Complexes for delivery of nucleic acids

Abstract

The present disclosure provides nucleic acid particles comprising an immunomodulator, RNA, and a cationic lipid or cationic polymer, wherein the nucleic acid particles described herein reduce inflammatory responses and / or increase protein or antigen expression associated with a previous formulation.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to PCT application number PCT / EP22 / 64542, filed on May 30, 2022, the entire contents of which are incorporated by reference. Background Art

[0003] Nucleic acid particles are complexes that can be used to deliver nucleic acid therapies to patients. Typically, nucleic acid particles comprise lipids (e.g., lipid nanoparticles (LNPs), liposomes, and lipid complexes) and / or cationic polymers (e.g., polyplexes) and nucleic acids, e.g., ribonucleic acids (RNAs). Summary of the Invention

[0004] When being administered to a patient, nucleic acid therapy faces specific challenges. In order to be effective, nucleic acid molecules need to reach the target tissue and produce a specific protein of interest. However, nucleic acids may be unstable, easily degraded after administration, and have limited ability to enter the target tissue alone. Therefore, it is necessary to encapsulate nucleic acid and conveniently deliver it to the nucleic acid particle delivery technology of the target of interest in the patient and the patient's body. In particular, nucleic acid particles comprising lipids (e.g., lipid nanoparticles (LNP), liposomes, and lipid complexes) and nucleic acid particles comprising polymers (e.g., polyplexes) have become vehicles that promote nucleic acid delivery to the target of interest.

[0005] The particle comprising cationic lipid and / or cationic polymer is a carefully constructed medium, which can rely on the interaction of different components to provide a safe way of passing through for nucleic acid goods. For example, lipid nanoparticles (LNP) include cationic lipids and specific auxiliary compounds of stable particles to ensure that LNP can release goods at the right time and position. Certain particles, such as particles comprising lipids, including LNP, are widely considered to be safe and effective for delivering nucleic acid therapy, and are indeed used in global commercial products, but can still cause an inflammatory response of the immune system after administration. For example, it has been noted that intradermal and intramuscular administration of LNP can cause "inflammation characterized by leukocyte infiltration, activation of different inflammatory pathways, and secretion of multiple inflammatory cytokines and chemokines". Ndeupen et al., iScience, 24, 103479 (Dec. 17, 2021). These reactions can be characterized as pain, swelling, fever, etc.

[0006] The present disclosure encompasses the insight that inclusion of specific agents as part of nucleic acid particles, such as lipid-based particles (e.g., LNPs, lipoplexes, and liposomes) and polymer-based particles (e.g., polyplexes), upon administration reduces the inflammatory response and, in addition, in some embodiments, can increase translation. Without wishing to be bound by theory, it is hypothesized that provided nucleic acid particles not only retain the stability for delivery of the nucleic acid to the target, but also further reduce the patient's inflammatory response, thereby avoiding specific side effects such as pain, fever, and the like. The nucleic acid particles described herein incorporate these agents into the structure of the particle itself. Furthermore, the nucleic acid particles described herein also surprisingly exhibit improved expression of a protein or antigen encoded by the nucleic acid delivered by the particle.

[0007] Other efforts to reduce the side effects have focused on modifying certain components of the nanoparticles, including, for example, modifying cationic lipids to incorporate certain steroid structural features. In contrast, the present disclosure incorporates immunomodulatory compounds (e.g., TLR inhibitors and / or inflammasome inhibitors) as discrete agents directly into the structure of the particles.

[0008] In addition, others have tried to use dexamethasone to reduce inflammation after administration of a formulation containing nucleic acid (e.g., RNA). See, for example, Chen et al., J. of Controlled Release, 286:46-54 (2018); Zhang et al., J. Biomed. Mater. Res. 2022; 1-8; I. Vlatkovic, Biomedicines, 9:520 (2021). Applicants have discovered an alternative agent to address the problem of inflammatory response after administration of nucleic acid particles.

[0009] In some embodiments, the present disclosure provides nucleic acid particles comprising RNA, an immunomodulatory agent, and a cationic lipid or cationic polymer. In some embodiments, the immunomodulatory agent is not dexamethasone.

[0010] In some embodiments, the nucleic acid particles include an immunomodulator, a cationic lipid, and RNA. In some embodiments, the nucleic acid particles are in the form of lipid nanoparticles. In some embodiments, the lipid nanoparticles further include one or more of a helper lipid and a polymer-conjugated lipid.

[0011] In some embodiments, the nucleic acid particle comprises an immunomodulatory agent, a cationic polymer, and RNA.

[0012] In some embodiments, the present disclosure provides a method of increasing or causing an increase in RNA expression in a target in a subject, the method comprising administering to the subject a nucleic acid particle as described herein.

[0013] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a subject, the method comprising administering to the subject a nucleic acid particle described herein.

[0014] In some embodiments, the present disclosure provides a nucleic acid particle as described herein for use as a medicament.

[0015] In some embodiments, the present disclosure provides a nucleic acid particle as described herein for use in treating and / or preventing a disease or disorder, wherein the disease or disorder is an infectious disease, cancer, a genetic disorder, an autoimmune disease, or a rare disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is shown for every 5x10 5 Heatmap of cytokine profile concentrations in human PBMCs (hPBMCs) from Formulations 1 to 16 described herein following transfection of 3 μg or 0.3 μg of formulated modRNA per viable cell.

[0017] Figure 2 Is displayed every 2.5x10 4 Heatmap of luciferase activity in hepatocytes after transfection of 0.1 μg of formulated modRNA per cell.

[0018] Figure 3 is a series of graphs providing cytokine profiles at various concentrations (0.01 to 3 μg / well) of Formulations 1 to 4 and the results of XTT assays for Formulations 1 to 4.

[0019] Figure 4 is a series of graphs showing luciferase activity (measured as RLU) on days 1, 2, and 7 for Formulations 1 to 4 provided.

[0020] Figure 5 is a series of graphs providing cytokine profiles at various concentrations (0.01 to 3 μg / well) of Formulations 5 to 8 and the results of XTT assays for Formulations 5 to 8.

[0021] Figure 6 is a series of graphs showing luciferase activity (measured as RLU) on days 1, 2, and 7 for Formulations 5 to 8 provided.

[0022] Figure 7 is a series of graphs providing cytokine profiles at various concentrations (0.01 to 3 μg / well) of Formulations 13 to 16 and XTT assay results for Formulations 13 to 16.

[0023] Figure 8 is a series of graphs showing luciferase activity (measured as RLU) on days 1, 2, and 7 for formulations 13 to 16 provided.

[0024] Figure 9 is a series of graphs providing cytokine profiles at various concentrations of Formulations 9 to 12 (0.01 to 3 μg / well) and XTT assay results for Formulations 9 to 12.

[0025] Figure 10 is a series of graphs providing cytokine profiles at various concentrations (0.01 to 3 μg / well) of Formulations 13 to 16 and XTT assay results for Formulations 17 to 20.

[0026] Figure 11 is a series of graphs showing luciferase activity (measured as RLU) on days 1, 3, and 7 for Formulations 17 to 20 provided. DETAILED DESCRIPTION

[0027] The present disclosure provides, inter alia, nucleic acid particles (e.g., cationic lipid-based particles (such as lipid nanoparticles (LNPs), liposomes, lipoplexes) and cationic polymer-based particles (such as polyplexes)) that can be used to deliver nucleic acids (e.g., RNA) and uses thereof. The present disclosure also provides, inter alia, complexes that avoid problems associated with previously known nucleic acid particles (including inflammatory reactions after administration or elevated levels of cytokines or interleukins that can cause pain, fever, and other adverse reactions). As described herein, the present disclosure provides a nucleic acid particle (and composition, e.g., a pharmaceutical composition comprising the nucleic acid particle) comprising RNA, an immunomodulator, and a cationic lipid or cationic polymer. In some embodiments, the nucleic acid particles described herein can be used to treat a variety of diseases. In some embodiments, such nucleic acid particles can be administered systemically, intravenously, or intranasally.

[0028] definition

[0029] Compounds of the present disclosure include those generally described above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, editors: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0030] Unless otherwise indicated, the structures depicted herein are intended to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are considered to be part of this disclosure. Thus, single stereochemical isomers of the provided compounds, as well as enantiomeric, diastereomeric, and geometric (or conformational) isomer mixtures are within the scope of this disclosure. Unless otherwise indicated, all tautomeric forms of the provided compounds are within the scope of this disclosure.

[0031] Unless otherwise stated, structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures having the disclosed structures including the replacement of hydrogen by deuterium or tritium or the replacement of carbon by 13 C or 14 Compounds containing C-enriched carbon substitutes) are within the scope of the present disclosure.

[0032] About or approximately: As used herein, when applied to one or more values ​​of interest, the term "about" or "approximately" refers to a value similar to the reference value. Generally speaking, those skilled in the art who are familiar with the context will understand the relevant degree of variation encompassed by "about" or "approximately" in this context. For example, in some embodiments, the term "about" or "approximately" may encompass a range of values ​​within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less (i.e., ±) of the cited value.

[0033] Administration: As used herein, the term "administering" or "administerion" generally refers to administering a composition (e.g., a pharmaceutical composition) to a subject to achieve delivery of an agent that is a composition or an agent contained in a composition to a target site or site to be treated. One of ordinary skill in the art will recognize a variety of routes that can be used for administration to a subject (e.g., a human) where appropriate. For example, in some embodiments, administration can be ocular, oral, parenteral, topical, and the like. In certain specific embodiments, administration can be bronchial administration (e.g., by bronchial instillation), buccal administration, dermal administration (which can be or include, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.), enteral administration, intraarterial administration, intradermal administration, intragastric administration, intramedullary administration, intramuscular administration, intranasal administration, intraperitoneal administration, intrathecal administration, intravenous administration, intraventricular administration, administration within a specific organ (e.g., intrahepatic administration), mucosal administration, nasal administration, oral administration, rectal administration, subcutaneous administration, sublingual administration, topical administration, tracheal administration (e.g., by intratracheal instillation), vaginal administration, vitreous administration, etc. In some embodiments, administration can be parenteral administration. In some embodiments, administration can be oral administration. In some specific embodiments, administration can be intravenous administration. In some specific embodiments, administration can be subcutaneous administration. In some embodiments, administration can only involve a single dose. In some embodiments, administration can involve the use of a fixed number of doses. In some embodiments, administration may involve administration that is intermittent (e.g., multiple doses separated in time) and / or periodic (e.g., separate doses separated by a common time period). In some embodiments, administration may involve continuous administration (e.g., perfusion) for at least one selected time period. In some embodiments, administration may include a prime and boost regimen. A prime and boost regimen may include administering a first dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine), followed by administering a second or subsequent dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine) after a certain time interval. In the case of an immunogenic composition, a prime and boost regimen may result in an increased immune response in the patient.

[0034] Agonist: As used herein, the term "agonist" generally refers to an agent whose presence or level is associated with an increase in the level or activity of a target compared to the observed absence of the agent (or to a different level of the agent). In some embodiments, an agonist is an agonist whose presence or level is associated with a target level or activity that is comparable to or greater than a particular reference level or activity (e.g., observed under appropriate reference conditions, such as in the presence of a known agonist, e.g., a positive control). In some embodiments, an agonist can be a direct agonist, in that it exerts its effect directly on the target (e.g., interacts directly with the target); in some embodiments, an agonist can be an indirect agonist, in that it exerts its effect indirectly (e.g., by acting on, such as with a modulator of the target or interacting with some other component or entity).

[0035] Aliphatic: The term "aliphatic" refers to a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "alicyclic") that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single or more than one point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-12 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms (e.g., C 1-6 In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C 1-5 In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C 1-4 In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C 1-3 ), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C 1-2 Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl groups and hybrids thereof. Preferred aliphatic groups are C 1-6 alkyl.

[0036] Alkyl: The term "alkyl," used alone or as part of a larger moiety, refers to a group having (unless otherwise indicated) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C 1-12 、C 1-10 、C 1-8 、C 1-6 、C 1-4 、C 1-3 or C 1-2) is a saturated, optionally substituted, straight or branched chain hydrocarbon group. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl.

[0037] Alkylene: The term "alkylene" refers to a divalent alkyl group. In some embodiments, an "alkylene" is a divalent straight or branched chain alkyl group. In some embodiments, an "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, such as 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are optionally replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups, and also include those described in the specification herein. It should be understood that the two substituents of the alkylene group can be taken together to form a ring system. In certain embodiments, the two substituents can be taken together to form a 3- to 7-membered ring. The substituents may be on the same or different atoms. The suffix "-ene" or "-enyl" when attached to certain groups herein is intended to refer to the difunctional portion of the group. For example, "-ene" or "-enyl" becomes "cyclopropylene" or "cyclopropylenyl" when attached to "cyclopropyl" and is intended to refer to a difunctional cyclopropyl group, such as

[0038]

[0039] Alkenyl: The term "alkenyl," used alone or as part of a larger moiety, refers to an alkenyl group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-12 、C 2-10 、C 2-8 、C 2-6 、C 2-4 or C 2-3 ) is an optionally substituted straight or branched chain or cyclic hydrocarbon group. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl and heptenyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having from about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl.

