R 2 is hydrogen; z is 5-30; R 3 is halogen, hydroxy, cyano, nitro, oxo or aryl.

[0090] In some embodiments, in Formula (I), R 1b is alkyl, alkenyl, alkynyl or cycloalkyl; R la and R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1b is an alkyl group; R 1a and R 2is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1b is alkenyl; R 1a and R 2 is hydrogen; z is 5-30. In some embodiments, R 1b is an alkynyl group; R 1a and R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1b is optionally replaced by one or more R 3 Substituted alkenyl, R 1a and R 2 is hydrogen; z is 5-30; R 3 is halogen, hydroxy, cyano, nitro, oxo or aryl.

[0091] In some embodiments, in Formula (I), R 1a and R 1b Each is an alkyl group; R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a and R 1 b are each C5-C11 alkyl; R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R la and R 1b Each is an alkenyl group; R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a and R 1b Each is a C5-C11 alkenyl group; R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R la and R 1b Each is an alkynyl group; R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a and R 1b Each is a C5-C11 alkynyl group; R 2 is hydrogen; z is 5-30.

[0092] In some embodiments, in Formula (I), R 1a is an alkyl group; R 1b is alkenyl; R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a is a C5-11 alkyl group; R 1b is a C5-C11 alkenyl group; R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a is alkenyl; R 1bis an alkyl group; R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a is a C5-11 alkenyl group; R 1b is a C5-C11 alkyl group; R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a is an alkyl group; R 1 b is an alkynyl group; R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a is a C5-11 alkyl group; R 1b is a C5-C11 alkynyl group; R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a is an alkynyl group; R 1b Dialkyl; R 2 is hydrogen; z is 5-30. In some embodiments, in formula (I), R 1a is a C5-11 alkynyl group; R 1b is a C5-C11 alkyl group; R 2 is hydrogen; z is 5-30.

[0093] In some embodiments, the present disclosure contemplates that R of the polymer of formula (I) la 、R 1b and R 2 Substitutions are made to add functionality that was not originally present, including but not limited to detectable groups, fluorescent labels, or substrates. One skilled in the art will recognize that isotopically enriched materials can be used as useful probes in biological assays, such as quantitative whole body autoradiography (QWBA) assays for determining the distribution of a composition in an animal. In certain embodiments, R 1a 、R 1b or R 2 In some embodiments, R 1a Contains rich 14 In some embodiments, R 2 Contains rich 14 C isotope hydrocarbons.

[0094] In some embodiments, the polymer of formula (I) is formula (la):

[0095] or a pharmaceutically acceptable salt thereof, wherein R 1 is alkyl, alkenyl, alkynyl or heteroalkyl, each of which may be optionally substituted by one or more R 3 Replacement, R 3 is hydrogen, halogen, oxo, cyano, nitro, OR C, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement, R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, heteroalkyl or OR C , z is 5-250.

[0096] In some embodiments, in Formula (Ia), R 1 is an alkyl group; z is 10-30. In certain embodiments, in Formula (Ia), R 1 is C11-19 alkyl; z is 10-30. In certain embodiments, in formula (Ia), R 1 is alkenyl; z is 10-30. In certain embodiments, in Formula (Ia), R 1 is C11-19 alkenyl; z is 10-30. In certain embodiments, in formula (Ia), R 1 is alkynyl; z is 10-30. In certain embodiments, in Formula (Ia), R 1 is a C11-19 alkynyl group; z is 10-30.

[0097] In some embodiments, the polymer of formula (I) is a polymer of formula (Ib):

[0098] or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Each is (C6-C12)alkyl, (C6-C12)alkenyl or (C6-C12)alkynyl, each of which is optionally substituted by one or more R 3 Replacement, R 3 is hydrogen, halogen, oxo, cyano, nitro, OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, heteroalkyl or OR C , and z is 5-50.

[0099] In some embodiments, the present disclosure provides a polymer of Formula (Ic):

[0100] or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1bare each hydrogen, (C6-C12)alkyl, (C6-C12)alkenyl or (C6-C12)alkynyl, each of which is optionally substituted by one or more R 3 Replacement, R 5 is (C11-C19)alkyl, (C11-C19)alkenyl or (C11-C19)alkynyl, optionally substituted by one or more R 3 Replacement, R 3 is hydrogen, halogen, oxo, cyano, nitro, OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, heteroalkyl or OR C , z is 5-50.

[0101] In some embodiments, in Formula (Ic), R 2 is (C11-C18) alkyl. In some embodiments, in formula (Ic), R 2 In some embodiments, in formula (Ic), R 2 In some embodiments, in formula (Ic), R 2 It is a C17 alkenyl group.

[0102] In some embodiments, the present disclosure provides a polymer of formula (I) or formula (Id):

[0103] or a pharmaceutically acceptable salt thereof, wherein R 6 、R 7 and R 8 are each independently hydrogen, heteroalkyl, alkyl, alkenyl or alkynyl; R 9a 、R 9b 、R 10a and R 10b are each independently hydrogen, alkyl or halogen; x and y are each independently an integer between 1 and 20; z is an integer between 5 and 90;

[0104] In some embodiments, in Formula (Id), R 6 、R 7 and R 8 is hydrogen; x and y are each independently 1-10; z is 5-30. In some embodiments, in formula (Id), R 6 、R 7 and R 8is hydrogen; x is 8; y is 8; z is 5-30. In some embodiments, in formula (Id), R 6 、R 7 and R 8 is hydrogen; x is 8; y is 8; z is 5. In some embodiments, in Formula (Id), R 6 、R 7 and R 8 is hydrogen; x is 8; y is 8; z is 10. In some embodiments, in Formula (Id), R 6 、R 7 and R 8 is hydrogen; x is 8; y is 8; z is 15. In some embodiments, in Formula (Id), R 6 、R 7 and R 8 is hydrogen; x is 8; y is 8; z is 20. In some embodiments, in Formula (Id), R 6 、R 7 and R 8 is hydrogen; x is 8; y is 8; z is 5-25. In some embodiments, in Formula (Id), R 6 、R 7 and R 8 is hydrogen; x is 8, y is 8; and z is 30.

[0105] In some embodiments, the present disclosure provides a polymer of formula (I) or formula (Ie):

[0106] or a pharmaceutically acceptable salt thereof, wherein R 6 、R 7 and R 8 are each independently hydrogen, heteroalkyl, alkyl, alkenyl or alkynyl; R 9a 、R 9b 、R 10a and R 10b are each independently hydrogen, alkyl or halogen; x and y are each independently an integer between 1 and 20; and z is an integer between 5 and 90.

[0107] In some embodiments, in Formula (Ie), R 6 、R 7 and R 8 is hydrogen; x and y are each independently 1-10; z is 5-30. In some embodiments, in formula (Ie), R 6 、R 7 and R 8 is hydrogen; x is 8; y is 8; z is 5-30. In some embodiments, in formula (Ie), R 6 、R 7 and R8 is hydrogen; x is 8; y is 8; z is 5. In some embodiments, in Formula (Ie), R 6 、R 7 and R 8 is hydrogen; x is 8; y is 8; z is 10. In some embodiments, in Formula (Ie), R 6 、R 7 and R 8 is hydrogen; x is 8; y is 8; z is 15. In some embodiments, in Formula (Ie), R 6 、R 7 and R 8 is hydrogen; x is 8; y is 8; z is 20. In some embodiments, in Formula (Ie), R 6 、R 7 and R 8 is hydrogen; x is 8; y is 8; z is 5-25. In some embodiments, in formula (Ie), R 6 、R 7 and R 8 is hydrogen; x is 8; y is 8; and z is 30.

[0108] In some embodiments, the present disclosure provides particles comprising a polymer of Formula (If):

[0109] or a pharmaceutically acceptable salt thereof, wherein z is 5-90.

[0110] In some embodiments, in Formula (If), z is 10. In some embodiments, z is 11. In some embodiments, z is 12. In some embodiments, z is 13. In some embodiments, z is 14. In some embodiments, z is 15. In some embodiments, z is 16. In some embodiments, z is 17. In some embodiments, z is 18. In some embodiments, z is 19. In some embodiments, z is 20. In some embodiments, z is 21. In some embodiments, z is 22. In some embodiments, z is 23. In some embodiments, z is 24. In some embodiments, z is 25. In some embodiments, z is 26. In some embodiments, z is 27. In some embodiments, z is 28. In some embodiments, z is 29. In some embodiments, x is 30. In some embodiments, x is 35. In some embodiments, x is 40. In some embodiments, x is 45.

[0111] In some embodiments, the present disclosure provides particles comprising a polymer of Formula (Ig):

[0112] or a pharmaceutically acceptable salt thereof, wherein z is 5-90.

[0113] In some embodiments, in Formula (Ig), z is 10. In some embodiments, z is 11. In some embodiments, z is 12. In some embodiments, z is 13. In some embodiments, z is 14. In some embodiments, z is 15. In some embodiments, z is 16. In some embodiments, z is 17. In some embodiments, z is 18. In some embodiments, z is 19. In some embodiments, x is 20. In some embodiments, z is 21. In some embodiments, z is 22. In some embodiments, z is 23. In some embodiments, z is 24. In some embodiments, z is 25. In some embodiments, z is 26. In some embodiments, z is 27. In some embodiments, z is 28. In some embodiments, z is 29. In some embodiments, x is 30. In some embodiments, x is 35. In some embodiments, x is 40. In some embodiments, x is 45.

[0114] In some embodiments, the present disclosure provides a particle comprising a polymer having any of the following structures for use in the present invention:

[0115]

[0116]

[0117]

[0118] In some embodiments, the present disclosure provides a polymer having the following structure:

[0119]

[0120] In some embodiments, the present disclosure provides a polymer having the following structure:

[0121]

[0122] In some embodiments, the present disclosure provides a polymer having the following structure:

[0123]

[0124] In some embodiments, the present disclosure provides a polymer having the following structure:

[0125]

[0126] Lipids and lipid components

[0127] The present disclosure provides particle compositions (such as lipid nanoparticles, such as 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 a derivative thereof. In some embodiments, the phospholipid is a compound of formula (II):

[0128] or a pharmaceutically acceptable salt thereof, wherein each R 9 and R 10 Each is independently alkyl, alkenyl or alkynyl, optionally substituted by one or more R 3 Replacement; R 11 is alkyl, alkenyl, alkynyl or heteroalkyl, optionally substituted by one or more R 12 Replacement; R 3 is hydrogen, halogen, oxo, cyano, nitro, OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, heteroalkyl or OR C ; R 12 Alkyl, alkenyl, alkynyl, -NR D R E , oxo or hydroxy; and R D and R E Each is independently hydrogen or alkyl.

[0129] In some embodiments, the phospholipid is phosphatidylcholine. In some embodiments, the phospholipid of formula (II) is a compound of formula (II-a):

[0130] or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 Each is independently (C1-C25)alkyl, (C2-C25)alkenyl or (C2-C25)alkynyl, optionally substituted by one or more R 3 Replacement; R 13 、R 14 and R 15 Each is independently alkyl, alkenyl, alkynyl or heteroalkyl, optionally substituted by one or more R 12 Substitution; R3 is hydrogen, halogen, oxo, cyano, nitro, OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, heteroalkyl or OR C ; R 12 is alkyl, alkenyl, alkynyl, oxo or hydroxy.

[0131] In some embodiments, in Formula (II-a), R 9 、R 10 、R 13 、R 14 and R 15 In some embodiments, in (II-a), R 9 and R 10 are alkenyl, R 13 、R 14 and R 15 In some embodiments, in formula (II-a), R 9 and R 10 are all C6 alkyl; and R 13 、R 14 and R 15 In some embodiments, in formula (II-a), R 9 and R 10 are all C7 alkyl; and R 13 、R 14 and R 15 In some embodiments, in formula (II-a), R 9 and R 10 are all C8 alkyl; and R 13 、R 14 and R 15 All are C1 alkyl.

[0132] In some embodiments, the phospholipid is phosphatidylserine. In some embodiments, the phospholipid of formula (III) is a compound of formula (II-b):

[0133] or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 Each is independently (C1-C25)alkyl, (C2-C25)alkenyl or (C2-C25)alkynyl, optionally substituted by one or more R 3 Replacement; R 16 and R 17 Each is independently alkyl, alkenyl, alkynyl or heteroalkyl, optionally substituted by one or more R 12 Replacement; R 3 is hydrogen, halogen, oxo, cyano, nitro, OR C, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, heteroalkyl or OR C ; R 12 Alkyl, alkenyl, alkynyl, -NR D R E , oxo or hydroxyl; R D and R E Each is independently hydrogen or alkyl.

[0134] In some embodiments, in Formula (II-b), R 9 and R 10 All are alkyl; R 16 -NR D R E ; R 17 is hydroxyl; R D and R E All are hydrogen.

[0135] In some embodiments, the phospholipid is phosphatidylglycerol. In certain embodiments, the phospholipid of formula (II) is a compound of formula (II-c):

[0136] or a pharmaceutically acceptable salt thereof, wherein each R 9 and R 10 are independently (C1-C25)alkyl, (C2-C25)alkenyl or (C2-C25)alkynyl, optionally substituted by one or more R 3 Replacement; R 18 and R 19 Each is independently alkyl, alkenyl, alkynyl or heteroalkyl, optionally substituted by one or more R 12 Replacement; R 3 is hydrogen, halogen, oxo, cyano, nitro, OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, heteroalkyl or OR C ; R 12 Alkyl, alkenyl, alkynyl, -NR D R E , oxo or hydroxyl; R D and R E Each is independently hydrogen or alkyl.

[0137] In some embodiments, the phospholipid is phosphatidylethanolamine. In some embodiments, the phospholipid is a compound of formula (II-d):

[0138] or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 Each is independently (C1-C25)alkyl, (C2-C25)alkenyl or (C2-C25)alkynyl, optionally substituted by one or more R 3 Replacement; R 3 is hydrogen, halogen, oxo, cyano, nitro, OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, heteroalkyl or OR C ; R 12 Alkyl, alkenyl, alkynyl, -NR D R E , oxo or hydroxyl; R D and R E Each is independently hydrogen or alkyl.

[0139] 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-undecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-decanoyl Octadenyl-glycerol-3-phosphocholine (18:0 diether PC), 1-oleoyl-2-cholesterol hemisuccinyl-sn-glycerol-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycerol-3-phosphocholine (C16LysoPC), 1,2-dialinolenoyl-sn-glycerol-3-phosphocholine, 1,2-arachidonoyl-sn-glycerol-3-phosphocholine, 1,2-docosahexaenoyl-sn-glycerol-3-phosphocholine, DOPE, 1,2-dioleoyl-sn-glycerol-3-phosphoethanolamine, 1,2-diphytanoyl-sn-glycerol-3-phosphoethanolamine (ME 16.0PE), 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-docosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphatidyl-rac-(1-glycerol) sodium salt (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoyloleoylphosphatidylethanolamine (POPE) , distearoylphosphatidylethanolamine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphatidylethanolamine (DMPE), 1-stearoyl-2-oleoyl-phosphatidylethanolamine (SOPE), 1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC), sphingosine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloleoylphosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine (LPE), decyl (2-(dioctylammonio)ethyl) phosphate; ePC, ethyl phosphatidylcholine, or a salt thereof.

[0140] In some embodiments, the lipid is a polyethylene glycol-modified (PEGylated) lipid or a derivative thereof. In some embodiments, the PEGylated lipids include: methoxypolyethylene glycol (2000)-N,N-tetracosyl acetamide (ALC-0159), 1,2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000), 1,2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol-5000 (DMG-PEG 5000), 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine-N-[amino(polyethylene glycol)-2000](DOPE-PEG(2000)), 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine-N-[amino(polyethylene glycol)-5000](DOPE-PEG(5000)), 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[amino(polyethylene glycol)-2000](DSPE-PEG(2000)), 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[amino(polyethylene glycol)-5000](DSPE-PEG(5000)), distearoyl-rac-glycero-PEG2K(DSG-PEG 2000), distearoyl-rac-glycerol-PEG5K (DSG-PEG 5000).

[0141] In some embodiments, the phospholipid is a combination of one or more phospholipids described herein in formulas (II)-(II-d).

[0142] In another aspect, the present disclosure provides a particle composition (e.g., a lipid nanoparticle, such as a 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):

[0143] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein ring positions 1-17 are each optionally replaced by one or more R 3 Replacement; R 3 is hydrogen, halogen, oxo, cyano, nitro, OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, alkenyl, alkynyl, heteroalkyl or OR C ; R 12 Alkyl, alkenyl, alkynyl, -NR D R E, oxo or hydroxyl; R D and R E Each is independently hydrogen or alkyl; the dotted line "---" represents a single bond or a double bond determined according to the chemical valence rules.

[0144] In some embodiments, in Formula (III), ring positions 3, 10, 13, and 17 are each replaced by one R 3 substituted; the bond between ring positions 5 and 6 is a double bond. In some embodiments, the compound of formula (III) is a sterane 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.

[0145] In some embodiments, the steroid of formula (III) is a compound of formula (III-a):

[0146] 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 are each independently hydrogen, oxo, hydroxy, halogen, alkyl, alkenyl, alkynyl or heteroalkyl, optionally substituted by one or more R 3 Replacement; R 3 is hydrogen, halogen, oxo, cyano, nitro, OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, alkenyl, alkynyl, heteroalkyl or OR C ; R 12 Alkyl, alkenyl, alkynyl, -NR D R E , oxo or hydroxyl; R D and R E Each is independently hydrogen or alkyl.

[0147] In some embodiments, in Formula (III-a), R 21 OR C , R 24 and R 25 is an alkyl group (eg, a methyl group); R 26 To be two R 3 Substituted alkyl (eg, heptyl); R 22 、R 23and R 27 is hydrogen; R 3 is an alkyl group (e.g., a methyl group). In some embodiments, the compound of formula (III-a) is a sterane or a derivative thereof. In certain embodiments, the compound of formula (III-a) is a sterol or a derivative thereof. In certain embodiments, the compound of formula (III-a) is cholesterol or a derivative thereof.

[0148] In some embodiments, the steroid of formula (III) is a compound of formula (III-b):

[0149] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 31 、R 32 、R 33 、R 34 、R 35 and R 36 are each independently hydrogen, oxo, hydroxy, halogen, alkyl, alkenyl, alkynyl or heteroalkyl, optionally substituted by one or more R 3 Replacement; R 3 is hydrogen, halogen, oxo, cyano, nitro, OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, alkenyl, alkynyl, heteroalkyl or OR C ; R 12 Alkyl, alkenyl, alkynyl, -NR D R E , oxo or hydroxyl; R D and R E Each is independently hydrogen or alkyl.

[0150] In some embodiments of the compound of Formula (III-b), R 31 OR A (e.g., hydroxyl group, e.g., -OH), R 32 、R 33 、R 34 、R 35 and R 36 is an alkyl group (eg, methyl).

[0151] In some embodiments, the steroid is cholesterol or a cholesterol derivative. In some embodiments, the cholesterol derivative is cholesteryl-5,7-dien-3β-ol, cholesteryl-5-en-3-ol, 7β-hydroxycholesterol, cholesteryl-7-en-3β-ol, lanostane-8,24-dien-3-ol, (3S,8S,9S,10R,13R,14S,17R)-17-[(2S,5S)-5-ethyl-6-methyl-heptane-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3-ol, (3S)-17-[(5S)-5-ethyl-6-methyl-heptane-2-yl]-10,13-dimethyl-2,3 ,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3-ol, (3S,8S,9S,10R,13R,14S,17R)-17-[(2R,5S)-5-ethyl-6-methyl-hept-3-en-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3-ol, 17-[(5R)-5,6-dimethyl-hept-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[ a]phenanthren-3-ol, cholesterol isopropyl ether, stigmaster-5-en-3-ol, 10-(iodomethyl)-17-(6-methyl-heptane-2-yl)-1,2,3,4,7,8,9,11,12,13,14,15,16,17-tetradecahydro-cyclopenta[a]phenanthren-3-ol, (3S,5S,10S,13R,17R)-3-hydroxy-10,13-dimethyl-17-(6-methyl-heptane-2-yl)-1,2,3,4,5,6,7,9,11,12,16,17-dodecahydrocyclopenta[a]phenanthren-15-one, 25-hydroxycholesterol, phytosterol, 3-methoxycholesterol-5-ene, 17-(5-ethyl-6 -methyl-hept-6-en-2-yl)-4,10,13-trimethyl-2,3,4,5,6,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3-ol, 17-(5,6-dimethyl-hept-2-yl)-10,13-dimethyl-2,3,4,5,6,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3-ol, (7R,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methyl-hept-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3,7-diol, 24-methylcholesterol, yeast sterol, 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-amino)-N,N-bis(2-hydroxyethyl)-N-methylethane-1-ammonium bromide, DC-cholesterol, 3β-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol; dihydrocholesterol, enantiocholesterol, epicholesterol, chain sterol, cholesteranol, cholesteranone, cholesterenone, cholesteryl-2'-hydroxyethyl ether, cholesteryl-4'-hydroxybutyl ether, 3β-[N-(N',N'-dimethylaminoethyl)-carbamoyl]cholesterol; )carbamoyl cholesterol (DC-cholesterol), 24(S)-hydroxycholesterol, 25-hydroxycholesterol, 25(R)-27-hydroxycholesterol, 22-oxa-cholesterol, 23-oxa-cholesterol, 24-oxa-cholesterol, cycloartenol, 22-ketosterol, 20-hydroxysterol, 7-hydroxycholesterol, 19-hydroxycholesterol, 22-hydroxycholesterol, 25-hydroxycholesterol, 7-dehydrocholesterol, 5α-cholesterol-7-en-3β-ol, 3,6,9-trioxaoctane-1-ol-cholesterol-3e-ol, dehydroergosterol, dehydroepiandrosterone, lanosterol, dihydrolanosterol, lanosterenol, luminosterol, sitolcalciferol, calcipotriol, coprostanol, cholecalciferol, lupeol, ergocalciferol, 22-dihydroergocalciferol, ergosterol, brassinosteroid, tomatine aglycone, tomatine, ursolic acid, cholic acid, chenodeoxycholic acid, zymosterol, diosgenin, fuccasterol, fecosterol or fecosterol or its salts, stereoisomers or tautomers.

[0152] In some embodiments, the lipid is a cationic lipid or an ionizable lipid (i.e., a lipid that can be protonated at low pH values). In some embodiments, the lipid (e.g., a cationic lipid or an ionizable lipid) is a compound of formula (IV):

[0153] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein each R 41 、R 42 、R 43 、R 44 、R 45 and R 46 are each independently hydrogen, oxo, hydroxy, halogen, alkyl, alkenyl, alkynyl or heteroalkyl, optionally substituted by one or more R 3Substituted; W, X, Y and Z are each independently -N(R 3 )-、-N(R 3 )(R3')- or C(R 3 )(R 3’ )-;R 3 and R 3' is hydrogen, halogen, oxo, cyano, nitro, OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, alkenyl, alkynyl, heteroalkyl or OR C ; R 12 Alkyl, alkenyl, alkynyl, -NR D R E , oxo or hydroxyl; R D and R E Each is independently hydrogen or alkyl.

[0154] In some embodiments, the lipid is a compound of formula (IV-a):

[0155] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein each R 47 、R 48 and R 49 Each is independently hydrogen, oxo, hydroxy, halogen, alkyl, alkenyl, alkynyl or heteroalkyl, optionally replaced by one or more R 3 Replacement; R 3 is hydrogen, halogen, oxo, cyano, nitro, OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, alkenyl, alkynyl, heteroalkyl or OR C ; R 12 Alkyl, alkenyl, alkynyl, -NR D R E , oxo or hydroxyl; R D and R E Each is independently hydrogen or alkyl.