[0040] Alkynyl: The term "alkynyl," used alone or as part of a larger moiety, refers to a radical having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-12 、C 2-10 、C 2-8 、C 2-6 、C2-4 or C 2-3 ) is an optionally substituted straight or branched chain hydrocarbon group. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0041] Antagonist: As will be understood by those skilled in the art, the term "antagonist" generally refers to an agent whose presence or level is associated with a decrease in the level or activity of a target compared to that observed in the absence of the agent (or with a different level of the agent). In some embodiments, an antagonist is one whose presence or level is associated with a target level or activity that is comparable to or less than a particular reference level or activity (e.g., observed under appropriate reference conditions, such as in the presence of a known antagonist, e.g., a positive control). In some embodiments, an antagonist can be a direct antagonist, in that it exerts its effect directly on the target (e.g., directly interacts with the target); in some embodiments, an antagonist can be an indirect antagonist, in that it exerts its effect indirectly (e.g., by acting on, such as with a modulator of the target or interacting with some other component or entity).

[0042] Aryl: The term "aryl" refers to a group having a total of six to fourteen ring members (e.g., C6-C 14 ), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, "aryl" contains between six and twelve total ring members (e.g., C6-C 12 ). The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments, "aryl" refers to an aromatic ring system, which includes but is not limited to phenyl, biphenyl, naphthyl, anthracenyl, etc., which may bear one or more substituents. Unless otherwise specified, "aryl" is a hydrocarbon. In some embodiments, an "aryl" ring system is an aromatic ring (e.g., phenyl) fused to a non-aromatic ring (e.g., cycloalkyl). Examples of fused aryl rings include

[0043] Biological sample: As used herein, the term "biological sample" generally refers to a sample obtained from or derived from a biological source of interest (e.g., a tissue or organism or cell culture), as described herein. In some embodiments, the source of interest includes an organism, such as an animal or a human. In some embodiments, a biological sample is or includes a biological tissue or fluid. In some embodiments, a biological sample can be or include bone marrow; blood; blood cells; ascites; tissue or fine needle aspiration biopsy samples; body fluids containing cells; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph fluid; gynecological fluid; skin swab; vaginal swab; oral swab; nasal swab; washings or lavages, such as duct lavage or bronchoalveolar lavage; aspirates; scrapings; bone marrow samples; tissue biopsy samples; surgical samples; feces, other body fluids, secretions and / or excretions; and / or cells therefrom, etc. In some embodiments, a biological sample is or includes cells obtained from an individual. In some embodiments, the cell obtained is or includes the cell from the individuality of obtaining the sample. In some embodiments, sample is " original sample " obtained directly from the source of interest by any appropriate means. For example, in some embodiments, the original biological sample is obtained by the method selected from the group consisting of: biopsy (for example, fine needle aspiration or tissue biopsy), surgery, body fluid (for example, blood, lymph, feces, etc.) collection, etc. In some embodiments, it is clear from the context that the term " sample " refers to the preparation obtained by processing the original sample (for example, by removing one or more components of the original sample and / or adding one or more agents to the original sample). For example, using a semipermeable membrane filter. Such " processed sample " may include, for example, nucleic acid or protein extracted from the sample or nucleic acid or protein obtained by making the original sample undergo technology (such as amplification or reverse transcription of mRNA, separation and / or purification of some components, etc.).

[0044] Carrier: As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, a carrier may include sterile liquids such as, for example, water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. In some embodiments, a carrier is or includes one or more solid components.

[0045] Combination therapy: As used herein, the term "combination therapy" refers to those situations in which a subject is exposed to two or more treatment regimens (e.g., two or more therapeutic agents or modalities) simultaneously. In some embodiments, two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all "dosages" of the first regimen are administered prior to administering any doses of the second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may involve administering one or more agents or modalities to a subject who is receiving one or more other agents or modalities in the combination. For clarity, combination therapy does not require that the separate agents be administered together in a single composition (or even necessarily be administered simultaneously), but in some embodiments, two or more agents, or their active portions, may be administered together in a combination composition or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0046] Comparable: As used herein, the term "comparable" refers to two or more agents, entities, situations, sets of conditions, etc. that may not be identical to one another but are sufficiently similar to allow comparisons to be made therebetween such that one skilled in the art would understand that conclusions can reasonably be drawn based on the observed differences or similarities. In some embodiments, a collection of comparable conditions, situations, individuals, or populations is characterized by a plurality of substantially identical characteristics and one or a few different characteristics. One of ordinary skill in the art would understand what degree of identity is required between two or more such agents, entities, situations, sets of conditions, etc. in any given case in the context to be considered comparable. For example, one of ordinary skill in the art would understand that a collection of environments, individuals, or populations are comparable to one another when they are characterized by a sufficient number and type of substantially identical characteristics to warrant the reasonable conclusion that differences in the results or observed phenomena obtained under the different collections of environments, individuals, or populations are caused or indicated by variations in those different characteristics.

[0047] Composition: It will be understood by those skilled in the art that the term "composition" may be used to refer to a discrete physical entity comprising one or more specified components. Generally, unless otherwise specified, a composition can be in any form, for example, gas, gel, liquid, solid, etc.

[0048] Alicyclic: As used herein, the term "alicyclic" refers to a monocyclic C-cyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic and has a single or more than one point of attachment to the rest of the molecule. 3-8 Hydrocarbon or bicyclic C 6-10 hydrocarbon.

[0049] Cycloalkyl: As used herein, the term "cycloalkyl" refers to an optionally substituted saturated monocyclic or polycyclic ring system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0050] Dosage form or unit dosage form: It will be understood by those skilled in the art that the term "dosage form" can be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic agent or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, this amount is a unit dose amount (or a fraction thereof) suitable for administration according to a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., a therapeutic dosing regimen).

[0051] Dosing regimen or treatment regimen: It will be understood by those skilled in the art that the terms "dosing regimen" and "treatment regimen" can be used to refer to a group of unit doses (usually more than one) administered separately to a subject, usually separated by time periods. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, the dosing regimen includes multiple doses, each dose separated in time from the other doses. In some embodiments, each dose is separated from each other by a time period of the same length; in some embodiments, the dosing regimen includes multiple doses and at least two different time periods separating the individual doses. In some embodiments, all doses within a dosing regimen are the same unit dose amount. In some embodiments, different doses within a dosing regimen have different amounts. In some embodiments, the dosing regimen includes a first dose of a first dose amount, followed by one or more additional doses of a second dose amount that is different from the first dose amount. In some embodiments, the dosing regimen includes a first dose of a first dose amount, followed by one or more additional doses of a second dose amount that is the same as the first dose amount. In some embodiments, the dosing regimen is associated with a desired or beneficial outcome when administered to a relevant population (i.e., a therapeutic dosing regimen).

[0052] Excipients: As used herein, the term "excipient" refers to non-therapeutic agents that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilization effect. Examples of suitable pharmaceutical excipients include, for example, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, and the like.

[0053] Heteroaliphatic: As used herein, the term "heteroaliphatic" or "heteroaliphatic group" means an optionally substituted hydrocarbon moiety having one to five heteroatoms in addition to carbon atoms, which may be linear (i.e., unbranched), branched, or cyclic ("heterocyclic"), and may be fully saturated, or may contain one or more unsaturated but non-aromatic units. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of a basic nitrogen. The term "nitrogen" also includes substituted nitrogen. Unless otherwise specified, a heteroaliphatic group contains 1-10 carbon atoms, of which 1-3 carbon atoms are optionally and independently replaced by heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, a heteroaliphatic group contains 1-4 carbon atoms, of which 1-2 carbon atoms are optionally and independently replaced by heteroatoms selected from oxygen, nitrogen, and sulfur. In other embodiments, heteroaliphatic groups contain 1-3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced by a heteroatom selected from oxygen, nitrogen and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched heteroalkyl, heteroalkenyl and heteroalkynyl. For example, heteroaliphatic groups of 1 to 10 atoms include the following exemplary groups: -O-CH3, -CH2-O-CH3, -O-CH2-CH2-O-CH2-CH2-O-CH3, etc.

[0054] Heteroaryl: The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy") refer to monocyclic or bicyclic groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 pi electrons shared in the ring array; and having one to five heteroatoms other than carbon atoms. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrrolopyridinyl, pyrrolopyrazinyl, thienopyrimidinyl, triazolopyridinyl, and benzisoxazolyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., bicyclic heteroaryl rings having from 1 to 3 heteroatoms). Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, and benzisoxazolyl. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted.

[0055] Heteroatom: As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0056] Heterocycle: As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 3- to 8-membered monocyclic, 6- to 10-membered bicyclic or 10- to 16-membered polycyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more (such as one to four) heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used to refer to the ring atoms of a heterocycle includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl). The heterocycle may be attached to its side group at any heteroatom or carbon atom that produces a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, oxadiazolyl ... Oxazolin thiazolinone The heterocyclic group can be monocyclic, bicyclic, tricyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic, more preferably monocyclic or bicyclic. The bicyclic heterocycle also includes a group in which the heterocycle is fused to one or more aryl rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl and tetrahydroquinolinyl. The bicyclic heterocycle can also be a spirocyclic system (e.g., a 7 to 11-membered spirocyclic fused heterocycle having one or more heteroatoms (e.g., one, two, three or four heteroatoms) as defined above in addition to carbon atoms). The bicyclic heterocycle can also be a bridged ring system (e.g., a 7 to 11-membered bridged heterocycle having one, two or three bridging atoms).

[0057] Lipid: As used herein, the term "lipid" refers to a molecule comprising one or more hydrophobic moieties or groups and optionally further comprising one or more hydrophilic moieties or groups. Molecules comprising a hydrophobic moiety and a hydrophilic moiety are also often referred to as amphiphiles. Lipids are generally poorly soluble in water. In an aqueous environment, the amphiphilic nature enables the molecules to self-assemble into organized structures and different phases. One of these phases consists of a lipid bilayer, which is present in vesicles, multilamellar / unilamellar liposomes, or membranes in an aqueous environment. Hydrophobicity can be imparted by including non-polar groups, including but not limited to long-chain saturated and unsaturated aliphatic hydrocarbon groups and such groups substituted with one or more aromatic, alicyclic, or heterocyclic groups. In some embodiments, the hydrophilic group may include polar and / or charged groups, and include carbohydrates, phosphates, carboxylic acids, sulfates, amino groups, sulfhydryls, nitro groups, hydroxyl groups, and other similar groups.

[0058] Modulator: As used herein, the term "modulator" refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein). For example, in some embodiments, a modulator can cause an increase or decrease in the intensity of a certain activity of a class of molecules compared to the intensity of the activity in the absence of the modulator. For example, a modulator can be an agonist or antagonist of a particular target, as those terms are defined herein. For example, in some embodiments, a modulator is an agonist. In some embodiments, a modulator is an antagonist.

[0059] Oral: As used herein, the phrases "oral administration" and "administered orally" have their art-understood meanings and refer to administration of a compound or composition through the mouth.

[0060] Parenteral: As used herein, the phrases "parenteral administration" and "administered parenterally" have their art-understood meanings and refer to modes of administration other than enteral and topical administration, typically injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0061] Partially unsaturated: As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties as defined herein.

[0062] Patient or subject: As used herein, the term "patient" or "subject" refers to any organism to which a provided composition is administered or can be administered, e.g., for experimental, diagnostic, preventive, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. In some embodiments, the patient or subject suffers from or is susceptible to one or more conditions or disorders. In some embodiments, the patient or subject exhibits one or more symptoms of a condition or disorder. In some embodiments, the patient or subject has been diagnosed with one or more conditions or disorders. In some embodiments, the patient or subject is receiving or has received certain therapies to diagnose and / or treat the disease, condition, or disorder.

[0063] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dosage amount suitable for administration in a therapeutic or dosing regimen that, when administered to a relevant population, shows a statistically significant probability of achieving a predetermined therapeutic effect. In some embodiments, the pharmaceutical compositions can be specially formulated for administration in solid or liquid form, including pharmaceutical compositions suitable for oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those for buccal, sublingual, and systemic absorption), pills, powders, granules, pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, such as sterile solutions or suspensions, or sustained-release formulations; topical application, e.g., as a cream, ointment, or controlled-release patch or spray to the skin, lungs, or mouth; intravaginally or intrarectally, e.g., as a vaginal suppository, cream, or foam; sublingually; ophthalmically; transdermally; or via the nose, lungs, and other mucosal surfaces.

[0064] Pharmaceutically acceptable: As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0065] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of compounds suitable for use in a pharmaceutical context, i.e., salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).