[0156] In some embodiments, the lipid is a compound of formula (II-b):

[0157] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R50 、R 51 、R 52 、R 53 、R 54 、R 55 、R 56 、R 57 and R 58 Each is independently hydrogen, oxo, hydroxy, halogen, alkyl, alkenyl, alkynyl or heteroalkyl, optionally replaced by one or more R 3 Replacement; R 3 is hydrogen, halogen, oxo, cyano, nitro, OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, alkenyl, alkynyl, heteroalkyl or OR C ; R 12 Alkyl, alkenyl, alkynyl, -NR D R E , oxo or hydroxyl; R D and R E Each is independently hydrogen or alkyl.

[0158] In some embodiments, the lipid (e.g., a cationic lipid or an ionizable lipid) is selected from the group consisting of lipids described in International Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638, WO2010080724, WO201021865, and WO2008103276, U.S. Patent Nos. 7893302, 7404969, and 8283333, and U.S. Patent Publication Nos. US20100036115 and US20120202871.

[0159] In some embodiments, the lipid (e.g., any lipid, cationic lipid, or ionizable lipid) is didecyldimethylammonium bromide, 1,2-dioleoyloxy-3-(trimethylammonium)propane, dioctyldecylamine, trimethyl[2,3-(dioleoyloxy)propyl]ammonium, N-tert-butyl-N-tetradecyl-3-(tetradecylamino)propionamidine, hexadecyltrimethylammonium, tridecylamine, dimethyldioctadecylammonium, stearyltrimethylammonium, N,N-dimethyltetradecylamine, trioctylamine, cetrimide, ide), hexadecyldimethylammonium, bispalmitoyldimethylammonium, hexadecyldimethylamine, methyltrioctylamine, dipalmitylamine, dimyristylamine, 1,2-bis(oleoyloxy)-3-(dimethylamino)propane or 2,5-bis(3-aminopropylamino)-N-[2-[di(heptadecyl)amino]-2-oxoethyl]pentanamide, ([(4-hydroxybutyl)azadiyl]bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC-0315, 9-heptadecyl 8-{(2-hydroxyethyl )[6-oxo-6-(undedecyloxy)hexylamino}octanoate (SM-102), N,N-dimethyl-2,3-dioleyl)propylamine (DODMA), N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-neodymium dimethylammonium bromide (DDAB), N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(1-(2,3-dioleoyloxy)propyl)-N,N,N -trimethylammonium chloride (DOTMA), 1,2-dilinoleoyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinolenoyloxy-N,N-dimethylaminopropane (DLenDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA) or a pharmaceutically acceptable salt thereof.

[0160] Particle composition

[0161] The present disclosure relates to particles (e.g., lipid nanoparticles) comprising polysarcosine lipid conjugates (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) as described herein) and related compositions. Exemplary lipid nanoparticles include liposomes / vesicles, nanostructured lipid carriers, cationic lipid-nucleic acid complexes, and solid lipid nanoparticles. Detailed information about each of the above particles is further provided below.

[0162] lipid nanoparticles

[0163] Described herein are lipid nanoparticle compositions comprising polysarcosine lipid conjugates, e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) as described herein. In some embodiments, the disclosure provides a particle comprising: (i) a polysarcosine lipid conjugate (e.g., a polymer of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig)); (ii) a phospholipid (e.g., a compound of Formula (II)-(II-e)); (iii) a steroid (e.g., a compound of Formula (III)-(III-b)); (iv) a payload (e.g., a nucleic acid or drug); and (v) an additional lipid component (e.g., a cationic lipid, i.e., an ionizable lipid, e.g., a compound of Formula (IV)-(IV-e)), wherein components (i)-(iv) are as described herein.

[0164] Exemplary lipid nanoparticle compositions are disclosed in International Patent Publication WO2010005721, U.S. Patent Nos. 10703789; US20200254086, U.S. Patent Nos. 11406706 and US20200345641, all of which are incorporated herein by reference in their entirety.

[0165] In some embodiments, the lipid nanoparticles comprise a polysarcosine lipid conjugate (e.g., a polymer of any of Formula (I)-(Ig) described herein) in an amount of 0.1-50 mol%, 0.1-45 mol%, 0.1-40 mol%, 0.1-35 mol%, 0.1-30 mol%, 0.1-20 mol%, 0.25-20 mol%, 0.5-20 mol%, 1-20 mol%, 1.5-20 mol%, 0.1-15 mol%, 0.25-15 mol%, 0.5-15 mol%, 1-15 mol%, 1.5-15 mol%, 2-15 mol%, 2.5-15 mol%, 0.1-12.5 mol%. %, 0.25-12.5mol%, 0.5-12.5mol%, 1-12.5mol%, 1.5-12.5mol%, 2-12.5mol%, 2.5-12.5mol%, 0.1-10mol%, 0.25-10mol%, 0.5-10mol%, 1-10mol%, 1.5- 10mol%, 2-10mol%, 2.5-10mol%, 0.1-7.5mol%, 0.25-7.5mol%, 0.5-7.5mol%, 1-7.5mol%, 1.5-7.5mol%, 2-7.5mol%, 2.5-7.5mol%, 0.1-5mol%, 0.25-5m ol%, 0.5-5mol%, 1-5mol%, 1.5-5mol%, 2-5mol%, 2.5-5mol%, 0.1-3mol%, 0.25-3mol%, 0.5-3mol%, 1-3mol%, 1.5-3mol%, 2-3mol%, 2.5-3mol%, 0.1-2.5 mol%, 0.25-2.5mol%, 0.5-2.5mol%, 1-2.5mol%, 1.5-2.5mol%, 2-2.5mol%, 0.1-4.5mol%, 0.25-4.5mol%, 0.5-4.5mol%, 1-4.5mol%, 1.5-4.5mol%, 2-4 .5mol%, 2.5-4.5mol%, 0.1-4mol%, 0.25-4mol%, 0.5-4mol%, 1-4mol%, 1.5-4mol%, 2-4mol%, 2.5-4mol%, 0.1-3.5mol%, 0.25-3.5mol%, 0.5-3.5mol%, 1 -3.5mol%, 1.5-3.5mol%, 2-3.5mol%, 2.5-3.5mol%, 0.1-2.0mol%, 0.1-1.5mol%mol%, 0.1-1.0mol%, 0.5-2.0mol%, 0.5-1.5mol%, 0.5-1.0mol%, 1.0-2.0 mol%, 1.0-1.5 mol%, 1.5-2.0 mol%, 1.0 mol% or 1.5 mol%.

[0166] In some embodiments, the lipid nanoparticles comprise a polysarcosine lipid conjugate (e.g., a polymer of any of Formula (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 a polysarcosine lipid conjugate (e.g., a polymer of any of Formula (I)-(Ig) as 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%.

[0167] In some embodiments, the lipid nanoparticles comprise phospholipids (e.g., compounds of formula (II)-(II-e) described herein) in an amount of 1-75 mol%, 5-7 mol%, 10-75 mol%, 20-75 mol%, 35-75 mol%, 1-60 mol%, 5-60 mol%, 10-60 mol%, 20-60 mol%, 30-60 mol%, 1-50 mol%, 5-50 mol%, % 5-40 mol%, 5-30 mol%, 5-25 mol%, 5-20 mol%, 5-15 mol%, 5-13 mol%, 5-10 mol%, 10-30 mol%, 10-25 mol%, 10-20 mol%, 10-15 mol%, 10-13 mol%, 15-30 mol%, 15-25 mol%, 15-20 mol%, 20-30 mol%, or 20-25 mol%.

[0168] In some embodiments, the lipid nanoparticles comprise a phospholipid (e.g., a compound of any one 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 a phospholipid (e.g., a compound of any one of Formulas (II)-(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%.

[0169] 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) as described herein) in an amount of 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%, 30-40 mol%, 30-39 mol%, 35-60 mol%, 35-55 mol%, 35-52.5mol%, 35-52mol%, 35-51mol%, 35-50mol%, 35-47.5mol%, 35-45mol%, 35-44mol%, 35-43.5mol%, 35-43mol%, 35-41.5mol%, 35-40mo l%, 35-39mol%, 37-60mol%, 37-55mol%, 37-52mol%, 37-52mol%, 37-51mol%, 37-50mol%, 37.5-47mol%, 37-45mol%, 37-44mol%, 37-43mol%, 37-43 mol%, 37.5-41mol%, 37.5-40mol%, 37.5-39.5mol%, 39.5-60mol%, 39.5-55mol%, 39.5-52mol%, 39-52mol%, 39-51mol%, 39-50mol%, 39-47mol%, 3 9-45mol%, 39-44mol%, 39-43mol%, 39-43mol%, 3-4mol%, 39-40mol%, 40-60mol%, 40-55mol%, 40-52mol%, 40-52mol%, 40-51mol%, 40-50mol%, 40- 47mol%, 40-45mol%, 40-44mol%, 40-43mol%, 40-43mol%, 40-41.5mol%, 41.-60mol%, 41.5-55mol%, 41.5-52mol%, 41-52mol%, 41-51mol%, 41-50m ol%, 41-47mol%, 41-45mol%, 41-44mol%, 41-43mol%, 41-43mol%, 43-60mol%, 43-55mol%, 43-52mol%, 43-52mol%, 43-51mol%, 43-50mol%, 43-47.5mol%, 43-45mol%, 43-44mol%, 43-43mol%, 43-60mol%, 43-55mol%, 43-52mol%, 43-52mol%, 43-51mol%, 43-50mol%, 43-47 mol%, 43-45mol%, 43-44mol%, 45-60mol%, 45-55mol%, 45-52mol%, 45-52mol%, 45-51mol%, 45-50mol%, 45-47mol%, 47-60m ol%, 47-55mol%, 47.5-52mol%, 47-52mol%, 47-51mol%, 47-50mol%, 50-60mol%, 50-55mol%, 50-52mol%, 50-52mol%, 50-52 mol%, 50-51 mol%, 51-60 mol%, 51-55 mol%, 51-52.5 mol%, or 51-52 mol%, 51-60 mol%, 51-55 mol%, 51-52.5 mol%, or 51-52 mol%. .

[0170] 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%.

[0171] In some embodiments, the lipid nanoparticles contain additional lipid components (e.g., cationic lipids, e.g., ionizable lipids, e.g., compounds of formula (IV)-(IV-c) described herein) in an amount equal to (100-(mol% of polysarcosine lipid conjugate + molar% of steroid + molar% of phospholipid)) molar%. According to one example, the amount of cationic or ionizable lipid in the lipid nanoparticles can be 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%, 15-42.5 mol%. .5mol%, 15-40mol%, 15-35mol%, 15-30mol%, 15-26.5mol%, 15-25mol%, 15-20mol%, 20-60mol%, 20-55mol%, 20-50mol%, 2 0-45mol%, 20-42.5mol%, 20-40mol%, 20-35mol%, 20-30mol%, 20-26.5mol%, 20-25mol%, 25-60mol%, 25-55mol%, 25-50mo l%, 25-45mol%, 25-42.5mol%, 25-40mol%, 25-35mol%, 25-30mol%, 25-26.5mol%, 26.5-60mol%, 26.5-55mol%, 26.5-50m ol%, 26.5-45mol%, 26.5-42.5mol%, 26.5-40mol%, 26.5-35mol%, 26.5-30mol%, 30-60mol%, 30-55mol%, 30-50mol%, 30-4 5mol%, 30-42.5mol%, 30-40mol%, 30-35mol%, 35-60mol%, 35-55mol%, 35-50mol%, 35-45mol%, 35-42.5mol%, 35-40mol%, 40-60mol%, 40-55mol%, 40-50mol%, 40-45mol%, 40-42.5mol%, 42.5-60mol%, 42.5-55mol%, 42.5-50mol% or 42.5-45mol%.

[0172] In some embodiments, the lipid nanoparticles comprise additional lipid components (e.g., cationic lipids, e.g., ionizable lipids, e.g., compounds 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%, 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%, less than 0.1 mol%.

[0173] In some embodiments, the average diameter of the lipid nanoparticles is 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 110 nm, about 80 nm to about 100 nm, about 90 nm to about 100 nm, about 70 nm to about 110 nm, about 8 ... 0 nm to about 80 nm, 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 greater, and is substantially non-toxic to human subjects.

[0174] In some embodiments, the average diameter of the lipid nanoparticles is determined by dynamic light scattering. In some embodiments, the average diameter of the lipid nanoparticles is determined by optical microscopy. In some embodiments, the average diameter of the 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.