[0066] Polypeptide: As used herein, the term "polypeptide" generally has its art-recognized meaning of a polymer of at least three amino acids or more. One of ordinary skill in the art will understand that the term "polypeptide" is intended to be general enough to encompass not only polypeptides having complete sequences as described herein, but also polypeptides that represent functional, biologically active, or characteristic fragments, portions, or domains of such complete polypeptides (e.g., fragments, portions, or domains that retain at least one activity). In some embodiments, a polypeptide may contain L-amino acids, D-amino acids, or both and / or may contain any of a variety of amino acid modifications or analogs known in the art. Available modifications include, for example, terminal acetylation, amidation, methylation, and the like. In some embodiments, a polypeptide may comprise natural amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof (e.g., may be or comprise a peptidomimetic).

[0067] Polymer: As used herein, the term "polymer" refers to a composition comprising one or more molecules comprising repeating units of one or more monomers. As used herein, "polymer" and "polymer composition" are used interchangeably and, unless otherwise indicated, refer to a composition of polymer molecules. It will be understood by those skilled in the art that a polymer composition comprises polymer molecules having molecules of different lengths (e.g., comprising different amounts of monomers). The polymer compositions described herein are characterized by number average molecular weight (M) n ), weight average molecular weight (M w) and / or polydispersity index (PDI) to characterize. The polymers described herein can also be characterized by degree of polymerization (DP), which refers to the number of monomer units in the polymer. The polymers described herein can be homopolymers, heteropolymers, or block copolymers. As used herein, "homopolymer" refers to a polymer having a single type of monomer repeated throughout the polymer chain, for example, -AAAA-. As used herein, "heteropolymer" refers to a polymer having more than one type (e.g., two or more types) of monomers present in the entire polymer chain, for example, -ABABA-. As used herein, "block copolymer" refers to a polymer having a block arrangement of polymerized monomers, for example, -AAAABBBB- (diblock polymer) or -AAAABBBBAAA- (triblock polymer). The polymers described herein can be linear or branched.

[0068] Prevent or prevention: As used herein, the terms "prevent" or "prevention," when used in connection with the occurrence of a disease, condition, and / or disorder, refer to reducing the risk of developing a disease, condition, and / or disorder and / or delaying the onset of one or more features or symptoms of a disease, condition, or disorder. Prevention is considered complete when the onset of a disease, condition, or disorder has been delayed for a predetermined period of time.

[0069] Ribonucleotide: As used herein, the term "ribonucleotide" encompasses unmodified ribonucleotides and modified ribonucleotides. For example, unmodified ribonucleotides include the purine bases adenine (A) and guanine (G) and the pyrimidine bases cytosine (C) and uracil (U). Modified ribonucleotides may comprise one or more modifications, including but not limited to, for example (a) terminal modifications, such as 5' terminal modifications (e.g., phosphorylation, dephosphorylation, conjugation, reverse linkage, etc.), 3' terminal modifications (e.g., conjugation, reverse linkage, etc.), (b) base modifications, such as replacement with modified bases, stabilized bases, destabilized bases, or bases that pair with an expanded repertoire of partners or conjugated bases, (c) sugar modifications (e.g., at the 2' position or the 4' position) or replacement of sugars, and (d) internucleoside linkage modifications, including modification or replacement of phosphodiester linkages. The term "ribonucleotide" also encompasses ribonucleotide triphosphates, including modified and unmodified ribonucleotide triphosphates.

[0070] Ribonucleic acid (RNA): As used herein, the term "RNA" refers to a polymer of ribonucleotides. In some embodiments, RNA is single-stranded. In some embodiments, RNA is double-stranded. In some embodiments, RNA comprises both single-stranded and double-stranded portions. In some embodiments, RNA may comprise a backbone structure as described above in the definition of "nucleic acid / polynucleotide". RNA may be regulatory RNA (e.g., siRNA, microRNA, etc.) or messenger RNA (mRNA). In some embodiments, wherein the RNA is mRNA. In some embodiments wherein the RNA is mRNA, the RNA typically comprises a poly(A) region at its 3' end. In some embodiments wherein the RNA is mRNA, the RNA typically comprises an art-recognized cap structure at its 5' end, for example, for recognizing mRNA and attaching it to the ribosome to initiate translation. In some embodiments, the RNA is synthetic RNA. Synthetic RNA includes RNA synthesized in vitro (e.g., by enzymatic synthesis and / or by chemical synthesis). As used herein, "monomeric RNA," also referred to as "single-molecule RNA," refers to a single RNA molecule that is not an aggregate, dimer, trimer, or oligomer of RNA.

[0071] Sample: As used herein, the term "sample" generally refers to an aliquot of a material obtained from or derived from a source of interest. In some embodiments, the source of interest is a biological or environmental source. In some embodiments, the source of interest can be or include cells, tissues, or organisms, such as microorganisms, plants, or animals (e.g., humans). In some embodiments, the source of interest is or includes biological tissue or fluid. In some embodiments, the source of interest can be or include a preparation generated in a production run. In some embodiments, a sample is a "raw sample" obtained directly from a source of interest by any appropriate means. In some embodiments, it will be clear from the context that the term "sample" refers to a preparation obtained by processing the raw sample (e.g., by removing one or more components of the raw sample and / or by adding one or more agents to the raw sample).

[0072] Substituted or optionally substituted: As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogen atoms of the designated moiety are replaced with a suitable substituent. "Substituted" applies to structures where one or more hydrogen atoms are replaced, either explicitly or implicitly (e.g., At least and At least ). Unless otherwise stated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituent at each position may be the same or different. The substituent combinations contemplated by the present invention are preferably those that form stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow the compound to be produced, detected, and in certain embodiments, recovered, purified, and used for one or more purposes provided herein. The group described as "substituted" preferably has between 1 and 4 substituents, more preferably 1 or 2 substituents. The group described as "optionally substituted" may be unsubstituted or "substituted" as described above.

[0073] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ;-O(CH2) 0-4 R o 、-O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2;-(CH2) 0- 4SR o ; -(CH2) 0-4 Ph, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be R o Substitution; -CH=CHPh, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be R o Substitution; -NO2; -CN; -N3; ​​(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2; N(R o )C(S)NR o 2; -(CH2) 0-4 N(Ro )C(O)OR o ;-N(R o )N(R o )C(O)R o ;N(R o )N(R o )C(O)NR o 2;N(R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;(CH2) 0-4 C(O)OSiR o 3;-(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0- 4SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o 、(CH2) 0-4 OC(O)NR o 2;C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;(CH2) 0-4 S(O)R o ;N(R o )S(O)2NRo 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)NR o 2;-P(O)2R o ;P(O)R o 2;OP(O)R o 2;-OP(O)(OR o )2;SiR o 3;-(C 1-4 linear or branched alkylene)ON(R o )2; or -(C 1-4 linear or branched alkylene) C(O)ON(R o )2, where each R o may be substituted as defined below and are independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5- to 6-membered heteroaryl ring) or a 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of R o Together with its middle atoms, it forms a 3- to 12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0074] R o (or through two independent occurrences of R o Suitable monovalent substituents on the ring formed together with its middle atoms are independently halogen, -(CH2) 0-2 R · 、-(halogenated R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · 、-(CH2) 0-2 CH(OR · )2、O(halogenated R · )、-CN、-N3、-(CH2) 0-2 C(O)R · 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · 、-(CH2) 0-2 SR · 、-(CH2) 0-2 SH, -(CH2) 0-2NH2, -(CH2) 0-2 NHR · 、-(CH2) 0-2 NR · 2. -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · 、-(C 1-4 linear or branched alkylene)C(O)OR · or -SSR · , where each R · is unsubstituted or, in the case of "halo" being preceded by "halo", is substituted only by one or more halogens, and is independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0075] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0 ("oxo"), =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6 An aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bonded to an ortho-substitutable carbon of an "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6 an aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0076] R * Suitable substituents on the aliphatic group include halogen, -R · 、(halogenated R ·), OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · is unsubstituted or, when preceded by "halo", is substituted only with one or more halogens, and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0077] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or Each of these are independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of Together with its middle atoms, it forms an unsubstituted 3- to 12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0078] Suitable substituents on the aliphatic group are independently halogen, -R · 、(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or NO2, where each R · is unsubstituted or, when preceded by "halo", is substituted only with one or more halogens, and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0079] Small molecule: As used herein, the term "small molecule" means an organic and / or inorganic compound of low molecular weight. Generally speaking, a "small molecule" is a molecule having a size of less than about 5 kilodaltons (kD). In some embodiments, a small molecule is less than about 4kD, 3kD, about 2kD, or about 1kD. In some embodiments, a small molecule is less than about 800 daltons (D), about 600D, about 500D, about 400D, about 300D, about 200D, or about 100D. In some embodiments, a small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, a small molecule is not a polymer.

[0080] In some embodiments, the small molecule does not comprise a polymeric portion. In some embodiments, the small molecule is not and / or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, the small molecule is not and / or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, the small molecule is not and / or does not comprise a polysaccharide; for example, in some embodiments, the small molecule is not a glycoprotein, a proteoglycan, a glycolipid, etc. In some embodiments, the small molecule is not a lipid.

[0081] In some embodiments, small molecules are modulators (e.g., inhibitors or activators). In some embodiments, small molecules have biological activity. In some embodiments, small molecules are detectable (e.g., comprise at least one detectable moiety). In some embodiments, small molecules are therapeutic agents.

[0082] A person of ordinary skill in the art will understand, after reading this disclosure, that certain small molecule compounds described herein may be provided and / or utilized in a variety of forms, such as, for example, crystalline forms (e.g., polymorphs, solvates, etc.), salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0083] It will be understood by those skilled in the art that certain small molecule compounds have structures that can exist in one or more stereoisomeric forms. In some embodiments, such small molecules can be used in accordance with the present disclosure as individual enantiomers, diastereomers, or geometric isomers, or as mixtures of stereoisomers; in some embodiments, such small molecules can be used in accordance with the present disclosure as racemic mixtures.

[0084] It will be appreciated by those skilled in the art that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such small molecules can be used in accordance with the present disclosure in the form of individual tautomers, or in a form that can be interconverted between tautomeric forms.

[0085] It will be understood by those skilled in the art that certain small molecule compounds have structures that allow isotopic substitution (e.g., 2 H or 3 H replaces H; 11 C. 13 C or 14 C substitution 12 C; 13 N or 15 N substitution 14 N; 17 O or 18 O substitution 16 O; 36 Cl substitution 35 Cl or 37 Cl; 18 F substitution 19 F; 131 I replace 127 I; etc.). In some embodiments, such small molecules may be used according to the present disclosure in one or more isotopically modified forms, or mixtures thereof.

[0086] In some embodiments, reference to a particular small molecule compound may refer to a particular form of that compound. In some embodiments, a particular small molecule compound may be provided and / or utilized in salt form (e.g., in the form of an acid addition salt or a base addition salt, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0087] In some embodiments, when the small molecule compound is a compound that exists or is found in nature, the compound may be provided and / or used in accordance with the present disclosure in a form that is different from the form in which it exists or is found in nature. One of ordinary skill in the art will understand that in some embodiments, a formulation of a particular small molecule compound containing an absolute or relative amount of the compound or a particular form thereof is different from the compound as present in a reference formulation or source, the absolute or relative amount being different from the absolute or relative amount of the compound or form present in a reference formulation of interest (e.g., an original sample from a source of interest such as a biological or environmental source) (relative to another component of the formulation, including, for example, another form of the compound). Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound can be considered a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound can be considered a different form than another salt form of the compound; a preparation containing only one form of the compound containing a double bond conformer ((Z) or (E)) can be considered a different form of the compound than a preparation containing another double bond conformer ((E) or (Z)); a preparation in which one or more atoms is an isotope different from the isotope present in a reference preparation can be considered a different form; and so on.

[0088] It will also be understood by those skilled in the art that in small molecule structures, as used herein, the symbol refers to the point of connection between two atoms. Additionally or alternatively, the symbol Refers to the points where rings are connected in a spirocyclic manner.

[0089] Therapeutic agent: As used herein, the phrase "therapeutic agent" generally refers to any agent that causes a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered a therapeutic agent if it shows a statistically significant effect in an appropriate population. In some embodiments, the appropriate population can be a model organism population. In some embodiments, the appropriate population can be defined by various criteria, such as a certain age group, gender, genetic background, pre-existing clinical conditions, etc. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, improve, reduce, inhibit, prevent a disease, condition, and / or illness, delay its onset, reduce its severity, and / or reduce the incidence of one or more symptoms or characteristics thereof. In some embodiments, a "therapeutic agent" is an agent that has or requires approval from a government agency before it can be marketed for administration to humans. In some embodiments, a "therapeutic agent" is an agent that requires a doctor's prescription before it can be administered to humans.