[0175] 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 a preferred embodiment, the particles have a net positive charge. In some embodiments, the charge is determined by zeta potential measurement.

[0176] liposomes

[0177] Another exemplary particle composition comprising the polysarcosine lipid conjugates described herein is a liposome. Liposomes are lipid vesicles composed of a lipid bilayer (e.g., a phospholipid bilayer), typically with an additional lipid component (e.g., cholesterol). Liposomes can be made from several different types of lipids, such as common phospholipids. Exemplary liposome formulations are disclosed in U.S. Pat. No. 10,722,508, U.S. Pat. No. 10,220,095, and U.S. Pat. No. 11,071,713, all of which are incorporated herein by reference in their entirety.

[0178] Methods for preparing multilamellar lipid vesicles are known in the art (e.g., see U.S. Patent No. 6,693,086, which is incorporated herein by reference for its teachings on the preparation of multilamellar lipid vesicles). Although vesicle formation can occur spontaneously when the lipid film is mixed with an aqueous solution, this process can also be accelerated by applying a shaking force using a homogenizer, sonicator, or extrusion device (see review by 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 extrusion through filters of gradually decreasing size, as described in Templeton et al., Nature Biotech, 15: 647-652, 1997, which is incorporated herein by reference for its teachings on the preparation of extruded lipids.

[0179] Other particles

[0180] Nanostructured lipid carriers (NLCs) are modified solid lipid nanoparticles (SLNs) that retain the properties of SLNs, improving drug stability and loading capacity while preventing drug leakage. Polymeric nanoparticles (PNPs) are a key component of drug delivery systems. These nanoparticles can effectively deliver drugs to specific targets, improve drug stability, and achieve controlled drug release. Lipid-polymer nanoparticles (PLNs), a novel carrier that combines the characteristics of liposomes and polymers, may also be used. These nanoparticles offer the complementary advantages of both PNPs and liposomes. PLNs consist of a core-shell structure; the polymer core provides structural stability, while the phospholipid shell provides good biocompatibility. Therefore, these two components enhance drug encapsulation efficiency, facilitate 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.

[0181] Payload

[0182] The present disclosure also provides particle compositions (e.g., lipid nanoparticles, e.g., liposomes, e.g., nanostructured lipid carriers) comprising polysarcosine lipid conjugates, which further comprise a payload. Exemplary payloads include proteins (e.g., enzymes, antibodies, lipoproteins), natural or synthetic peptides, peptides containing non-natural 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.

[0183] 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 can be tumor necrosis factor (TNF) α or β, renin, colchicine, prolactin, adrenocorticotropic hormone, vasopressin, somatostatin, reserpine, trypsin, leuprorelin, α1-antitrypsin; coagulation factors such as factor VIIIC, factor IX, tissue factor and von Willebrand factor, anticoagulant factors such as protein C; atrial natriuretic factor, pulmonary surfactant, plasminogen activators other than tissue-type plasminogen activator (t-PA), bombesin, thrombin, hematopoietic growth factor, enkephalinase, RANTES (activation of normal T cell-expressed and secreted regulatory protein), human macrophage inflammatory protein (MIP-1α), serum albumin, such as human serum albumin, Müllerian inhibitory substance, relaxin A chain, relaxin B chain, relaxin precursor, mouse gonadotropin-related peptide, chorionic gonadotropin, microbial proteins, such as β-lactamase, deoxyribonuclease (DNase), inhibin, activin, hormone or growth factor receptor, integrin, protein A or D, rheumatoid factor, platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor (TGF), such as T GF-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 protein, CD proteins, such as CD-3, CD-4, CD-8 and CD-19, erythropoietin, osteoinductive factors, immunotoxins, interferons, such as α interferon (e.g., α2A type interferon), β interferon, γ interferon, λ interferon and consensus interferon , colony stimulating factors (CSFs), such as M-CSF, GM-CSF and G-CSF, interleukins (ILs), such as IL-1 to IL-10, superoxide dismutase, T cell receptors, surface membrane proteins, decay accelerating factors, transporters, homing receptors, addressins, fertility inhibitors, such as prostaglandins; fertility promoters, regulatory proteins, antibodies (including fragments thereof) and chimeric proteins, such as immunoadhesins; precursors, derivatives, prodrugs and analogs of these compounds, as well as pharmaceutically acceptable salts of these compounds, or precursors, derivatives, prodrugs and analogs thereof. Applicable proteins or peptides can be natural or recombinant, for example, including fusion proteins.

[0184] Examples of protein payloads also include CCL1, CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES), CCL6, CCL7, CCL8, CCL9 (CCL10), CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CXCL1 (KC), CXCL2 (SDF1a), CXCL3, CXCL4, CXCL5, CXCL6 , CXCL7, CXCL8(IL8), CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CX3CL1, XCL1, XCL2, TNFA, TNFB(LTA), TNFC(LTB), TNF SF4, TNFSF5(CD40LG), TNFSF6, TNFSF7, TNFSF8, TNFSF9, TNFSF10, TNFSF11, TNFSF13B, EDA, IL2, IL15, IL4, IL13, IL7, IL9, IL21, IL3, IL5, IL6, IL11, I L27, IL30, IL31, OSM, LIF, CNTF, CTF1, IL12a, IL12b, IL23, IL27, IL35, IL14, IL16, IL32, IL34, IL10, IL22, IL19, IL20, IL24, IL26, IL29, IFNL1, IFNL2 , IFNL3, IL28, IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA21, IFNB1, IFNK, IFNW1, IFNG, IL1A (IL 1F1), IL1B(IL1F2), IL1Ra(IL1F3), IL1F5(IL36RN), IL1F6(IL36A), IL1F7(IL37), IL1F8(IL36B), IL1F9(IL36G), IL1F10(IL38), IL33(IL1F11), IL18 (IL1G), IL17, KITLG, IL25(IL17E), CSF1(M-CSF), CSF2(GM-CSF), CSF3(G-CSF), SPP1, TGFB1, TGFB2, TGFB3, CCL3L1, CCL3L2, CCL3L3, CCL4L1, CCL4L2,IL17B, IL17C, IL17D, IL17F, AIMP1(SCYE1), MIF, Areg, BC096441, Bmp1, Bmp10, Bmp15, Bmp2, Bmp3, Bmp4, Bmp5, Bmp6, Bmp7, Bmp8a, Bmp8b, C1qtnf4, Ccl 2la, Ccl27a, Cd70, Cer1, Cklf, Clcfl, Cmtm2a, Cmtm2b, Cmtm3, Cmtm4, Cmtm5, Cmtm6, Cmtm7, Cmtm8, Crlfl, Ctf2, Ebi3, Edn1, Fam3b, Fasl, Fgf2, Flt31, Gdf10, Gdf11, Gdf15, Gdf2, Gdf3, Gdf5, Gdf6, Gdf7, Gdf9, Gm12597, Gm1327 1. Gm13275, Gm13276, Gm13280, Gm13283, Gm2564, Gpi1, Grem1, Grem2, Grn, H mgb1, 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, Tnfsf13b, Tnfsf14, Tnfsf15, Tnfsf18, Tnfsf4, Tnfsf8, Tnfsf9, Tslp, Vegfa, Wnt1, Wnt2, Wnt5a, Wnt7a, Xcl1, epinephrine, melatonin, triiodothyronine, thyroxine, prostaglandins, leukotrienes, prostacyclin, thromboxane, islet amylin, Müllerian inhibitory factor or hormone, adiponectin, adrenocorticotropic hormone, angiotensin, vasopressin, arginine vasopressin, atrial peptide, brain sodium Urinary peptide, calcitonin, cholecystokinin, cortisol, 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, insulin, insulin-like growth factor (somatomedin), leptin, lipoprotein, 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.

[0185] Protein payloads can also be hormones, such as antidiuretic hormone (ADH), which is produced by the posterior pituitary gland and acts on the kidneys to affect water balance and blood pressure; oxytocin, which is produced by the posterior pituitary gland and acts on the uterus and mammary glands to stimulate uterine contractions and milk secretion; growth hormone (GH), which is produced by the anterior pituitary gland and acts on body cells, bones and muscles to affect growth and development; prolactin, which is produced by the anterior pituitary gland and acts on the mammary glands to maintain milk secretion; growth hormone-releasing hormone (GHRH), which is a releasing hormone of growth hormone (GH) and is produced by the arcuate nucleus of the hypothalamus; thyroid stimulating hormone (TSH), which is produced by the anterior pituitary gland and acts on the thyroid gland to regulate the secretion of thyroid hormones; thyroid stimulating hormone-releasing hormone (THR) Thyrotropin (TRH), produced by the hypothalamus, stimulates the anterior pituitary to secrete thyroid-stimulating hormone (TSH) and prolactin. Adrenocorticotropic hormone (ACTH), produced by the anterior pituitary, acts on the adrenal cortex to regulate the secretion of adrenocortical hormones. Follicle-stimulating hormone (FSH), produced by the anterior pituitary, acts on the ovaries and testicles to stimulate egg and sperm production. Luteinizing hormone (LH), produced by the anterior pituitary, acts on the ovaries and testicles to stimulate ovulation and the release of sex hormones. Luteinizing hormone-releasing hormone (LHRH), also known as gonadotropin-releasing hormone (GnRH), is synthesized and released by GnRH neurons in the hypothalamus. It is a nutritional peptide hormone responsible for the release of FSH and LH. Thyroxine, produced by the thyroid gland, acts on body cells to regulate metabolism. Calcitonin, produced by the thyroid gland, acts on the adrenal cortex to lower blood calcium levels. Parathyroid hormone, produced by the parathyroid glands, acts on the bone matrix to increase blood calcium levels. Aldosterone, produced by the adrenal cortex, acts on the kidneys to regulate water balance; cortisol, produced by the adrenal cortex, acts on body cells, suppresses the immune system and participates in stress response; epinephrine, produced by the adrenal medulla, acts on the heart, lungs, liver and body cells, affecting the primary response of "fight or flight"; glucagon, produced by the pancreas, acts on the liver to increase blood sugar levels; insulin, produced by the pancreas, acts on body cells to lower blood sugar levels; estrogen, produced by the ovaries, acts on the reproductive system, affecting puberty development, menstrual cycle and gonadal development; progesterone, produced by the ovaries, acts on the reproductive system, affecting puberty development, menstrual cycle and gonadal development; testosterone, produced by the adrenal glands and testicles, acts on the reproductive system, affecting puberty development, gonadal development and sperm production.

[0186] 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, desphenylalanine 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 factors I and II (IGF-I and IGF-II).

[0187] In one embodiment, the protein payload is a vaccine component, such as an antigen. The antigen may comprise any protein or polypeptide that is foreign to the host organism. Preferred antigens can be presented on the surface of the host's antigen-presenting cells (APCs) for monitoring by immune effector cells (such as white blood cells expressing CD4 receptors (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 antigens that are essential for the survival of tumor cells.

[0188] Certain antigens are considered by those skilled in the art to be immunostimulating (i.e., capable of stimulating effective immune recognition) and to provide effective immune protection for the organism or molecule from which they are derived. Antigens can be peptides, proteins, polysaccharides, carbohydrates, 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 be whole cells or immunogenic components thereof, such as cell wall components or molecular components. Suitable antigens are known in the art and can be obtained from commercial, governmental, and scientific sources. Antigens can be purified or partially purified polypeptides derived from tumors or viral or bacterial sources. Antigens can be recombinant polypeptides produced by expressing DNA encoding a polypeptide antigen in a heterologous expression system. Antigens can also be DNA encoding all or part of an antigenic protein. Antigens can be provided alone or in combination. Antigens can also be provided as a complex mixture of polypeptides or nucleic acids.