[0090] Treatment: As used herein, the terms "treat," "treatment," or "treating" refer to any method for partially or completely alleviating, ameliorating, alleviating, inhibiting, preventing, delaying the onset of one or more symptoms or features of, reducing the severity of, and / or reducing the incidence of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of the disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example, for the purpose of reducing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0091] Complexes for nucleic acid delivery

[0092] The present disclosure provides nucleic acid particles (including compositions comprising the nucleic acid particles), wherein the nucleic acid particles comprise a nucleic acid (e.g., RNA), an immunomodulator, and a cationic lipid or cationic polymer. The present disclosure particularly encompasses the surprising insight that specific agents (such as immunomodulators) can be added to the nucleic acid particles described herein and result in a reduction in the inflammatory response previously seen with the particles. In addition, the nucleic acid particles described herein also surprisingly exhibit improved expression of a protein or antigen encoded by the nucleic acid delivered by the particles.

[0093] "Nucleic acid particles" (e.g., ribonucleic acid particles) refer to particles that encompass or contain nucleic acids and are used as part of a composition (e.g., a pharmaceutical composition) comprising a plurality of nucleic acid particles to deliver nucleic acids to a target site of interest (e.g., a cell, tissue, organ, etc.). As described herein, nucleic acid particles (e.g., ribonucleic acid particles) can be formed from i) at least one cationic or cationic ionizable lipid or lipid-like material, ii) at least one cationic polymer (such as polyethyleneimine, protamine), or a mixture thereof (i.e., a mixture of i) and ii) and iii) nucleic acid. Nucleic acid particles (e.g., ribonucleic acid particles) include lipid nanoparticles (LNPs), lipoplexes, liposomes, and polyplexes. In some embodiments, the nucleic acid particles described herein do not comprise oligosaccharides.

[0094] In some embodiments, the particle for nucleic acid delivery as described herein is a lipid nanoparticle comprising i) a nucleic acid, (ii) at least one cationic or cationically ionizable lipid, and (iii) an immunomodulator. In some embodiments, the particle for nucleic acid delivery comprises (i) a nucleic acid (such as DNA or RNA, e.g., mRNA); (ii) at least one cationic or cationically ionizable lipid as disclosed herein; (iii) an immunomodulator, and (iv) at least one additional lipid as described herein (e.g., a steroid, a helper lipid (also known as a "neutral lipid"), a polymer-conjugated lipid, or a combination thereof).

[0095] Electrostatic interactions between positively charged molecules (such as cationic polymers and cationic lipids) and negatively charged nucleic acids contribute to particle formation. This results in complexation and spontaneous formation of nucleic acid particles.

[0096] Without being bound by any theory, it is believed that cationic or cationic ionizable lipids or lipid-like materials and / or cationic polymers are combined with nucleic acids to form aggregates, and this aggregation produces colloidally stable particles. In some embodiments, the particles comprise amphiphilic lipids, particularly cationic or cationic ionizable amphiphilic lipids, and nucleic acids as described herein (such as DNA or RNA, e.g., mRNA). In some embodiments, the particles comprise or consist of: cationic / cationic ionizable lipids (e.g., cationic ionizable lipids of the formula described herein); and at least one additional lipid, such as a neutral lipid (such as a phospholipid), an immunomodulator, a polymer-conjugated lipid, an optional steroid (such as cholesterol), and combinations thereof. In some embodiments, the particles comprise a cationic polymer and a nucleic acid.

[0097] In some embodiments, a nucleic acid particle (e.g., a ribonucleotide particle) comprises more than one type of nucleic acid molecule, wherein the molecular parameters of the nucleic acid molecules may be similar or different from each other, such as with respect to molar mass or basic structural elements, such as molecular structure, capping, coding region, or other characteristics.

[0098] In some embodiments, nucleic acid particles as described herein are nanoparticles. As used in the present disclosure, " nanoparticles " refer to particles with an average diameter applicable to parenteral administration and are less than 1000nm in diameter. In some embodiments, the compositions comprising nanoparticles can have an average nanoparticle size (for example, average diameter) of about 30nm to about 150nm, about 40nm to about 150nm, about 50nm to about 150nm, about 60nm to about 130nm, about 70nm to about 110nm, about 70nm to about 100nm, about 70nm to about 90nm or about 70nm to about 80nm. In some embodiments, the compositions comprising nanoparticles can have an average nanoparticle size (for example, average diameter) of about 50nm to about 100nm. In some embodiments, the compositions comprising nanoparticles can have an average nanoparticle size (for example, average diameter) of about 50nm to about 150nm. In some embodiments, the compositions comprising nanoparticles can have an average nanoparticle size (for example, average diameter) of about 60nm to about 120nm. In some embodiments, a composition comprising nanoparticles may have an average nanoparticle size (e.g., average diameter) of 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, or 150 nm.

[0099] Compositions comprising nucleic acid particles (e.g., ribonucleic acid particles) as described herein can exhibit a polydispersity index of less than about 0.5, less than about 0.4, less than about 0.3, or about 0.2 or less of the nanoparticles. For example, compositions comprising nucleic acid particles (e.g., ribonucleic acid particles) as described herein can exhibit a polydispersity index in the range of about 0.1 to about 0.3 or about 0.2 to about 0.3.

[0100] The nucleic acid particles described herein (e.g., ribonucleic acid particles) can be characterized by an "N / P ratio," which is the molar ratio of cationic (nitrogen) groups in the cationic polymer (the "N" in N / P) to anionic (phosphate) groups in the RNA (the "P" in N / P). It is understood that the cationic groups are in the form of cations (e.g., N +) groups or groups that can be ionized into cations. The use of a single number in the N / P ratio (e.g., an N / P ratio of about 5) is intended to mean that this number exceeds 1, for example, an N / P ratio of about 4 is intended to mean about 4:1. In some embodiments, the nucleic acid particles described herein (e.g., ribonucleic acid particles) have an N / P ratio greater than or equal to 4. In some embodiments, the nucleic acid particles described herein (e.g., ribonucleic acid particles) have an N / P ratio of about 4 to about 12. In some embodiments, the nucleic acid particles described herein (e.g., ribonucleic acid particles) have an N / P ratio of about 4, 5, 6, 7, 8, 9, 10, 11 or 12. In some embodiments, the nucleic acid particles described herein (e.g., ribonucleic acid particles) have an N / P ratio of about 6.

[0101] The nucleic acid particles (e.g., ribonucleic acid particles) described herein can be prepared using a variety of methods, which can involve obtaining a colloid from at least one cationic or cationic ionizable lipid or lipid-like material and / or at least one cationic polymer, and mixing the colloid with the nucleic acid to obtain the nucleic acid particles. As used herein, an "ionizable" lipid, such as a "cationically ionizable" lipid or an "ionizable" polymer, such as a "cationically ionizable" polymer, is a lipid or polymer that, in some embodiments, can be neutral at physiological pH but can become cationic (i.e., become positively charged) at neutral pH.

[0102] The term "average diameter" or "mean diameter" refers to the average hydrodynamic diameter of the particles measured by dynamic laser light scattering (DLS), using the so-called cumulant algorithm for data analysis, which provides the so-called Z-average with a length dimension and the dimensionless polydispersity index (PDI) as a result (Koppel, D., J. Chem. Phys. 57, 1972, pp. 4814-4820, ISO 13321). Here, the "average diameter", "mean diameter", "diameter" or "size" of the particles are used synonymously with the value of the Z-average.

[0103] "Polydispersity index" is preferably calculated based on dynamic light scattering measurements by so-called cumulative analysis, as mentioned in the definition of "average diameter". Under certain prerequisites, it can be used as a measure of the size distribution of ribonucleic acid nanoparticles (e.g., ribonucleic acid nanoparticles) as a whole.

[0104] Different types of nucleic acid particles suitable for delivering nucleic acids in particulate form have been previously described (e.g., Kaczmarek, JC et al., 2017, Genome Medicine 9, 60). For non-viral nucleic acid delivery vehicles, nanoparticle encapsulation of nucleic acids physically protects the nucleic acids from degradation and, depending on their specific chemical properties, can aid in cellular uptake and endosomal escape.

[0105] The present disclosure describes particles comprising nucleic acids, at least one cation or cation ionizable lipid or lipid-like material and / or at least one cationic polymer, the cationic polymer associated with the nucleic acid to form nucleic acid particles (e.g., ribonucleic acid particles, e.g., ribonucleic acid nanoparticles) and compositions comprising such particles. Nucleic acid particles (e.g., ribonucleic acid particles, e.g., ribonucleic acid nanoparticles) can comprise nucleic acids complexed with the particles in different forms by non-covalent interactions. In some embodiments, the particles described herein are not viral particles, in particular, they are not infectious viral particles, i.e., they cannot virally infect cells.

[0106] Some embodiments described herein relate to compositions, methods, and uses involving more than one (eg, 2, 3, 4, 5, 6, or even more) nucleic acid species.

[0107] In nucleic acid particles (e.g., ribonucleic acid particles, e.g., ribonucleic acid nanoparticles) compositions, it is possible that each nucleic acid species is formulated as an independent nucleic acid particle (e.g., ribonucleic acid particles, e.g., ribonucleic acid nanoparticles) preparation. In this case, each independent nucleic acid particle (e.g., ribonucleic acid particles, e.g., ribonucleic acid nanoparticles) preparation will comprise a nucleic acid species. Independent nucleic acid particles (e.g., ribonucleic acid particles, e.g., ribonucleic acid nanoparticles) preparations can exist as independent entities, e.g., in independent containers. Such preparations can be obtained by providing each nucleic acid species (usually each in the form of a solution containing nucleic acid) and a particle forming agent, thereby allowing particle formation to occur. The corresponding particles will only contain the specific nucleic acid species (independent particle preparation) provided when the particles are formed.

[0108] In some embodiments, a composition (such as a pharmaceutical composition) comprises more than one separate nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) preparation. The corresponding pharmaceutical composition is referred to as a "mixed particle preparation". The mixed particle preparation according to the present invention can be obtained by separately forming the separate nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) preparations as described above, and then mixing the separate nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) preparations. By the mixing step, a preparation comprising a mixed population of particles containing nucleic acids can be obtained. The separate nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) populations can be together in a container, which includes a mixed population of separate nucleic acid particle (e.g., ribonucleic acid particle, e.g., ribonucleic acid nanoparticle) preparations.

[0109] Alternatively, it is possible to formulate different nucleic acid species together as a "combination particle formulation". Such a formulation can be obtained by providing a combination formulation (typically a combination solution) of the different nucleic acid species together with a particle-forming agent, thereby allowing particle formation. In contrast to a "mixed particle formulation", a "combination particle formulation" will typically contain particles comprising more than one nucleic acid species. In a combination particle composition, the different nucleic acid species are typically present together in a single particle.

[0110] In certain embodiments, the nucleic acid is resistant to nuclease degradation in aqueous solution when present in a provided nucleic acid particle (e.g., a ribonucleic acid particle, e.g., a lipid nanoparticle, a liposome, a lipoplex, a polyplex).

[0111] lipid nanoparticles

[0112] In some embodiments, the nucleic acid particles (e.g., ribonucleic acid particles) are lipid nanoparticles. In some embodiments, the lipid nanoparticles are cationic lipid nanoparticles comprising one or more cationic lipids (e.g., cationic lipids as described herein), nucleic acids (e.g., RNA) and immunomodulators. In some embodiments, the cationic lipid nanoparticles may comprise at least one cationic lipid, an immunomodulator, at least one polymer-conjugated lipid and at least one auxiliary lipid. Lipid nanoparticles (LNPs) have been shown to be useful for delivering nucleic acid cargo to tissues of interest. For example, LNPs are used in certain commercial vaccines for the treatment of COVID-19. However, some LNP preparations cause inflammatory responses in vivo, such as increases in cytokines and interleukins. This inflammatory response is associated with pain, swelling, fever, etc. However, the LNPs disclosed herein are not plagued by the same defects associated with previous preparations.

[0113] The LNPs of the present disclosure comprise i) cationic lipids; ii) helper lipids; iii) polymer-conjugated lipids (e.g., polyethylene glycol-conjugated lipids "PEG lipids"); and iv) immunomodulators. In some embodiments, the LNPs described herein may also comprise additional additives, as described herein. The LNPs of the present disclosure may be used in a variety of situations. For example, LNPs comprising nucleic acids (e.g., RNA) as described herein may be used to deliver the nucleic acids to cells of a subject. In some embodiments, LNPs comprising nucleic acids (e.g., RNA) as described herein may be used to cause increased protein expression in a subject. In some embodiments, LNPs comprising nucleic acids (e.g., RNA) as described herein may be used to cause pharmacological effects induced by protein expression in a subject. The lipid nanoparticles described herein are characterized by the molar percentage (mol%) of the components in the lipid nanoparticles. The mol% used when referring to the lipid components of the lipid nanoparticles is relative to the total other lipid components in the lipid nanoparticles.

[0114] Cationic lipids

[0115] As described herein, LNP of the present disclosure comprises cationic lipids.As described herein, cationic lipids are positively charged or ionizable lipids, such that the cationic lipids will become positively charged when experiencing specific physiological conditions (e.g., about 7.4 or lower pH), and lipid aggregation can be promoted. In some embodiments, the cationic lipids are lipids comprising one or more amine groups that carry or can carry (i.e., ionizable) positive charges.

[0116] In some embodiments, the cationic lipid is selected from 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (DMEPC); 2-dimyristoyl-3-trimethylammonium propane (DMTAP); dioleoyl ether phosphatidylcholine (DOEPC); N,N-dioleoyl-N,N-dimethylammonium chloride (DODAC); N-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA); N,N-distearyl-N,N-dimethylammonium bromide (DDAB); N-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTA P); 3-(N-(N',N'-dimethylaminoethane)-carbamoyl)cholesterol (DC-Chol), N-(1-(2,3-dioleoyloxy)propyl)N-2-(sperminecarboxamido)ethyl)-N,N-dimethylammonium trifluoroacetate (DOSPA), dioctadecylamidoglycylcarboxyspermine (DOGS), 1,2-dioleoyl-3-dimethylammoniumpropane (DODAP), N,N-dimethyl-2,3-dioleoyloxy)propylamine (DODMA), and N-(1,2-dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE).

[0117] In some embodiments, the cationic lipid is a cationic lipid provided in WO2012 / 016184, which is incorporated herein by reference in its entirety. For example, in some embodiments, the cationic lipid is selected from 1,2-dilinoleoyloxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2-dilinoleoyloxy-3-morpholinopropane (DLin-MA), 1,2-dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2-dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), 1-linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), 1,2-dilinoleyloxy-3-trimethylaminopropane chloride (DLin-TMA.Cl). , 1,2-dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.Cl), 1,2-dilinoleyloxy-3-(N-methylpiperazin-o)propane (DLin-MPZ), 3-(N,N-dilinoleylamino)-1,2-propanediol (DLinAP), 3-(N,N-dioleylamino)-1,2-propanediol (DOAP), 1,2-dilinoleyloxy-3-(2-N,N-dimethylamino)ethoxypropane (DLin-EG-DMA) and 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA).

[0118] In some embodiments, the cationic lipid is selected from N,N-dimethyl-2,3-dioleoyloxypropylamine (DODMA), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), 3-(N-(N',N'-dimethylaminoethane)-carbamoyl) cholesterol (DC-Chol), dimethyldioctadecyl ammonium (DDAB); 1,2-dioleoyl-3-trimethylammonium propane (DOTAP); 1,2-dioleoyl-3-dimethylammonium-propane (DODAP); 1,2-diacyloxy-3-dimethylammonium propane; 1,2-dialkoxy-3-dimethylammonium propane; dioctadecyldimethylammonium chloride (DODAC), 1,2-distearoyloxy- N,N-dimethyl-3-aminopropane (DSDMA), 2,3-di-tetradecyloxypropyl-(2-hydroxyethyl)-dimethylammonium (DMRIE), 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (DMEPC), l,2-dimyristoyl-3-trimethylammonium propane (DMTAP), 1,2-dioleyloxypropyl-3-dimethyl-hydroxyethylammonium bromide (DORIE) and 2,3-dioleoyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanium trifluoroacetate (DOSPA), 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinolenyloxy-N,N- dimethylaminopropane (DLenDMA), dioctadecylamidoglycyl spermine (DOGS), 3-dimethylamino-2-(cholesterol-5-ene-3-β-oxybutane-4-oxy)-1-(cis,cis-9,12-octadecadienyloxy)propane (CLinDMA), 2-[5'-(cholesterol-5-ene-3-β-oxy)-3'-oxapentyloxy)-3-dimethyl-1-(cis,cis-9',12'-octadecadienyloxy)propane (CpLinDMA), N,N-dimethyl-3,4-dioleyloxybenzylamine (DMOBA), 1,2-N,N'-dioleylcarbamoyl-3-dimethylaminopropane (DOcarbDAP), 2,3-diaminodiphenylamine (DMAP), Oleyloxy-N,N-dimethylpropylamine (DLinDAP), 1,2-N,N'-dilinoleylcarbamoyl-3-dimethylaminopropane (DLincarbDAP), 1,2-dilinoleylcarbamoyl-3-dimethylaminopropane (DLinCDAP), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA), 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-K-XTC2-DMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA), heptahexaenoic acid-6,9,28,31-Tetraen-19-yl-4-(dimethylamino)butyrate (DLin-MC3-DMA), N-(2-hydroxyethyl)-N,N-dimethyl-2,3-bis(tetradecyloxy)-1-propylammonium bromide (DMRIE), (±)-N-(3-aminopropyl)-N,N-dimethyl-2,3-bis(cis-9-tetradecenyloxy)-1-propylammonium bromide (GAP-DMORIE), (±)-N-(3-aminopropyl)-N,N-dimethyl-2,3-bis(dodecyloxy)-1-propylammonium bromide (GAP-DLRIE), (±)-N-(3-aminopropyl)-N,N-dimethyl-2,3-bis(tetradecyloxy)-1-propylammonium bromide (GAP-D MRIE), N-(2-aminoethyl)-N,N-dimethyl-2,3-bis(tetradecyloxy)-1-propylammonium bromide (βAE-DMRIE), N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propane-1-amine (DOBAQ), 2-({8-[(3β)-cholesterol-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-octadec-9,12-dien-1-yloxy]propane-1-amine (octyl-CLinDMA), 1,2-dimyristoyl-3-dimethylammonium-propane (DMDAP), 1,2-dipalmitoyl-3-dimethylammonium-propane (DPDAP), N1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[bis(3-amino-propyl)amino]butylcarboxamido)ethyl]-3,4-di[oleyloxy]-benzamide (MVL5), 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (DOEPC), 2,3-bis(dodecyloxy)-N-(2-hydroxyethyl)-N,N-dimethylpropane-1-ammonium bromide (DLRIE), N-(2-aminoethyl)-N,N-dimethyl-2,3-bis(tetradecyloxy)propane-1-ammonium bromide (DMORIE), di((Z)-non-2-en-1-yl)8,8'-((((2(dimethylamino)ethyl)thio)carbonyl)nitrogen N,N-dimethyl-2,3-bis(dodecyloxy)propane-1-amine (DLDMA), N,N-dimethyl-2,3-bis(tetradecyloxy)propane-1-amine (DMDMA), di((Z)-non-2-en-1-yl)-9-((4-(dimethylaminobutyryl)oxy)heptadecanedioate (L319), N-dodecyl-3-((2-dodecylcarbamoyl-ethyl)-{2-[(2-dodecylcarbamoyl-ethyl)-2-{(2-dodecylcarbamoyl-ethyl)-[2-(2-dodecylcarbamoyl-ethylamino)-ethyl]-amino}-ethyl-amino)propionamide (lipid 98N, 12-5), 1-[2-[bis(2-hydroxydodecyl)amino]ethyl-[2-[4-[2-[bis(2-hydroxydodecyl)amino]ethyl]piperazin-1-yl]ethyl]amino]dodecan-2-ol (lipid C12-200), and the following structures (XV-1) to (XV-6):

[0119]

[0120]

[0121] In some embodiments, the cationic lipid is a cationic lipid provided in WO2021 / 026358, WO2020 / 219941, WO2017 / 075531, WO2016 / 118725, WO2016 / 118724, WO2016 / 176330, WO2017 / 049245, U.S. Patent No. 9,670,152, each of which is herein incorporated by reference in its entirety.

[0122] In some embodiments, the cationic lipid is a compound of Formula I:

[0123]

[0124] or a pharmaceutically acceptable salt thereof, wherein:

[0125] L 1 or L 2 One of them is -OC(O)-, -C(O)O-, -C(O)-, -O-, -S(O) x -, -SS-, -C(O)S-, SC(O)-, -NR a C(O)-、-C(O)NR a -、-NR a C(O)NR a -、-OC(O)NR a -or-NR a C(O)O-, and L 1 or L 2 Another one is -OC(O)-、-C(O)O-、-C(O)-、-O-、-S(O) x -, -SS-, -C(O)S-, SC(O)-, -NR a C(O)-、-C(O)NR a -、-NR a C(O)NR a -、-OC(O)NR a -、-NR a C(O)O- or direct bond;

[0126] G 1 and G 2 Each independently is an unsubstituted C1-C 12 Alkylene or C1-C 12 alkenylene;

[0127] G 3 It is C1-C 24 Alkylene, C1-C 24 Alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene;

[0128] R a Is H or C1-C 12 alkyl;

[0129] R 1 and R 2 Each independently is C6-C 24 Alkyl or C6-C 24 alkenyl;

[0130] R 3 It is H, OR 5 、CN、-C(O)OR 4 、-OC(O)R 4 or -R 5 C(O)R 4 ;

[0131] R 4 It is C1-C 12 alkyl;

[0132] R 5 is H or C1-C6 alkyl; and

[0133] x is 0, 1, or 2.

[0134] In some embodiments, L 1 or L 2 One of them is -OC(O)- or -C(O)O-. In some embodiments, L 1 and L 2 Each of is -OC(O)- or -C(O)O-.

[0135] In some embodiments, G 1 It is C1-C 12 In some embodiments, G 2 It is C1-C 12 In some embodiments, G 1 and G 2 Each is independently C1-C 12 In some embodiments, G 1 and G2 Each independently is C5-C 12 Alkylene.

[0136] In some embodiments, G 3 It is C1-C 24 In some embodiments, G 3 It is a C1-C6 alkylene group.

[0137] In some embodiments, R 1 and R 2 Each independently selected from:

[0138]

[0139] In some embodiments, R 3 It's OH.

[0140] In some embodiments, L 1 and L 2 Each of them is -OC(O)-, G 1 and G 2 Each independently is C5-C 12 Alkylene, G 3 is C1-C6 alkylene, R 3 is OH, and R 1 and R 2 Each independently selected from:

[0141]

[0142]

[0143] In some embodiments, the cationic lipid is a compound of Formula Ia or Ib

[0144]

[0145] or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 15, A is a C3-C8 alicyclic, and each R 6 Independently selected from H, OH and C1-C 24 aliphatic, and wherein R 1 、R 2 、R 3 , L 1 , L 2 , G 1 and G 2 As described herein, individually and in combination, in the categories and subcategories.

[0146] In some embodiments, cationic lipids that may be useful according to the present disclosure are amino lipids comprising a titratable tertiary amino head group connected to at least two saturated alkyl chains via an ester bond that can be readily hydrolyzed to promote rapid degradation and / or excretion via the renal route. In some embodiments, such amino lipids have an apparent pK of about 6.0-6.5. a (For example, in one embodiment, the apparent pK a In some embodiments, the amino lipids can be incorporated into LNPs to impart unique physicochemical properties that regulate particle formation, cellular uptake, fusogenicity, and / or the endosome release of RNA. In some embodiments, aqueous RNA solutions are introduced into lipid mixtures comprising the pH 4.0 of such amino lipids to cause electrostatic interactions between negatively charged RNA backbones and positively charged cationic lipids. Without being bound by any particular theory, such electrostatic interactions cause particle formation to occur simultaneously with the effective encapsulation of RNA drug substances. After RNA encapsulation, the pH of the medium around the resulting LNP is adjusted to a more neutral pH (e.g., pH 7.4) to neutralize the surface charge of the LNP. When all other variables remain unchanged, such electrically neutral particles demonstrate longer in vivo circulation life and are better delivered to hepatocytes than charged particles rapidly removed by the reticuloendothelial system. Upon endosomal uptake, the low pH of the endosomal compartment renders LNPs containing such amino lipids fusogenic and allows RNA release into the cytosol of target cells.

[0147] As described herein, LNP comprises at least one cationic lipid. In some embodiments, the cationic lipid is selected from Table 1:

[0148] Table 1

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162] Or a pharmaceutically acceptable salt thereof. In some embodiments, provided compounds are provided and / or used in salt form (e.g., a pharmaceutically acceptable salt form). Unless otherwise indicated, reference to a compound provided herein should be understood to include reference to a salt thereof.

[0163] In some embodiments, the cationic lipid is selected from Table 2:

[0164] Table 2

[0165]

[0166]

[0167]

[0168]

[0169] Or a pharmaceutically acceptable salt thereof. In some embodiments, provided compounds are provided and / or used in salt form (e.g., a pharmaceutically acceptable salt form). Unless otherwise indicated, reference to a compound provided herein should be understood to include reference to a salt thereof.

[0170] In some embodiments, the cationic lipid is selected from Table 1 and / or Table 2.