[0189] Exemplary antigens can be isolated from any virus, including but not limited to viruses in the following virus 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, Pea Ear Mosaic Virus Enamovirus, Filoviridae (e.g., Marburg virus and Ebola virus (e.g., Zaire, Reston, Ivory Coast, or Sudan)), Flaviviridae (e.g., Hepatitis C virus, Dengue virus 1, Dengue virus 2, Dengue virus 3, and Dengue virus 4), Hepadnaviridae, Herpesviridae (e.g., Herpes simplex virus types 1, 3, 4, 5, and 6, and cytomegalovirus), Hypoviridae, Iridoviridae, Leviviridae, Lipothrixviridae ae), 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 foot-and-mouth disease virus), Poxviridae (e.g., variola virus and vaccinia virus), Reoviridae (e.g., rotavirus), Retroviridae (e.g., lentiviruses such as human immunodeficiency virus (HIV) types 1 and 2), Rhabdoviridae (e.g.,Applicable viral antigens also include dengue protein M, dengue protein E, dengue DINS1, dengue DINS2 and dengue DINS3. Viral antigens can be derived from specific viral strains, such as papillomaviruses, herpes viruses (such as herpes simplex virus types 1 and 2), hepatitis viruses (e.g., hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus (HEV), and hepatitis G virus (HGV)), tick-borne encephalitis virus, parainfluenza virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, rotavirus, rhinovirus, adenovirus, coxsackie virus, equine encephalitis virus, Japanese encephalitis virus, yellow fever virus, Rift Valley fever virus, and lymphocytic choriomeningitis virus.

[0190] Other exemplary antigens can be derived from any bacteria, including but not limited to Actinomyces, Anabaena, Bacillus, Bacteroides, Bdellovibrio, Bordetella, Borrelia, Campylobacter, Canulobacter, Chlamydia, Chlorobium, Chromatium, Clostridium, Corynebacterium, Cytophaga, Deinococcus, Escherichia, Francisella, Halobacterium, Heliobacter, Haemophilus, Hemophilus influenzae type B,HIB), Hyphomicrobium, Legionella, Leptospira, Listeria, Meningococcus A, B, and C, Methanobacterium, Micrococcus, Mycobacterium, Mycoplasma, Myxococcus, Neisseria, Nitrobacter, Oscillatoria, Prochloron, Proteus, Pseudomonas, Rhodospirillum, Rickettsia ettsia), Salmonella, Shigella, Spirillum, Spirochaeta, Staphylococcus, Streptococcus, Streptomyces, Sulfolobus, Thermoplasma, Thiobacillus, Treponema, Vibrio, and Yersinia. Other exemplary antigens can also be obtained from parasites,Antigens include, but are not limited to, those derived from 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, Toxoplasma gondii, Trichomonas vaginalis, and Schistosoma mansoni. These antigens include all or part of sporozoite antigens, Plasmodium antigens, such as circumsporozoite protein, sporozoite surface protein, liver stage antigen, apical membrane associated protein or merozoite surface protein.

[0191] Further exemplary antigens may be allergens or environmental antigens, such as, but not limited to, antigens derived from natural allergens, such as pollen allergens (tree, herb, weed and grass pollen allergens), insect allergens (inhalant, salivary and venom allergens), animal hair and dander allergens and food allergens. Important pollen allergens from trees, grasses and herbs are from the Fagales, Oleales, Pinales and Platanaceae, including but not limited to birch (Betula), alder (Alnus), hazel (Corylus), hornbeam (Carpinus) and olive (Olea), cedar (Cryptomeriand Juniperus), Platanus; the Poales, including, for example, genera of the Poaceae family such as Lolium, Phleum, Poa, Cynodon, Dactylis, Holcus, Phalaris, Secale, and Sorghum; the Asterales and Urticales, including herbaceous plant genera such as Ambrosia, Artemisia, and Parietaria.

[0192] Other allergen antigens that can be used include mite allergens from the genera Dermatophagoides and Euroglyphus, and allergens from storage mites (e.g., Lepidoglyphys, Glycyphagus, and Tyrophagus), as well as allergens from cockroaches, midges, and fleas (e.g., Blatella, Periplaneta, Chironomus, and Ctenocephalides), allergens from mammals and birds such as cats, dogs, and horses, and venom allergens (including allergens from stinging or biting insects, such as bees (Sealoidea), wasps (Vespoidea), and ants (Apioidea) from the order Hymenoptera. Other allergen antigens that can be used include inhalant allergens from fungi (e.g., Aspergillus and Cladosporium).

[0193] Other exemplary antigens may include tumor antigens, including tumor-associated or tumor-specific antigens, such as, 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, hsp702, KIAAO205, Mart2, Mum-1, Mum-2 and Mum-3, neo-PAP, myosin class I, OS-9, pml-RARa fusion protein, PTPRK, K-ras, N-ras, triosephosphate isomerase, Bage-1, Gage 3,4,5,6,7, GnTV, HervK-mel, Lage-1, Mage-A1, Mage-A2, Mage-A3, Mage-A4, Mage-A6, Mage-A10, Mage-A12, Mage-C2, NA-88, NY-Eso-1 / Lage-2, SP17, SSX-2, TRP2-Int2, melanoma-associated antigen A (MART-1), 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, Home / 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, alpha-fetoprotein, 13HCG, BCA225, BTAA, CA125, CA15-3 (CA27.29 / BCAA), CA195, CA 242, CA-50, CAM43, CD68 / KP1, CO-029, FGF5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein / cyclosporine C-associated protein), TAAL6, TAG72, TLP, and TPS.

[0194] In another embodiment, the payload is an antibody. The text describes antibodies that work by directly binding to one or more epitopes, other ligands or auxiliary molecules on the surface of eukaryotic cells. Typically, antibodies or their antigen-binding fragments have affinity for receptors on the surface of specific cell types, such as receptors expressed on the surface of macrophages. Various types of antibodies and antibody fragments can be used in the compositions and methods, including complete immunoglobulins of any class, fragments thereof, and synthetic proteins comprising antibody antigen-binding variable domains. 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 a Fab fragment, a F(ab')2 fragment, a single-chain variable region, etc. The antibody can be a polyclonal antibody or a monoclonal antibody (mAb). Monoclonal antibodies include "chimeric" antibodies, i.e., a portion of the heavy and / or light chain is identical or homologous to a corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, as long as they are able to specifically bind to the target antigen and / or exhibit the desired biological activity (US Patent No. 4,816,567; and Morrison, et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984)). The antibodies can also be modified by recombinant means, for example, by deletion, addition or substitution of amino acids, to enhance the effectiveness of the antibody in mediating the desired function. The substitutions can be conservative substitutions. For example, at least one amino acid in the constant region of an antibody can be replaced with a different residue (see, e.g., US Patent No. 5,624,821; US Patent No. 6,194,551; WO 9958572; and Angal, et al., Mol. Immunol. 30: 105-08 (1993)). In some cases, antibodies are engineered to reduce undesirable activities, such as complement-dependent cytotoxicity. The antibody can be a bispecific antibody having binding specificities for at least two different antigenic epitopes. In one embodiment, these epitopes are from the same antigen. In another embodiment, these 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. Immnol., 152: 5368 (1994)).

[0195] Antibodies can be produced by any method known in the art. Descriptions of exemplary antibody generation and production methods include: 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, most recent edition). Intact Ig molecule fragments can be produced by methods well known in the art, including enzymatic and recombinant methods.

[0196] In some embodiments, the payload is a small molecule drug. In some embodiments, the small molecule drug is a cytotoxic drug, a chemotherapeutic drug, a natural product, an antiviral drug, an antibiotic or other therapeutic agent. Cytotoxic drugs can include, for example, SN-38, paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthraquinone dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, maytansine, cytotoxic drugs ... compounds, rachelmycin, amiodarone, isavuconazonium, delafloxacin, remdesivir, carfilzomib, posaconazole, allopregnanolone, dalbavancin, plerixafor, netupitant, eribulin, letermovir, palonosetron, copanlixib, lurbinectedin, and their analogs. Other therapeutic agents can include, for example, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil and decitabine), alkylating agents (e.g., mechlorethamine, thiotepa, chlorambucil, rachelmycin, melphalan, carmustine, lomustine, cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C and cisplatin (II) (DDP) and cisplatin), anthracyclines (e.g., daunorubicin and doxorubicin), antibiotics (e.g., dactinomycin D, bleomycin, mithramycin and anthramycin) and antimitotics (e.g., vincristine, vinblastine and maytansine).

[0197] In some embodiments, the particle composition (eg, lipid nanoparticle) comprises a payload selected from the therapeutic agents described in U.S. Patent No.: 8,734,846 or U.S. Patent Publication No. US20100087337.

[0198] Exemplary embodiments

[0199] 1. A particle comprising:

[0200] (i) A polymer having formula (Id):

[0201] or a pharmaceutically acceptable salt thereof, wherein R 6 、R 7 and R 8 are each independently hydrogen, heteroalkyl, alkyl, alkenyl or alkynyl; R 9a 、R 9b 、R 10a and R 10b are each independently hydrogen, alkyl or halogen; x and y are each independently an integer between 1 and 20; z is an integer between 5 and 90;

[0202] And one or more of the following:

[0203] (ii) phospholipids;

[0204] (iii) steroids;

[0205] (iv) payload; and

[0206] (v) Additional lipid components.

[0207] 2. The particle according to embodiment 1, comprising (ii).

[0208] 3. The particle according to any one of the preceding embodiments, comprising (iii).

[0209] 4. The particle according to any one of the preceding embodiments, comprising (iv).

[0210] 5. The particle according to any one of the preceding embodiments, comprising (v).

[0211] 6. The particle according to any one of the preceding embodiments, comprising (ii) and (iii).

[0212] 7. The particle according to any one of the preceding embodiments, comprising (ii), (iii), and (iv).

[0213] 8. The particle according to any one of the preceding embodiments, comprising (ii), (iii), (iv), and (v).

[0214] 9. The particle according to any one of the preceding embodiments, comprising (ii), (iii), and (v).

[0215] 10. The particle according to any one of the preceding embodiments, comprising (ii), (iv), and (v).

[0216] 11. The particle according to any one of the preceding embodiments, comprising (ii) and (iii).

[0217] 12. The particle according to any one of the preceding embodiments, excluding (iii).

[0218] 13. The particle according to any one of the preceding embodiments, excluding (iv).

[0219] 14. The particle according to any one of the preceding embodiments, excluding (v).

[0220] 15. The particle according to any one of the preceding embodiments, wherein R 6 、R 7 and R 8 are each independently hydrogen.

[0221] 16. The particle according to any one of the preceding embodiments, wherein R 6 For hydrogen.

[0222] 17. The particle according to any one of the preceding embodiments, wherein R 7 For hydrogen.

[0223] 18. The particle according to any one of the preceding embodiments, wherein R 8 For hydrogen.

[0224] 19. The particle according to any one of the preceding embodiments, wherein R 9a 、R 9b 、R 10a and R 10b are each independently hydrogen.

[0225] 20. The particle according to any one of the preceding embodiments, wherein R 9a For hydrogen.

[0226] 21. The particle according to any one of the preceding embodiments, wherein R 9b For hydrogen.

[0227] 22. The particle according to any one of the preceding embodiments, wherein R10a For hydrogen.

[0228] 23. The particle according to any one of the preceding embodiments, wherein R 10b For hydrogen.

[0229] 24. The particles according to any one of the preceding embodiments, wherein z is 5-50.

[0230] 25. The particle according to 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.

[0231] 26. The particles according to any one of the preceding embodiments, wherein z is 15.

[0232] 27. The particles according to any one of the preceding embodiments, wherein z is 25.

[0233] 28. The particles according to any one of the preceding embodiments, wherein z is 30.

[0234] 29. The particles according to any one of the preceding embodiments, wherein z is 35.

[0235] 30. The particles according to any one of the preceding embodiments, wherein z is 40.

[0236] 31. The particles according to any one of the preceding embodiments, wherein z is 45.

[0237] 32. The particle according to any one of the preceding embodiments, wherein x is between 5 and 10.

[0238] 33. The particles according to any one of the preceding embodiments, wherein x is between 6 and 8.

[0239] 34. The particles according to any one of the preceding embodiments, wherein x is 5.

[0240] 35. The particles according to any one of the preceding embodiments, wherein x is 6.

[0241] 36. The particles according to any one of the preceding embodiments, wherein x is 7.

[0242] 37. The particles according to any one of the preceding embodiments, wherein x is 8.

[0243] 38. The particles according to any one of the preceding embodiments, wherein x is 9.

[0244] 39. The particles according to any one of the preceding embodiments, wherein x is 10.

[0245] 40. The particle according to any one of the preceding embodiments, wherein y is between 5 and 10.

[0246] 41. The particle according to any one of the preceding embodiments, wherein y is between 6 and 9.

[0247] 42. The particles according to any one of the preceding embodiments, wherein y is 5.

[0248] 43. The particles according to any one of the preceding embodiments, wherein y is 6.

[0249] 44. The particles according to any one of the preceding embodiments, wherein y is 7.

[0250] 45. The particles according to any one of the preceding embodiments, wherein y is 8.

[0251] 46. The particles according to any one of the preceding embodiments, wherein y is 9.

[0252] 47. The particles according to any one of the preceding embodiments, wherein y is 10.

[0253] 48. A particle according to any of the preceding embodiments, wherein the molar percentage of the polymer represented by formula (Id) is about 1%-60%, 1%-55%, 1%-50%, 1%-45%, 1%-40%, 1%-35%, 1%-30%, 1%-25%, 1%-20%, 1%-15%, 1%-10%, 1%- to 5%, 1%-4%, 1% to 3%, 1%-2%, 0.5%-2% or 0.5%-1%.

[0254] 49. The particle according to any one of the preceding embodiments, wherein the molar percentage of the polymer represented by formula (Id) is about 1% to about 60%.

[0255] 50. The particle according to any one of the preceding embodiments, wherein the molar percentage of the polymer represented by formula (Id) is about 1% to 20%.

[0256] 51. The particle according to any one of the preceding embodiments, wherein the molar percentage of the polymer represented by formula (Id) is about 1% to 10%.

[0257] 52. The particle according to any one of the preceding embodiments, wherein the mole percentage of the polymer represented by formula (Id) is about 1% to 5%.

[0258] 53. The particle according to any one of the preceding embodiments, wherein the mole percentage of the polymer represented by formula (Id) is about 1% to 4%.

[0259] 54. The particle according to any one of the preceding embodiments, wherein the mole percentage of the polymer represented by formula (Id) is about 1% to 3%.

[0260] 55. The particle according to any one of the preceding embodiments, wherein the molar percentage of the polymer represented by formula (Id) is about 1% to 2%.

[0261] 56. The particle according to any one of the preceding embodiments, wherein the mole percentage of the polymer represented by formula (Id) is about 0.5% to 2%.

[0262] 57. The particle according to any one of the preceding embodiments, wherein the mole percentage of the polymer represented by formula (Id) is about 1% to 15%.

[0263] 58. The particle according to any one of the preceding embodiments, wherein the mole percentage of the polymer represented by formula (Id) is about 1.5%.

[0264] 59. The particle according to any one of the preceding embodiments, wherein the mole percentage of the polymer represented by formula (Id) is about 2.5%.

[0265] 60. The particle according to any one of the preceding embodiments, wherein the particle is a liposome, a vesicle or a lipid nanoparticle.

[0266] 61. The particle according to any preceding embodiment, wherein the particle is a liposome.

[0267] 62. The particle according to any one of the preceding embodiments, wherein the particle is a vesicle.

[0268] 63. The particle according to any one of the preceding embodiments, wherein the particle is a lipid nanoparticle.

[0269] 64. The particle according to any one of the preceding embodiments, wherein the phospholipid is selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylglycerol.

[0270] 65. The particle according to any one of the preceding embodiments, wherein the phospholipid is phosphatidylcholine.

[0271] 66. The particle according to any one of the preceding embodiments, wherein the phospholipid is phosphatidylethanolamine.

[0272] 67. The particle according to any preceding embodiment, wherein the phospholipid is phosphatidylserine.

[0273] 68. The particle according to any preceding embodiment, wherein the phospholipid is phosphatidylglycerol.

[0274] 69. The particle according to any one of the preceding embodiments, wherein the phospholipid is a compound represented by any one of formulas (II) to (II-d) as described herein.

[0275] 70. The particle according to any one of the preceding embodiments, wherein the phospholipid is a compound of formula (II):

[0276] or a pharmaceutically acceptable salt thereof, wherein each R 9 and R 10 are independently alkyl, alkenyl or alkynyl, optionally substituted by one or more R 3 Replacement; R 11 is alkyl, alkenyl, alkynyl or heteroalkyl, optionally substituted by one or more R 12 Replacement; R 3 is hydrogen, halogen, oxo, cyano, nitro, -OR C , alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more R 4 Replacement; R C is hydrogen, alkyl, alkenyl, alkynyl or heteroalkyl; R 4 is halogen, alkyl, heteroalkyl or OR C ; R 12 Alkyl, alkenyl, alkynyl, -NR D R E , oxo or hydroxy; and R D and R E Each is independently hydrogen or alkyl.

[0277] 71. The particles according to embodiment 70, wherein, for formula (II), R 9 is an alkyl group, R 10 is an alkyl group, and R 11 It is a heteroalkyl group.

[0278] 72. The particle according to embodiment 70 or 71, wherein, for formula (II), R 9 is a C17 alkyl group, R 10 is a C17 alkyl group, and R 11 is heteroalkyl (e.g., -CH2CH3N(CH3)3).

[0279] 73. The particle according to any one of embodiments 70-72, wherein the phospholipid is of formula (II):

[0280]

[0281] 74. The particle according to any one of the preceding embodiments, wherein the phospholipid is a compound of formula (II-a) as described herein.

[0282] 75. The particles according to embodiment 74, wherein, for formula (II-a), R 9 is an alkyl group, R 10 is an alkyl group, R 13 is an alkyl group, R 14 is an alkyl group, and R 15 For alkyl.

[0283] 76. The particle according to embodiment 74 or 75, wherein for formula (II-a), R 9 is a C17 alkyl group, R 10 is a C17 alkyl group, R 13 is a C1 alkyl group, R 14 is a C1 alkyl group, and R 15 It is a C1 alkyl group.

[0284] 77. The particle according to any one of the preceding embodiments, wherein the phospholipid is a compound of formula (II-b) as described herein.

[0285] 78. The particle according to any one of the preceding embodiments, wherein the phospholipid is a compound of formula (II-c) as described herein.

[0286] 79. The particle according to any one of the preceding embodiments, wherein the phospholipid is a compound of formula (II-d) as described herein.

[0287] 80. The particle according to any one of the preceding embodiments, wherein the phospholipid is 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC).

[0288] 81. The particle according to any one of the preceding embodiments, wherein the phospholipid is 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC).

[0289] 82. The particle according to any one of the preceding embodiments, wherein the phospholipid is 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC).

[0290] 83. The particle according to any one of the preceding embodiments, wherein the phospholipid is 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC).

[0291] 84. The particle according to any one of the preceding embodiments, wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

[0292] 85. The particle according to any one of the preceding embodiments, wherein the phospholipid is 1,2-undecanoyl-sn-glycero-phosphocholine (DUPC).

[0293] 86. The particle according to any one of the preceding embodiments, wherein the phospholipid is 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC).

[0294] 87. The particle according to any one of the preceding embodiments, wherein the phospholipid further comprises a polyethylene glycol modification.

[0295] 88. The particles according to embodiment 87, wherein the polyethylene glycol-modified phospholipids are selected from the group consisting of methoxypolyethylene glycol (2000)-N,N-tetracosyl acetamide (ALC-0159), 1,2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol 2000 (DMG-PEG 2000), 1,2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol 5000 (DMG-PEG 5000), 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine-N-[amino(polyethylene glycol)-2000](DOPE-PEG(2000)), 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine-N-[amino(polyethylene glycol)-5000](DOPE-PEG(5000)), 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[amino(polyethylene glycol)-2000](DSPE-PEG(2000)), 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[amino(polyethylene glycol)-5000](DSPE-PEG(5000)), distearoyl-rac-glycero-PEG2K(DSG-PEG 2000) and distearoyl-rac-glycerol-PEG5K (DSG-PEG 5000).

[0296] 89. The particles according to embodiment 87 or 88, wherein the polyethylene glycol-modified phospholipid is selected from: 1,2-dimyristoyl-sn-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000), 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine-N-[amino(polyethylene glycol)-2000] (DOPE-PEG(2000)), 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG(2000)) and distearoyl-rac-glycero-PEG2K (DSG-PEG 2000).

[0297] 90. The particle according to embodiment 97 or 88, wherein the phospholipid modified with polyethylene glycol is 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol 2000 (DMG-PEG 2000).

[0298] 91. A particle according to any preceding embodiment, wherein the phospholipid is a combination of one or more phospholipids described herein.

[0299] 92. The particle according to any one of the preceding embodiments, wherein the steroid is any one of the compounds of formula (III)-(III-b) described herein.

[0300] 93. The particle according to any one of the preceding embodiments, wherein the steroid is a compound of formula (III) as described herein.

[0301] 94. The particle according to embodiment 90, wherein for formula (III): positions 3, 10, 13 and 17 on the ring are each replaced by one R 3 substituted; and the bond between positions 5 and 6 on the ring is a double bond.

[0302] 95. The particle according to any one of the preceding embodiments, wherein the steroid is a compound of formula (III-a) as described herein.

[0303] 96. The particle according to embodiment 95, wherein for formula (III-a): R 21 For-OR C , R 24 is an alkyl group, R 25 is an alkyl group, R 26 To be two R 3 Substituted alkyl, and R 22 、R 23 and R 27 For hydrogen.

[0304] 97. The particle according to embodiment 95 or 96, wherein for formula (III-a): R 21 -OH, R 24 is methyl, R 25 is methyl, R 26 To be two R 3 Substituted heptyl, and R 22 、R 23 and R 27 For hydrogen.

[0305] 98. The particle according to any one of the preceding embodiments, wherein the steroid is a compound of formula (III-b) as described herein.

[0306] 99. The particle according to embodiment 98, wherein for formula (III-b): R 31 For-OR A , R 32 is an alkyl group, R 33 is an alkyl group, R 34 is an alkyl group, R 35 is an alkyl group, and R 36 For alkyl.

[0307] 100. The particle according to any preceding embodiment, wherein the steroid is cholesterol or a cholesterol derivative.

[0308] 101. The particle according to any preceding embodiment, wherein the steroid is cholesterol.

[0309] 102. A particle according to any preceding embodiment, wherein the payload is selected from a protein, an enzyme, a peptide, a nucleic acid, a small molecule or a lipid.

[0310] 103. The particle according to any preceding embodiment, wherein the payload is a protein.

[0311] 104. The particle according to any preceding embodiment, wherein the payload is an enzyme or a peptide.

[0312] 105. The particle according to any preceding embodiment, wherein the payload is a peptide.

[0313] 106. The particle of any preceding embodiment, wherein the payload is a nucleic acid.

[0314] 107. The particle according to any preceding embodiment, wherein the payload is a small molecule.

[0315] 108. The particle according to any preceding embodiment, wherein the payload is a lipid.

[0316] 109. The particle of embodiment 102, wherein the nucleic acid is an RNA molecule.

[0317] 110. The particle of embodiment 105, wherein the RNA molecule is selected from the group consisting of: mRNA, tRNA, rRNA, and snRNA.

[0318] 111. The particle of embodiment 105 or 106, wherein the RNA molecule is an mRNA molecule.

[0319] 112. The particles of embodiment 102, wherein the payload is a small molecule selected from cytotoxic drugs, chemotherapeutic drugs, natural products, antiviral drugs, and antibiotics.

[0320] 113. The particles of embodiment 112, wherein the small molecule is a cytotoxic drug.

[0321] 114. The particles of embodiment 112, wherein the small molecule is a chemotherapy drug.

[0322] 115. The particles of embodiment 112, wherein the small molecule is a natural product.

[0323] 116. The particles of embodiment 112, wherein the small molecule is an antiviral drug.

[0324] 117. The particles of embodiment 112, wherein the small molecule is an antibiotic.