[0171] In some embodiments, the cationic lipid is selected from DODMA, HY-501, ALC-0315, ALC366, and SM-102. In some embodiments, the cationic lipid is selected from ALC-0315 and ALC366. In some embodiments, the cationic lipid is ALC-0315. In some embodiments, the cationic lipid is ALC366. In some embodiments, the cationic lipid is SM-102. In some embodiments, the cationic lipid is DODMA. In some embodiments, the cationic lipid is HY-501.

[0172] In some embodiments, LNP of the present disclosure comprises about 30 to about 70 mol% of cationic lipid relative to the total lipid in the LNP. In some embodiments, LNP comprises about 35 to about 65 mol% of cationic lipid. In some embodiments, LNP comprises about 40 to about 60 mol% of cationic lipid. In some embodiments, LNP comprises about 41 to about 49 mol% of cationic lipid. In some embodiments, LNP comprises about 48 mol% of cationic lipid. In some embodiments, LNP comprises about 50 mol% of cationic lipid.

[0173] In some embodiments, the cationic ionizable lipid has the structure of formula (X)

[0174]

[0175] or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:

[0176] L 10 and L 20 One of them is -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x' -, -SS-, -C(=O)S-, SC(=O)-, -NR a' C(=O)-, -C(=O)NR a' -、NR a' C(=O)NR a' -、-OC(=O)NR a' -or-NR a' C(=O)O-, and L 10 and L 20 Another one is -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x -, -SS-, -C(=O)S-, SC(=O)-, -NR a' C(=O)-, -C(=O)NR a' -、NR a' C(=O)NR a' -、-OC(=O)NR a' -or-NR a' C(=O)O- or direct bond;

[0177] G 1' and G 2' Each independently is an unsubstituted C1-C 12 Alkylene or C 2-12 alkenylene;

[0178] G 3 'It's C1-24 Alkylene, C 2-24 Alkenylene, C 3-8 Cycloalkylene or C 3-8 cycloalkenylene;

[0179] R a ' is H or C 1-12 alkyl;

[0180] R 35 and R 36 Each is independently C 6-24 Alkyl or C 6-24 alkenyl;

[0181] R 37 It is H, OR 50 、CN、-C(=O)OR 40 、-OC(=O)R 40 or -NR 50 C(=O)R 40 ;

[0182] R 40 It is C 1-12 alkyl;

[0183] R 50 Is H or C 1-6 alkyl; and

[0184] x' is 0, 1, or 2.

[0185] In some of the foregoing embodiments of Formula (X), the lipid has one of the following structures (XA) or (XB):

[0186]

[0187] where R 35、 L 10 , G 1 '、G 2 '、L 20 、R 36 、R 37 and R 60 As described individually and in combination in the categories and subcategories herein;

[0188] A is a 3- to 8-membered cycloalkyl or cycloalkylene group;

[0189] R 60 is independently H, OH or C1-C 24 alkyl; and

[0190] n 1 ' is an integer in the range of 1 to 15.

[0191] In some of the foregoing embodiments of Formula (X), the lipid has structure (XA), and in other embodiments, the lipid has structure (XB).

[0192] In other embodiments of Formula (X), the lipid has one of the following structures (XC) or (XD):

[0193]

[0194] where R 35、 L 10 , G 1 '、G 2 '、L 20 、R 36 、R 37 and R 60 and y' and z' are each independently an integer ranging from 1 to 12 as described in classes and subclasses herein, individually and in combination.

[0195] In any of the foregoing embodiments of Formula (X), L 10 and L 20 One of them is -O(C=O)-. For example, in some embodiments, L 10 and L 20 In some embodiments of any of the foregoing, L 10 and L 20 Each is independently -(C=O)O- or -O(C=O)-. For example, in some embodiments, L 10 and L 20 Each of them is -(C=O)O-.

[0196] In some embodiments of Formula (X), the lipid has one of the following structures (XE) or (XF):

[0197]

[0198] where R 35 、R 36 、R 37 , G 1 '、G 2 ' and G 3 'As defined herein, individually and in combination, in the classes and subclasses.

[0199] In some of the foregoing embodiments of Formula (X), the lipid has one of the following structures (XG), (XH), (XJ), or (XK):

[0200]

[0201]

[0202] where R 35 、R 36 、R 37 、R 60 、y'、z'、n 1 ' and A are as defined herein, individually and in combination in classes and subclasses.

[0203] In some of the foregoing embodiments of Formula (X), n 1 ' is an integer in the range of 2 to 12, such as 2 to 8 or 2 to 4. For example, in some embodiments, n 1 ' is 3, 4, 5 or 6. In some embodiments, n 1 ' is 3. In some embodiments, n 1 ' is 4. In some embodiments, n 1 ' is 5. In some embodiments, n 1 'It's 6.

[0204] In some other of the foregoing embodiments of Formula (X), y' and z' are each independently an integer ranging from 2 to 10. For example, in some embodiments, y' and z' are each independently an integer ranging from 4 to 9 or 4 to 6.

[0205] In some of the foregoing embodiments of Formula (X), R 60 is H. In other of the foregoing embodiments, R 60 It is C1-C 24 In other embodiments, R 60 It's OH.

[0206] In some embodiments of Formula (X), G 3 ' is unsubstituted. In other embodiments, G 3 ' is substituted. In various embodiments, G 3 ' is linear C1-C 24 Alkylene or linear C2-C 24 Alkenylene.

[0207] In some other of the foregoing embodiments of Formula (X), R 35 or R 36 or both are C6-C 24 For example, in some embodiments, R 35 and R 36 Each independently has the following structure:

[0208]

[0209] in:

[0210] R7a and R 7b is independently H or C1-C at each occurrence 12 alkyl; and

[0211] a is an integer from 2 to 12,

[0212] Each of them chooses R 7a 、R 7b and a makes R 35 and R 36 Each independently comprises 6 to 20 carbon atoms. For example, in some embodiments, a is an integer ranging from 5 to 9 or 8 to 12.

[0213] In some of the foregoing embodiments of Formula (X), R 7a At least one occurrence of is H. For example, in some embodiments, R 7a In each occurrence, R 7b At least one occurrence of is C1-C8 alkyl. For example, in some embodiments, C1-C8 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, or n-octyl.

[0214] In various embodiments of Formula (X), R 35 or R 36 or both have one of the following structures:

[0215]

[0216] In some of the foregoing embodiments of Formula (X), R 37 is OH, CN, -C(=O)OR 40 、-OC(=O)R 40 or -NHC(=O)R 40 In some embodiments, R 40 It is a methyl or ethyl group.

[0217] In various embodiments, the cationic lipid of formula (X) has one of the structures listed below.

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224] In various embodiments, the cationic ionizable lipid has one of the structures listed in the table below.

[0225]

[0226]

[0227] In some embodiments, the cationic ionizable lipid has the structure of Formula (XI):

[0228]

[0229] in

[0230] R 1” and R 2”” Each of them is independently R 5” or -G 1” -L 1” -R 6” , where R 1” and R 2” At least one of them is -G 1” -L 1” -R 6” ;

[0231] R 3” and R 4” Each of which is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, aryl and C 3-10 a group consisting of cycloalkyl groups;

[0232] R 5” and R 6” Each of is independently a non-cyclic hydrocarbon group having at least 10 carbon atoms;

[0233] G 1” and G 2” Each of which is independently unsubstituted C 1-12 Alkylene or C 2-12 alkenylene;

[0234] L 1” and L 2” Each of the following is independently selected from -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) x” -, -SS-, -C(=O)S-, -SC(=O)-, -NR a” C(=O)-, -C(=O)NR a” -、-NR a” C(=O)NRa” -、-OC(=O)NR a” -and-NR a” C(=O)O--composition group;

[0235] R a” Is H or C 1-12 alkyl;

[0236] m" is 0, 1, 2, 3, or 4; and

[0237] x" is 0, 1, or 2.

[0238] In some of the foregoing embodiments of Formula (XI), G 1” are independently unsubstituted C1-C 12 Alkylene or unsubstituted C 2-12 Alkenylene, such as unsubstituted straight chain C 1-12 Alkylene or unsubstituted straight chain C 2-12 In some embodiments, each G 1” independently unsubstituted C 6-12 Alkylene or unsubstituted C 6-12 Alkenylene, such as unsubstituted straight chain C 6-12 Alkylene or unsubstituted straight chain C 6-12 In some embodiments, each G 1” independently unsubstituted C 8-12 Alkylene or unsubstituted C 8-12 Alkenylene, such as unsubstituted straight chain C 8-12 Alkylene or unsubstituted straight chain C 8-12 In some embodiments, each G 1” independently unsubstituted C 6-10 Alkylene or unsubstituted C 6-10 Alkenylene, such as unsubstituted straight chain C 6-10 Alkylene or unsubstituted straight chain C 6-10 In some embodiments, each G 1” is independently an unsubstituted alkylene group having 8, 9, or 10 carbon atoms, such as an unsubstituted straight chain alkylene group having 8, 9, or 10 carbon atoms. 1” and R 2” are independently -G 1” -L 1” -R 6” When R 1” G 1” Can be used with R 2” G 1” For example, in some of these embodiments, R 1” G 1”is an unsubstituted straight chain C 1-12 Alkylene, and R 2” G 1” is an unsubstituted straight chain C 2-12 Alkenylene; or R 1” G 1” is an unsubstituted straight chain C 1-12 Alkylene, and R 2” G 1” are different unsubstituted straight chain C 1-12 In some embodiments, when R 1” and R 2” are independently -G 1” -L 1” -R 6” When R 1” G 1” Can be used with R 2” G 1” For example, in some of these embodiments, each G 1” are all the same unsubstituted straight chain C 8-12 Alkylene, such as unsubstituted straight chain C 8-10 Alkylene, or each G 1” are all the same unsubstituted straight chain C 6-12 Alkenylene.

[0239] In some of the foregoing embodiments of Formula (XI), each L 1” independently selected from -O(C=O)-, -(C=O)O-, -C(=O)S-, -SC(=O)-, -NR a” C(=O)- and -C(=O)NR a” -a group consisting of. In some embodiments, L 1” R a” Is H or C 1-12 In some embodiments, L 1” R a” Is H or C 1-6 Alkyl groups, such as H or C 1-3 In some embodiments, L 1” R a” is H, methyl or ethyl. In some embodiments, each L 1” In some embodiments, each L is independently selected from the group consisting of -O(C=O)-, -(C=O)O-, -C(=O)S-, and -SC(=O)-. 1” are independently -O(C=O)- or -(C=O)O-. In some embodiments, when R 1” and R 2” are independently -G 1” -L1” -R 6” When R 1” L 1” Can be used with R 2” L 1” For example, in some of these embodiments, R 1” L 1” is selected from -O(C=O)-, -(C=O)O-, -C(=O)S-, -SC(=O)-, -NR a” C(=O)- and -C(=O)NR a” - a part of a group (e.g. R 1” L 1” is -O(C=O)-), and R 2” L 1” is selected from -O(C=O)-, -(C=O)O-, -C(=O)S-, -SC(=O)-, -NR a” C(=O)- and -C(=O)NR a” - different parts of the group (e.g. R 2” L 1” is -(C=O)O-). In some embodiments, when R 1” and R 2” are independently -G 1” -L 1” -R 6” When R 1” L 1” Can be used with R 2” L 1” For example, in some of these embodiments, each L 1” are all selected from -O(C=O), -(C=O)O-, -C(=O)S-, -SC(=O)-, -NR a” C(=O)- and -C(=O)NR a” - The same part in the group, such as each L 1” All -O(C=O)- or each L 1” They are all -(C=O)O-.