[0325] 118. The particle according to any one of the preceding embodiments, wherein 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, dihydroxyanthraquinone dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, rachelmycin, amiodarone, isavuconazonium, delafloxacin, remdesivir, carfilzomib, posaconazole, allopregnanolone, dalbavancin, plerixafor, netupitant, eribulin, letermovir, palonosetron, copanlixib, lurbinectedin, methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil, dacarbazine, mechlorethamine, thiotepa, chlorambucil, raloxacin, melphalan, carmustine, lomustine, cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II), cisplatin, daunorubicin, doxorubicin, actinomycin D, bleomycin, mithramycin, anthramycin, vincristine, vinblastine, and maytansines.

[0326] 119. A particle according to any preceding embodiment, wherein the additional lipid component is a cationic lipid.

[0327] 120. A particle according to any preceding embodiment, wherein the additional lipid component is a compound of formula (IV)-(IV-b) as described herein.

[0328] 121. A particle according to any preceding embodiment, wherein the additional lipid component is a compound of formula (IV).

[0329] 122. A particle according to any preceding embodiment, wherein the additional lipid component is SM-102.

[0330] 123. A particle according to any preceding embodiment, wherein the additional lipid component is ALC-0315.

[0331] 124. A lipid nanoparticle comprising:

[0332] (i) A polymer having formula (Id):

[0333] or a pharmaceutically acceptable salt thereof, wherein R 6、R 7 and R 8 are each independently hydrogen, heteroalkyl, alkyl, alkenyl or alkynyl; R 9a 、R 9b 、R 10a and R 10b are each independently hydrogen, alkyl or halogen; x and y are each independently an integer between 1 and 20; z is an integer between 5 and 90;

[0334] And one or more of the following:

[0335] (ii) phospholipids;

[0336] (iii) steroids;

[0337] (iv) payload; and

[0338] (v) Additional lipid components.

[0339] 125. A lipid nanoparticle comprising:

[0340] (i) A polymer having formula (Id):

[0341] or a pharmaceutically acceptable salt thereof, wherein R 6 、R 7 and R 8 are each independently hydrogen, heteroalkyl, alkyl, alkenyl or alkynyl; R 9a 、R 9b 、R 10a and R 10b are each independently hydrogen, alkyl or halogen; x and y are each independently an integer between 1 and 20; z is an integer between 5 and 90;

[0342] And one or more of the following:

[0343] (ii) phospholipids;

[0344] (iii) steroids;

[0345] (iv) payload; and

[0346] (v) Additional lipid components.

[0347] 126. A lipid nanoparticle comprising:

[0348] (i) A polymer having the following structure:

[0349] or a pharmaceutically acceptable salt thereof, and one or more of the following:

[0350] (ii) phospholipids;

[0351] (iii) steroids;

[0352] (iv) payload; and

[0353] (v) Additional lipid components.

[0354] 127. A lipid nanoparticle comprising:

[0355] (i) A polymer having the following structure:

[0356] or a pharmaceutically acceptable salt thereof; (ii) a phospholipid;

[0357] (iii) steroids;

[0358] (iv) payload; and

[0359] (v) Additional lipid components.

[0360] 128. A lipid nanoparticle comprising:

[0361] (i) A polymer having the following structure:

[0362] or a pharmaceutically acceptable salt thereof,

[0363] And one or more of the following:

[0364] (ii) phospholipids;

[0365] (iii) steroids;

[0366] (iv) payload; and

[0367] (v) Additional lipid components.

[0368] 129. A particle or lipid nanoparticle according to any of the preceding embodiments, wherein the phospholipid comprises non-stearoylphosphocholine (DSPC) or 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (DMG-PEG).

[0369] 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-10000 or DMG-PEG-20000.

[0370] 131. The particle or lipid nanoparticle of embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-2000.

[0371] 132. The particle or lipid nanoparticle of embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-3000.

[0372] 133. The particle or lipid nanoparticle of embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-3350.

[0373] 134. The particle or lipid nanoparticle of embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-4000.

[0374] 135. The particle or lipid nanoparticle of embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-5000.

[0375] 136. The particle or lipid nanoparticle of embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-10000.

[0376] 137. The particle or lipid nanoparticle of embodiment 129 or 130, wherein the DMG-PEG comprises DMG-PEG-20000.

[0377] 138. A particle or lipid nanoparticle according to any preceding embodiment, wherein the particle or lipid nanoparticle comprises a plurality of phospholipids.

[0378] 139. The particle or lipid nanoparticle according to any preceding embodiment, wherein the particle comprises DSPC and DMG-PEG.

[0379] 140. The particle or lipid nanoparticle of embodiment 139, wherein the concentration of DSPC in the particle or lipid nanoparticle formulation is between 5-15%.

[0380] 141. The particle or lipid nanoparticle of any one of embodiments 139-140, wherein the concentration of DMG-PEG in the particle or lipid nanoparticle formulation is between 0.5-5%.

[0381] 142. The particle or lipid nanoparticle of any one of embodiments 129-141, wherein the concentration of DMG-PEG-2000 in the particle or lipid nanoparticle formulation is between 0.5-5%.

[0382] 143. The particle according to any one of the preceding embodiments, wherein the polymer represented by formula (Id) is selected from oleyl-pSar10, oleyl-pSar15 and oleyl-pSar30.

[0383] 144. The particle according to any one of the preceding embodiments, wherein the polymer represented by formula (Id) is oleyl-pSar10.

[0384] 145. The particle according to any one of the preceding embodiments, wherein the polymer represented by formula (Id) is oleyl-pSar15.

[0385] 146. The particle according to any one of the preceding embodiments, wherein the polymer represented by formula (Id) is oleyl-pSar30.

[0386] 147. The particle or lipid nanoparticle according to any preceding embodiment, wherein the concentration of the polymer represented by formula (Id) is between 0.5-5%.

[0387] 148. The particle or lipid nanoparticle according to any one of the preceding embodiments, wherein the diameter of the particle or lipid nanoparticle is between 50 nm and 1 mm.

[0388] 149. The particle or lipid nanoparticle according to any of the preceding embodiments, wherein the diameter of the particle or lipid nanoparticle is between 50 nm and 750 nm.

[0389] 150. The particle or lipid nanoparticle according to any one of the preceding embodiments, wherein the diameter of the particle or lipid nanoparticle is between 50 nm and 500 nm.

[0390] 151. The particle or lipid nanoparticle according to any one of the preceding embodiments, wherein the diameter of the particle or lipid nanoparticle is between 50 nm and 250 nm.

[0391] 152. The particle or lipid nanoparticle according to any one of the preceding embodiments, wherein the diameter of the particle or lipid nanoparticle is between 50 nm and 200 nm.

[0392] 143. The particle or lipid nanoparticle according to any one of the preceding embodiments, wherein the diameter of the particle or lipid nanoparticle is between 50 nm and 150 nm.

[0393] 154. The particle or lipid nanoparticle according to any preceding embodiment, wherein the polydispersity of the particle or lipid nanoparticle is between 0.05-0.5.

[0394] 155. The particle or lipid nanoparticle according to any preceding embodiment, wherein the polydispersity of the particle or lipid nanoparticle is between 0.1 and 0.4.

[0395] 156. The particle or lipid nanoparticle according to any preceding embodiment, wherein the polydispersity of the particle or lipid nanoparticle is between 0.1 and 0.3.

[0396] 157. The particles or lipid nanoparticles according to any of the preceding embodiments, wherein the polydispersity of the particles or lipid nanoparticles is between 0.1 and 0.2.

[0397] 158. A method of delivering a payload to a subject or cell, the method comprising administering to the subject or cell a particle comprising:

[0398] (i) A polymer having formula (Id):

[0399] or a pharmaceutically acceptable salt thereof, wherein R 6 、R 7 and R 8 are each independently hydrogen, heteroalkyl, alkyl, alkenyl or alkynyl; R 9a 、R 9b 、R 10a and R 10b are each independently hydrogen, alkyl or halogen; x and y are each independently an integer between 1 and 20; z is an integer between 5 and 90;

[0400] And one or more of the following:

[0401] (ii) phospholipids;

[0402] (iii) steroids;

[0403] (iv) payload; and

[0404] (v) Additional lipid components.

[0405] 159. The particle of embodiment 158, wherein the particle is a liposome, a vesicle, or a lipid nanoparticle.

[0406] 160. The particle of embodiment 158, wherein the particle is a liposome.

[0407] 161. The particle of embodiment 158, wherein the particle is a vesicle.

[0408] 162. The particle of embodiment 158, wherein the particle is a lipid nanoparticle.

[0409] 163. A particle according to any one of embodiments 158-162, wherein the payload is selected from a protein, an enzyme, a peptide, a nucleic acid, a small molecule or a lipid.

[0410] 164. A particle according to any one of embodiments 158-162, wherein the payload is a protein.

[0411] 165. A particle according to any one of embodiments 158-162, wherein the payload is an enzyme.

[0412] 166. A particle according to any one of embodiments 158-162, wherein the payload is a peptide.

[0413] 167. The particle of any one of embodiments 158-162, wherein the payload is a nucleic acid.

[0414] 168. A particle according to any one of embodiments 158-162, wherein the payload is a small molecule.

[0415] 169. A particle according to any one of embodiments 158-162, wherein the payload is a lipid.

[0416] 170. The particle of any one of embodiments 158-162, wherein the payload is mRNA.

[0417] 171. A method of treating a disease, disorder, or condition in a subject, the method comprising administering to the subject particles comprising:

[0418] (i) A polymer having formula (Id):

[0419] or a pharmaceutically acceptable salt thereof, wherein R 6 、R 7 and R 8 are each independently hydrogen, heteroalkyl, alkyl, alkenyl or alkynyl; R 9a 、R 9b 、R 10a and R10b are each independently hydrogen, alkyl or halogen; x and y are each independently an integer between 1 and 20; z is an integer between 5 and 90;

[0420] And one or more of the following:

[0421] (ii) phospholipids;

[0422] (iii) steroids;

[0423] (iv) payload; and

[0424] (v) Additional lipid components.

[0425] 172. The particle of embodiment 171, wherein the particle is a liposome, a vesicle, or a lipid nanoparticle.

[0426] 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.

[0427] 174. The particle of any one of embodiments 171-172, wherein the payload is a protein.

[0428] 175. A particle according to any one of embodiments 171-172, wherein the payload is an enzyme.

[0429] 176. A particle according to any one of embodiments 171-172, wherein the payload is a peptide.

[0430] 177. A particle according to any one of embodiments 171-172, wherein the payload is a nucleic acid.

[0431] 178. A particle according to any one of embodiments 171-172, wherein the payload is a small molecule.

[0432] 179. A particle according to any one of embodiments 171-172, wherein the payload is a lipid.

[0433] Example

[0434] In order to enable the present disclosure to be more fully understood, the following examples are provided. The examples described in this application are intended to illustrate the particles, compositions and methods provided herein and should not be construed in any way as limiting the scope thereof.

[0435] Example 1. Synthesis of lipid nanoparticles containing polysarcosine lipid conjugates

[0436] Lipid nanoparticles were prepared by mixing an 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 lipids, polysarcosine lipid conjugates, phospholipids, and cholesterol dissolved in ethanol in the proportions shown in Table 1. The mixture was dialyzed and then concentrated using a centrifugal filter with a molecular weight cutoff of 30 kDa.

[0437] Table 1 Organic phase composition of lipid nanoparticle compositions

[0438]

[0439]

[0440]

[0441] Example 2. Lipid Nanoparticle Formulation Containing Polysarcosine-Lipid Conjugates

[0442] according to Figure 1 The flow chart shown in the figure is used to prepare lipid nanoparticle (LNP) formulations containing polysarcosine lipid conjugates and encapsulating exemplary cargo (RNA, approximately 2 kDa in size). mRNA expressing firefly luciferase (Fluc; approximately 2 kDa) was purchased from CATUG. SM-102, ALC-0315, and ALC-0159 were purchased from SINOPEG. DSPC, cholesterol, and DMG-PEG 2000 (DMG-PEG-2K) were all purchased from AVT Pharma. Oleyl-polyglycine (15) was purchased from Curapath. Oleyl-polyglycine (30) and oleyl-polyglycine (10) were produced by Calusa Bio.