[0240] In some of the foregoing embodiments of Formula (XI), each R 6” is independently a non-cyclic hydrocarbon group having at least 10 carbon atoms, such as a straight chain hydrocarbon group having at least 10 carbon atoms. 6” independently have up to 30 carbon atoms, such as up to 28, up to 26, up to 24, up to 22, or up to 20 carbon atoms. In some embodiments, each R 6”is independently a non-cyclic hydrocarbon group having 10 to 30 carbon atoms, such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, for example, a straight chain hydrocarbon group having 10 to 30 carbon atoms, such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms. 6” All through R 6” The inner carbon atom is connected to L 1” In some embodiments, each R 6” independently has up to 30 carbon atoms (such as up to 28, up to 26, up to 24, up to 22, or up to 20 carbon atoms), and each R 6” All through R 6” The inner carbon atom is connected to L 1” In some embodiments, each R 6” is independently a non-cyclic hydrocarbon group having at least 10 carbon atoms, such as a straight chain hydrocarbon group having at least 10 carbon atoms, and each R 6” All through R 6” The inner carbon atom is connected to L 1” In some embodiments, each R 6” is independently a non-cyclic hydrocarbon group having 10 to 30 carbon atoms, such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, for example, a straight chain hydrocarbon group having 10 to 30 carbon atoms, such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, and each R 6” All through R 6” The inner carbon atom is connected to L 1” In some embodiments, R 6” The hydrocarbon group is an alkyl or alkenyl group, such as C 10-30 Thus, in some embodiments, each R 6” is independently a non-cyclic alkyl group having at least 10 carbon atoms or a non-cyclic alkenyl group having at least 10 carbon atoms, such as a straight-chain alkyl group having at least 10 carbon atoms or a straight-chain alkenyl group having at least 10 carbon atoms. 6”R is independently a non-cyclic alkyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms) or a non-cyclic alkenyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), for example, a straight-chain alkyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms) or a straight-chain alkenyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms). In some embodiments, each R 6” is independently a non-cyclic alkyl group having 11 to 19 carbon atoms, such as 11, 13, 15, 17, or 17 carbon atoms, for example, a straight chain alkyl group having 11 to 19 carbon atoms, such as 11, 13, 15, 17, or 17 carbon atoms. 6” is independently an acyclic alkyl group having 10 to 30 carbon atoms, such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, or an acyclic alkenyl group having 10 to 30 carbon atoms, such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, 例如 a linear alkyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22 or 10 to 20 carbon atoms) or a linear alkenyl group having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22 or 10 to 20 carbon atoms), and each R6" is connected by R 6” The inner carbon atom is connected to L 1” In some embodiments, each R 6” is independently a non-cyclic alkyl group having 11 to 19 carbon atoms, such as 11, 13, 15, 17 or 17 carbon atoms, for example, a straight chain alkyl group having 11 to 19 carbon atoms, such as 11, 13, 15, 17 or 17 carbon atoms, and each R 6” All through R 6” The inner carbon atom is connected to L 1” The expression "internal carbon atom" means R 6” Connect to L 1” R 6” The carbon atom is directly bonded to R 6” At least 2 other carbon atoms. For example, for the following C 11 For an alkyl group, each carbon atom at any of positions 2, 3, 4, 5, and 7 meets the criteria for an "interior carbon atom" according to the present disclosure, while the carbon atoms at positions 1, 6, 8, 9, 10, and 11 do not meet the criteria.

[0241]

[0242] Therefore, R 6” It is through R 6” The inner carbon of the 1” C 11 Alkyl groups include the following:

[0243]

[0244] in Represents R 6” Bind to L 1” In addition, for straight chain alkyl, such as straight chain C 11 Alkyl groups, excluding the first and last carbon atoms of a straight-chain alkyl group (i.e., excluding the first and last carbon atoms of a straight-chain C 11 Each carbon atom (except the carbon atoms at positions 1 and 11 of the alkyl group) meets the criteria for an "interior carbon atom." Thus, in some embodiments, R 6” is a straight chain alkyl group having p carbon atoms and is 6” The inner carbon atom is connected to L 1” Meaning R 6” By R 6” The carbon atom of is connected to L at any one of positions 2 to (p-1) (thereby excluding the terminal C atoms at positions 1 and p) 1” In some embodiments, when R 6” is a compound having p' carbon atoms (where p' is an even number) and having R 6” The inner carbon atom is connected to L 1” When the straight-linked alkyl group is 6” By R 6” The carbon at any one of the positions (p' / 2-1), (p' / 2) and (p' / 2+1) is connected to L 1” (For example, if p' is 10, then R 6” By R 6” The carbon atom at any one of positions 4, 5 and 6 is connected to L 1” In some embodiments, when R 6” is a compound having p' carbon atoms (where p' is an odd number) and having R 6” The inner carbon atom is connected to L 1” When the straight-linked alkyl group is 6” By R 6” The carbon atom at any one of the positions (p"-1) / 2 and (p"+1) / 2 is connected to L 1” (For example, if p' is 11, then R 6” By R 6”The carbon at any one of positions 5 and 6 is connected to L 1” ). Generally, it should be understood that if R 1” and R 2” All -G 1” -L 1” -R 6” And each R 6” By R 6” The inner carbon atom is connected to L 1” , then R 1” R 6” By R 1” R 6” The internal carbon atom is connected to R 1” L 1” (Instead of connecting to R 2” L 1” ), and R 2” R 6” By R 2” R 6” The internal carbon atom is connected to R 2” L 1” (Instead of connecting to R 1” L 1” ). In some embodiments, each R 6” Independently selected from the group consisting of:

[0245]

[0246] in Represents R 6” Bind to L 1” In some embodiments, when R 1” and R 2” are independently -G 1” -L 1” -R 6” When R 1” R 6” Can be used with R 2” R 6” For example, in some of these embodiments, R 1” R in 6” It may be an acyclic (preferably linear) hydrocarbon group having at least 10 carbon atoms (e.g., R 1” R 6” yes ), and R 2” R 6” can be different non-cyclic (preferably linear) hydrocarbon groups having at least 10 carbon atoms (e.g., R 2” R 6” yes In some embodiments, when R1” and R 2” are independently -G 1” -L 1” -R 6” When R 1” R 6” Can be used with R 2” R 6” For example, in some of these embodiments, each R 6” are all the same non-cyclic (preferably linear) hydrocarbon groups having at least 10 carbon atoms (e.g., each R 6” All ).

[0247] In some of the foregoing embodiments of Formula (XI), R 5” is a non-cyclic hydrocarbon group having at least 10 carbon atoms, such as a straight chain hydrocarbon group having at least 10 carbon atoms. 5” is a non-cyclic hydrocarbon group having at least 12 carbon atoms, such as at least 14, at least 16, or at least 18 carbon atoms, for example, a straight chain hydrocarbon group having at least 12, at least 14, at least 16, or at least 18 carbon atoms. 5” has up to 30 carbon atoms, such as up to 28, up to 26, up to 24, up to 22, or up to 20 carbon atoms. 5” is an acyclic hydrocarbon group, for example a straight chain hydrocarbon group, wherein each hydrocarbon group has 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, 10 to 20 carbon atoms, or 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 22, 12 to 20 carbon atoms, or 14 to 30, 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms). 5” The hydrocarbon group is an alkyl or alkenyl group, such as C 10-30 Thus, in some embodiments, R 5”is a non-cyclic alkyl group having at least 10 carbon atoms (such as at least 12, at least 14, at least 16, or at least 18 carbon atoms) or a non-cyclic alkenyl group having at least 10 carbon atoms (such as at least 12, at least 14, at least 16, or at least 18 carbon atoms), for example, a straight-chain alkyl group having at least 10 carbon atoms (such as at least 12, at least 14, at least 16, or at least 18 carbon atoms) or a straight-chain alkenyl group having at least 10 carbon atoms (such as at least 12, at least 14, at least 16, or at least 18 carbon atoms). In some embodiments, R 5” is an acyclic alkyl or acyclic alkenyl group, for example a straight-chain alkyl or alkenyl group, wherein each of the alkyl and alkenyl groups independently has 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, 10 to 20 carbon atoms, or 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 22, 12 to 20 carbon atoms, or 14 to 30, 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms). In some embodiments, the alkenyl group has at least 2 carbon-carbon double bonds, e.g., 2 or 3 carbon-carbon double bonds, such as 2 carbon-carbon double bonds. In some embodiments, the alkenyl group has at least 1 carbon-carbon double bond in the cis configuration, e.g., 1, 2, or 3, such as 2 carbon-carbon double bonds in the cis configuration. Thus, in some embodiments, R 5” is a non-cyclic alkyl or a non-cyclic alkenyl, such as a straight-chain alkyl or straight-chain alkenyl, wherein each of the alkyl and alkenyl groups independently has 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, 10 to 20 carbon atoms, or 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 22, 12 to 20 carbon atoms, or 14 to 30, 14 to 2 In some embodiments, R 5”is a non-cyclic alkyl or a non-cyclic alkenyl, such as a straight-chain alkyl or straight-chain alkenyl, wherein each of the alkyl and alkenyl groups independently has 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, 10 to 20 carbon atoms, or 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 22, 12 to 20 carbon atoms, or 14 to 30, 14 to 28, 1 In some embodiments, R 5” Has the following structure: in Represents R 5” A bond to the rest of a compound.

[0248] In some of the foregoing embodiments of Formula (XI), L 2” Selected from -O(C=O)-, -(C=O)O-, -C(=O)-, -SS-, -C(=O)S-, -SC(=O)-, -NR a” C(=O)-, -C(=O)NR a” -、-NR a” C(=O)NR a” 、-OC(=O)NR a” -and-NR a” In some embodiments, L 2” Selected from -O(C=O)-, -(C=O)O-, -C(=O)-, -C(=O)S-, -SC(=O)-, -NR a” C(=O)- and -C(=O)NR a” -a group consisting of. In some embodiments, L 2” R a” Is H or C 1-12 In some embodiments, L 2” R a” Is H or C 1-6 Alkyl groups, such as H or C 1-3 In some embodiments, L 2” R a” is H, methyl or ethyl. In some embodiments, L 2” is selected from the group consisting of -O(C=O)-, -(C=O)O-, -C(=O)S-, and -SC(=O).2” It is -O(C=O)- or -(C=O)O-.

[0249] In some of the foregoing embodiments of Formula (XI), G 2” is unsubstituted C 1-12 Alkylene or unsubstituted C 2-12 Alkenylene, such as unsubstituted straight chain C 1-12 Alkylene or unsubstituted straight chain C 2-12 In some embodiments, G 2” is unsubstituted C 2-10 Alkylene or unsubstituted C 2-10 Alkenylene, such as unsubstituted straight chain C 2-10 Alkylene or unsubstituted straight chain C 2-10 In some embodiments, G 2” is unsubstituted C 2-6 Alkylene or unsubstituted C 2-6 Alkenylene, such as unsubstituted straight chain C 2-6 Alkylene or unsubstituted straight chain C 2-6 In some embodiments, G 2” is unsubstituted C 2-4 Alkylene or unsubstituted C 2-4 Alkenylene, such as unsubstituted straight chain C 2-4 Alkylene or unsubstituted straight chain C 2-4 In some embodiments, G 2” It is ethylene or trimethylene.

[0250] In some of the foregoing embodiments of Formula (XI), R 3” and R 4” Each of them is independently C 1-6 Alkyl or C 2-6 In some embodiments, R 3” and R 4” Each of them is independently C 1-4 Alkyl or C 2-4 In some embodiments, R 3” and R 4” Each of them is independently C 1-3 In some embodiments, R 3” and R 4” Each of R is independently methyl or ethyl. 3” and R 4” Each of them is a methyl group.

[0251] In some of the foregoing embodiments of Formula (XI), m" is 0, 1, 2, or 3. In some embodiments, m" is 0 or 2. In some embodiments, m" is 0. In some embodiments, m" is 2.

[0252] In some of the foregoing embodiments of Formula (XI), the cationic ionizable lipid has the structure of Formula (XIIa) or (XIIb):

[0253]

[0254]

[0255] in

[0256] R 3” and R 4” Each of which is independently C1-C6 alkyl or C 2-6 alkenyl;

[0257] R 5” is a straight chain hydrocarbon group having at least 14 carbon atoms, such as at least 16 carbon atoms, wherein the hydrocarbon group preferably has at least 2 carbon-carbon double bonds;

[0258] Each R 6” is independently a straight chain hydrocarbon group (eg, a straight chain alkyl group) having at least 10 carbon atoms and / or each R 6” By R 6” The inner carbon atom is connected to L 1” , preferably each R 6” is independently a straight chain hydrocarbon group (eg, a straight chain alkyl group) having at least 10 carbon atoms, and each R 6” By R 6” The inner carbon atom is connected to L 1” ;

[0259] Each G 1” are independently unsubstituted linear C 4-12 Alkylene or C 4-12 Alkenylene, such as unsubstituted straight chain C 6-12 Alkylene or C 6-12 Alkenylene, such as unsubstituted straight-chain C 8-12 Alkylene or unsubstituted straight chain C 8-12 alkenylene;

[0260] G 2” is an unsubstituted C2-C 10 Alkylene or C 2-10 Alkenylene, preferably unsubstituted C2-C6 alkylene or C 2-6 alkenylene;

[0261] L 1”and L 2” Each of is independently -O(C=O)- or -(C=O)O-; and

[0262] m" is 0, 1, 2 or 3, preferably 0 or 2.