[0443] The mixing instrument used was a NanoAssemblr Ignite from PrecisionNanoSystems. The volume of the aqueous RNA solution before mixing ranged from 4 to 11 mL, with a density of approximately 1 g / mL. The volume of lipid and polysarcosine lipid conjugate (ethanol to water ratio of 95:5) was 1 / 3 of the RNA solution (volume / volume). Dialysis (10K MWCO) was performed at 2-8°C with stirring overnight. Concentration was performed by centrifugation (30K MWCO) at 2000 to 4000 × g at 2-8°C. Filtration was performed using a 0.22 μm PES filter.

[0444] Particle diameter and polydispersity (PDI) were measured using a Wyatt Dynapro PlateReader III. Encapsulation efficiency (EE%) was measured using a fluorescence-based assay (RiboGreen, purchased from Thermo Fisher) on a SpectraMax iD5 microplate reader. mRNA content was quantified by high-performance liquid chromatography (HPLC).

[0445] pass Figure 1 The mixed product steps in the flow chart shown were used to prepare and evaluate lipid nanoparticle (LNP) formulations LNP-01 to LNP-04. The mole percentages of the ingredients and the analytical results are listed in Tables 2 and 3 below.

[0446] Table 2 Molar percentages of components constituting LNP formulations LNP-01 to LNP-04

[0447]

[0448] Table 3 Analytical results of LNP formulations LNP-01 to LNP-04 at the mixed product stage.

[0449] LNP# Particle diameter PDI EE% LNP-01 (control) 63.1nm 0.14 96.1％ LNP-02 (control) 79.9nm 0.19 95.6％ LNP-03 84.8nm 0.25 92.6％ LNP-04 135.5nm 0.15 77.5％

[0450] Lipid nanoparticle (LNP) formulations LNP-03 and LNP-05 to LNP-10 were prepared to evaluate the effect of polysarcosine chain length in polysarcosine-lipid conjugates and to investigate the effect of polysarcosine chain length in polysarcosine-lipid conjugates. Figure 1 The mixed product steps shown in the flow chart were evaluated. The mole percentages of the components and the analytical results are listed in Tables 4 and 5.

[0451] Table 4. Mole percentages of ingredients constituting LNP formulations LNP-03 and LNP-05 to LNP-10.

[0452] LNP# SM-102 DSPC cholesterol Oil-based-pSar10 Oil-based-pSar15 Oil-based-pSar30 LNP-05 50％ 10％ 38.5％ 1.5％ - - LNP-06 50％ 10％ 37.5％ 2.5％ - - LNP-03 50％ 10％ 38.5％ - 1.5％ - LNP-08 50％ 10％ 37.5％ - 2.5％ - LNP-09 50％ 10％ 38.5％ - - 1.5％ LNP-10 50％ 10％ 37.5％ - - 2.5％

[0453] Table 5 Analytical results of LNP formulations LNP-03 and LNP-05 to LNP-10 in the mixed product step.

[0454] LNP# Polysarcosine lipid conjugate Particle diameter PDI EE% LNP-05 Oil-based-pSar10 86.3nm 0.26 90.9％ LNP-06 Oil-based-pSar10 87.5nm 0.31 92.3％ LNP-03 Oil-based-pSar15 84.8nm 0.25 92.6％ LNP-08 Oil-based-pSar15 78.9nm 0.33 95.3％ LNP-09 Oil-based-pSar30 79.4nm 0.35 94.9％ LNP-10 Oil-based-pSar30 69.5nm 0.34 97.6％

[0455] Lipid nanoparticle (LNP) formulations LNP-11 to LNP-22 were prepared to evaluate the effects of, for example, dilution buffer and dilution factor and were Figure 1 The mixed product steps shown in the flow chart were evaluated. The dilution buffer was CBS / Tris (citrate buffered saline + 3% 1M Tris) or 50 mM Tris. The molar percentages of the components and the analytical results are listed in Tables 6 and 7.

[0456] Table 6. Mole percentages of ingredients making up the LNP formulations, dilution buffers, and dilution factors LNP-11 to LNP-22.

[0457]

[0458]

[0459] Table 7 Analytical results of LNP formulations LNP-11 to LNP-22 in the mixed product step.

[0460]

[0461] Select some LNP preparations LNP-11 to LNP-22, and Figure 1 The lipid nanoparticles were further processed and evaluated in the final product step of the flow chart shown. The analytical results of these preparations are listed in Table 8.

[0462] Table 8 Analytical results of LNP formulations LNP-11 to 13, LNP-15 to 19, and LNP-21 to 22 in the final product step.

[0463]

[0464] *Target mRNA content = mg / mL

[0465] Equivalents and scope

[0466] This application cites various issued 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 cited document and this specification, the present specification controls. Furthermore, any specific embodiment of this disclosure that is prior art may be expressly excluded from one or more claims.

[0467] Because such embodiments are deemed to be known to those of ordinary skill in the art, they may be excluded even if not explicitly described in this document. Any specific embodiment of the present disclosure, whether or not related to the existence of prior art, may be excluded from any claim for any reason. Those skilled in the art will recognize or be able to determine using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the foregoing description, drawings, or examples, but is defined as follows. Those of ordinary skill in the art will understand that various changes and modifications may be made to this description without departing from the spirit and scope of the present disclosure as defined in the following claims.

Claims

1. A particle comprising: (i) A polymer having formula (Id): or a pharmaceutically acceptable salt thereof, wherein R 6 、R 7 and R 8 are each independently hydrogen, heteroalkyl, alkyl, alkenyl or alkynyl; R 9a 、R 9b 、R 10a and R 10b are each independently hydrogen, alkyl or halogen; x and y are each independently an integer between 1 and 20; z is an integer between 5 and 90; And one or more of the following: (ii) phospholipids; (iii) steroids; (iv) payload; and (v) Additional lipid components.

2. The particle according to claim 1, comprising (ii). The particle according to claim 1 , comprising (iii).

4. The particle according to claim 1, comprising (iv). The particle according to claim 1 , comprising (v). The particles according to claim 1 , wherein R 6 、R 7 、R 8 、R 9a 、R 9b 、R 10a and R 10b are each independently hydrogen.

7. A particle according to any preceding claim, wherein z is 5-50.

8. The particle according to claim 1, wherein x is between 5 and 10 (eg, between 6 and 8).

9. The particle according to claim 1, wherein y is between 5 and 10 (eg, between 6 and 8).

10. The particle according to claim 1, wherein The molar percentage of the polymer represented by formula (Id) is about 1% to 60%.

11. The particle according to claim 1, wherein The molar percentage of the polymer represented by formula (Id) is about 1% to 20%.

12. The particle according to claim 1, wherein The mole percentage of the polymer represented by formula (Id) is about 1% to 15%.

13. The particle according to claim 1, wherein The particles are liposomes, lipid vesicles or lipid nanoparticles.

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

15. The particle according to claim 1, wherein The phospholipid is a compound represented by any one of formula (II) to formula (II-e) described herein.

16. The particle according to claim 1, wherein The steroid is a compound represented by any one of formula (III) to formula (III-b) as described herein.

17. The particle according to claim 1, wherein The steroid is cholesterol or a cholesterol derivative.

18. The particle according to claim 1, wherein The payload is selected from proteins, enzymes, peptides, nucleic acids, small molecules or lipids.

19. The particle according to claim 18, wherein The payload is a nucleic acid.

20. The particle according to claim 19, wherein The nucleic acid is an mRNA molecule.

21. The particle according to claim 1, wherein The additional lipid component is a cationic lipid.

22. The particle according to claim 1, wherein The additional lipid component is a compound represented by any one of formula (IV) to formula (IV-b) as described herein.

23. A lipid nanoparticle comprising: (i) A polymer having formula (Id): or a pharmaceutically acceptable salt thereof, wherein R 6 、R 7 and R 8 are each independently hydrogen, heteroalkyl, alkyl, alkenyl or alkynyl; R 9a 、R 9b 、R 10a and R 10b are each independently hydrogen, alkyl or halogen; x and y are each independently an integer between 1 and 20; z is an integer between 5 and 90; And one or more of the following: (ii) phospholipids; (iii) steroids; (iv) payload; and (v) Additional lipid components.

24. A lipid nanoparticle comprising: (i) A polymer having formula (Id): or a pharmaceutically acceptable salt thereof, wherein R 6 、R 7 and R 8 are each independently hydrogen, heteroalkyl, alkyl, alkenyl or alkynyl; R 9a 、R 9b 、R 10a and R 10b are each independently hydrogen, alkyl or halogen; x and y are each independently an integer between 1 and 20; z is an integer between 5 and 90; (ii) phospholipids; (iii) steroids; (iv) payload; and (v) Additional lipid components.

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

26. A lipid nanoparticle comprising: (i) A polymer having the following structure: or a pharmaceutically acceptable salt thereof, and one or more of the following: (ii) phospholipids; (iii) steroids; (iv) payload; and (v) Additional lipid components.

27. A lipid nanoparticle comprising: (i) A polymer having the following structure: or a pharmaceutically acceptable salt thereof; (ii) phospholipids; (iii) steroids; (iv) payload; and (v) Additional lipid components.

28. The particle according to claim 1, wherein The phospholipids include distearoylphosphatidylcholine (DSPC) or 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (DMG-PEG).

29. The particle according to claim 28, wherein The DMG-PEG includes DMG-PEG-2,000, DMG-PEG-3,000, DMG-PEG-3,350, DMG-PEG-4,000, DMG-PEG-5,000, DMG-PEG-10,000 or DMG-PEG-20,000.

30. The particle according to claim 1, wherein The particles include various phospholipids (eg, DSPC or DMG-PEG).

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

32. The particle according to claim 1, wherein The concentration of DMG-PEG (eg, DMG-PEG-2000) provided in the particles or lipid nanoparticle formulation is between 0.5-5%.

33. The particle according to claim 1, wherein The polymer represented by formula (Id) is selected from oleyl-pSar10, oleyl-pSar15 and oleyl-pSar30.

34. The particle according to claim 1, wherein The concentration of the polymer represented by formula (Id) is between 0.5-5%.

35. The particle according to claim 1, wherein The particle or lipid nanoparticle has a diameter between 50 nm and 1 mm (eg, 50 nm to 750 nm, 50 nm to 500 nm, 50 nm to 250 nm).

36. The particle according to claim 1, wherein The particle or lipid nanoparticle has a diameter between 50 nm and 200 nm (eg, 50 nm and 150 nm).

37. The particle according to claim 1, wherein The particles or lipid nanoparticles have a polydispersity between 0.05-0.5 (eg, 0.1-0.4, 0.1-0.3, 0.1-0.2).

38. A method of delivering a payload to a subject or cell, the method comprising administering to the subject or cell a particle comprising: (i) A polymer having formula (Id): or a pharmaceutically acceptable salt thereof, wherein R 6 、R 7 and R 8 are each independently hydrogen, heteroalkyl, alkyl, alkenyl or alkynyl; R 9a 、R 9b 、R 10a and R 10b are each independently hydrogen, alkyl or halogen; x and y are each independently an integer between 1 and 20; z is an integer between 5 and 90; And one or more of the following: (ii) phospholipids; (iii) steroids; (iv) payload; and (v) Additional lipid components.

39. The particle according to claim 38, wherein The particles are liposomes, lipid vesicles or lipid nanoparticles.

40. The particle according to any one of claims 38-39, wherein The payload is selected from proteins, enzymes, peptides, nucleic acids, small molecules or lipids.

41. A method of treating a disease, disorder, or condition in a subject, the method comprising administering to the subject a particle comprising: (i) A polymer having formula (Id): or a pharmaceutically acceptable salt thereof, wherein R 6 、R 7 and R 8 are each independently hydrogen, heteroalkyl, alkyl, alkenyl or alkynyl; R 9a 、R 9b 、R 10a and R 10b are each independently hydrogen, alkyl or halogen; x and y are each independently an integer between 1 and 20; z is an integer between 5 and 90; And one or more of the following: (ii) phospholipids; (iii) steroids; (iv) payload; and (v) Additional lipid components.

42. The particle according to claim 41, wherein The particles are liposomes, lipid vesicles or lipid nanoparticles.

43. The particle according to claim 1, wherein The payload is selected from proteins, enzymes, peptides, nucleic acids, small molecules or lipids.

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