[0263] In some of the foregoing embodiments of Formula (XIIa), R 5” has up to 30 carbon atoms, such as up to 28, up to 26, up to 24, up to 22, or up to 20 carbon atoms. In some embodiments of Formula (XIIa), R 5” is a straight chain hydrocarbon group having 14 to 30 carbon atoms, such as 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms. 5” is a straight chain alkyl or alkenyl group having 14 to 30 carbon atoms, such as 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22 or 18 to 20 carbon atoms. In some embodiments of formula (XIIa), the alkenyl group has at least 2 carbon-carbon double bonds, for example 2 or 3 carbon-carbon double bonds, such as 2 carbon-carbon double bonds. In some embodiments, the alkenyl group has at least 1 carbon-carbon double bond in a cis configuration, for example 1, 2 or 3, such as 2 carbon-carbon double bonds in a cis configuration. Therefore, in some embodiments of formula (XIIa), R 5” is a straight chain alkyl or alkenyl group, wherein each of the alkyl and alkenyl groups independently has 14 to 30 carbon atoms (such as 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms), and the alkenyl group has at least 2 carbon-carbon double bonds, for example 2 or 3 carbon-carbon double bonds. In some embodiments of Formula (XIIa), R 5”is a straight chain alkyl or straight chain alkenyl group, wherein each of the alkyl and alkenyl groups independently has 14 to 30 carbon atoms (such as 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms), and the alkenyl group has at least one carbon-carbon double bond in the cis configuration, such as 1, 2, or 3 carbon-carbon double bonds. In some embodiments of Formula (XIIa), R 5” is a straight chain alkyl or straight chain alkenyl group, wherein each of the alkyl and alkenyl groups independently has 14 to 30 carbon atoms (such as 14 to 28, 14 to 26, 14 to 24, 14 to 22, 14 to 20 carbon atoms, or 16 to 30, 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms), and the alkenyl group has 2 or 3 carbon-carbon double bonds, wherein at least one carbon-carbon double bond, such as 1, 2, or 3 carbon-carbon double bonds, is in the cis configuration. In some embodiments of Formula (XIIa), R 5” Has the following structure:

[0264] in Represents R 5” A bond to the rest of the compound. In some embodiments of Formula (XIIa), R 6” has up to 30 carbon atoms, such as up to 28, up to 26, up to 24, up to 22, or up to 20 carbon atoms. In some embodiments of Formula (XIIa), R 6” is an acyclic hydrocarbon group (e.g., an acyclic alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), for example, a straight-chain hydrocarbon group (e.g., a straight-chain alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms). In some embodiments of Formula (XIIa), R 6” is a straight chain hydrocarbon group (e.g., a straight chain alkyl group) having at least 10 carbon atoms, and R 6” By R 6” The inner carbon atom is connected to L 1” In some embodiments of Formula (XIIa), R 6”is an acyclic hydrocarbon group (e.g., an acyclic alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), for example, a straight-chain hydrocarbon group (e.g., a straight-chain alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), and R 6” By R 6” The inner carbon atom is connected to L 1” In some embodiments of Formula (XIIa), G 1” are independently unsubstituted linear C 4-12 Alkylene or C 4-12 Alkenylene, such as unsubstituted straight chain C 6-12 Alkylene or C 6-12 In some embodiments of Formula (XIIa), R 5” is a straight chain hydrocarbon group, for example a straight chain alkenyl group having at least 14 carbon atoms (such as 14 to 30 carbon atoms) and 2 or 3 carbon-carbon double bonds; R 6” is a straight chain hydrocarbon group (eg, a straight chain alkyl group) having at least 10 carbon atoms (eg, having 10 to 30 carbon atoms), and R 6” By R 6” The inner carbon atom is connected to L 1” ; and G 1” are independently unsubstituted linear C 4-12 Alkylene or C 4-12 Alkenylene, such as unsubstituted straight chain C 6-12 Alkylene or C 6-12 Alkenylene.

[0265] In some of the foregoing embodiments of Formula (XIIb), each R 6” independently have up to 30 carbon atoms, such as up to 28, up to 26, up to 24, up to 22, or up to 20 carbon atoms. In some embodiments of Formula (XIIb), each R 6” is independently a straight chain hydrocarbon group (e.g., a straight chain alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, or 11 to 19 carbon atoms, such as 11, 13, 15, 17, or 17 carbon atoms). In some embodiments of Formula (XIIb), each R 6” is independently a straight chain hydrocarbon group (e.g., a straight chain alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, or 11 to 19 carbon atoms, such as 11, 13, 15, 17, or 17 carbon atoms), and each R 6” All through R6” The inner carbon atom is connected to L 1” In some embodiments of Formula (XIIb), each R 6” Independently selected from the group consisting of:

[0266]

[0267] in Represents R 6” Bind to L 1” In some embodiments of Formula (XIIb), each G 1” are independently unsubstituted linear C 6-12 Alkylene or C 6-12 In some embodiments of Formula (XIIb), each G 1” are independently unsubstituted linear C 8-12 Alkylene or C 8-12 In some embodiments of Formula (XIIb), each R 6” are independently straight chain hydrocarbon groups (e.g., straight chain alkyl groups) having at least 10 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, or 11 to 19 carbon atoms, such as 11, 13, 15, 17, or 17 carbon atoms), and are each represented by R 6” The inner carbon atom is connected to L 1” ; and each G 1” are independently unsubstituted linear C 8-12 Alkylene or C 8-12 Alkenylene.

[0268] In some of the foregoing embodiments of Formula (XI), the cationic ionizable lipid has the structure of Formula (XIIIa) or (XIIIb):

[0269]

[0270] in

[0271] R 3” and R 4” Each of them is independently C 1-4 Alkyl or C 2-4 Alkenyl, more preferably C 1-3 an alkyl group, such as a methyl or ethyl group;

[0272] R 5” is a straight-chain alkyl or alkenyl group having at least 16 carbon atoms, wherein the alkenyl group preferably has at least 2 carbon-carbon double bonds;

[0273] Each R 6”is independently a straight chain hydrocarbon group having at least 10 carbon atoms, wherein R 6” By R 6” The inner carbon atom is connected to L 1” ;

[0274] Each G 1” are independently unsubstituted linear C 6-12 Alkylene or unsubstituted straight chain C 6-12 Alkenylene, such as unsubstituted straight chain C 8-12 Alkylene or unsubstituted straight chain C 8-12 Alkenylene, such as unsubstituted straight-chain C 8-10 Alkylene or unsubstituted straight chain C 8-10 Alkenylene, such as unsubstituted straight-chain C8 alkylene;

[0275] G 2” is unsubstituted C 2-6 Alkylene or C 2-6 Alkenylene, preferably unsubstituted C 2-4 Alkylene or C 2-4 alkenylene, such as ethylene or trimethylene;

[0276] L 1” and L 2” Each of is independently -O(C=O)- or -(C=O)O-; and

[0277] M" is 0, 1, 2 or 3, preferably 0 or 2.

[0278] In some of the foregoing embodiments of Formula (XIIIa), R 5” has up to 30 carbon atoms, such as up to 28, up to 26, up to 24, up to 22, or up to 20 carbon atoms. In some embodiments of Formula (XIIIa), R 5” Is a straight chain alkyl or alkenyl group having 16 to 30 carbon atoms (such as 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22 or 18 to 20 carbon atoms). In some embodiments of formula (XIIIa), the alkenyl group has at least 2 carbon-carbon double bonds, for example 2 or 3 carbon-carbon double bonds, such as 2 carbon-carbon double bonds. In some embodiments, the alkenyl group has at least 1 carbon-carbon double bond in a cis configuration, for example 1, 2 or 3, such as 2 carbon-carbon double bonds in a cis configuration. Therefore, in some embodiments of formula (XIIIa), R 5”is a straight chain alkyl or straight chain alkenyl group, wherein each of the alkyl and alkenyl groups independently has 16 to 30 carbon atoms (such as 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms), and the alkenyl group has at least 2 carbon-carbon double bonds, for example 2 or 3 carbon-carbon double bonds. In some embodiments of Formula (XIIIa), R 5” is a straight chain alkyl or straight chain alkenyl group, wherein each of the alkyl and alkenyl groups independently has 16 to 30 carbon atoms (such as 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms), and the alkenyl group has at least one carbon-carbon double bond in a cis configuration, such as 1, 2, or 3 carbon-carbon double bonds. In some embodiments of Formula (XIIIa), R 5” is a straight chain alkyl or straight chain alkenyl group, wherein each of the alkyl and alkenyl groups independently has 16 to 30 carbon atoms (such as 16 to 28, 16 to 26, 16 to 24, 16 to 22, 16 to 20 carbon atoms, or 18 to 30, 18 to 28, 18 to 26, 18 to 24, 18 to 22, or 18 to 20 carbon atoms), and the alkenyl group has 2 or 3 carbon-carbon double bonds, wherein at least one carbon-carbon double bond, such as 1, 2, or 3 carbon-carbon double bonds, is in the cis configuration. In some embodiments of Formula (XIIIa), R 5” Has the following structure: in Represents R 5” A bond to the rest of the compound. In some embodiments of Formula (XIIIa), R 6” has up to 30 carbon atoms, such as up to 28, up to 26, up to 24, up to 22, or up to 20 carbon atoms. In some embodiments of Formula (XIIIa), R 6” is a straight chain hydrocarbon group (e.g., a straight chain alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms), and R 6” By R 6” The inner carbon atom is connected to L 1” In some embodiments of Formula (XIIIa), R 6” is a straight chain alkyl group having 10 to 30 carbon atoms, such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, and R 6” By R 6” The inner carbon atom is connected to L 1”In some embodiments of Formula (XIIIa), G 1” are independently unsubstituted linear C 4-12 Alkylene or C 4-12 Alkenylene, such as unsubstituted straight chain C 6-12 Alkylene or C 6-12 In some embodiments of Formula (XIIIa), R 5” is a straight chain hydrocarbon group, for example a straight chain alkenyl group having at least 16 carbon atoms (such as 16 to 30 carbon atoms) and 2 or 3 carbon-carbon double bonds; R 6” is a straight chain hydrocarbon group (eg, a straight chain alkyl group) having at least 10 carbon atoms (eg, having 10 to 30 carbon atoms), and R 6” By R 6” The inner carbon atom is connected to L 1” ; and G 1” are independently unsubstituted linear C 4-12 Alkylene or C 4-12 Alkenylene, such as unsubstituted straight chain C 6-12 Alkylene or C 6-12 Alkenylene.

[0279] In some of the foregoing embodiments of Formula (XIIIb), each R 6” independently have up to 30 carbon atoms, such as up to 28, up to 26, up to 24, up to 22, or up to 20 carbon atoms. In some embodiments of Formula (XIIIb), each R 6” is independently a straight chain hydrocarbon group (e.g., a straight chain alkyl group) having 10 to 30 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, or 11 to 19 carbon atoms, such as 11, 13, 15, 17, or 17 carbon atoms), and each R 6” All through R 6” The inner carbon atom is connected to L 1” In some embodiments of Formula (XIIIb), each R 6” By R 6” The inner carbon atom is connected to L 1” , and are independently selected from the group consisting of:

[0280]

[0281] in Represents R 6” Bind to L 1” In some embodiments of Formula (XIIIb), each G 1” are independently unsubstituted linear C 8-12 Alkylene or C 8-12Alkenylene, such as unsubstituted straight chain C 8-10 Alkylene or C 8-10 In some embodiments of Formula (XIIIb), each R 6” are independently straight chain hydrocarbon groups (e.g., straight chain alkyl groups) having at least 10 carbon atoms (such as 10 to 28, 10 to 26, 10 to 24, 10 to 22, or 10 to 20 carbon atoms, or 11 to 19 carbon atoms, such as 11, 13, 15, 17, or 17 carbon atoms), and are each represented by R 6” The inner carbon atom is connected to L 1” ; and each G 1” are independently unsubstituted linear C 8-12 Alkylene or C 8-12 Alkenylene, such as unsubstituted straight chain C 8-10 Alkylene or C 8-10 Alkenylene.

[0282] In some of the foregoing embodiments of Formula (XI), the cationic ionizable lipid has one of the following formulas (XIV-1), (XIV-2), and (XIV-3):

[0283]

[0284] In some embodiments, the cationic ionizable lipid is (6Z,16Z)-12-((Z)-dec-4-en-1-yl)docosa-6,16-dien-11-yl 5-(dimethylamino)pentanoate (3D-P-DMA). The structure of 3D-P-DMA can be represented as follows:

[0285]

[0286] In various embodiments, the cationic ionizable lipid is selected from the group consisting of: N,N-dimethyl-2,3-dioleyloxypropylamine (DODMA), 1,2-dioleoyl-3-dimethylammonium-propane (DODAP), heptadeca-6,9,28,31-tetraen-19-yl-4-(dimethylamino)butyrate (DLin-MC3-DMA), and 4-((di((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)oxy)-N,N-dimethyl-4-oxobutan-1-amine (DPL-14).

[0287] Other examples of cationic ionizable lipids include, but are not limited to, 3-(N-(N',N'-dimethylaminoethane)-carbamoyl)cholesterol (DC-Chol), 1,2-dioleoyl-3-dimethylammonium-propane (DODAP); 1,2-diacyloxy-3-dimethylammonium propane; 1,2-dialkoxy-3-dimethylammonium propane, 1,2-distearoyloxy-N,N-dimethyl-3-aminopropane (DSDMA), 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), dioctadecylamidoglycyl spermine (DOGS), 3-dimethyl Amino-2-(cholesterol-5-ene-3-β-oxybutane-4-oxy)-1-(cis,cis-9,12-octadecadienyloxy)propane (CLinDMA), 2-[5'-(cholesterol-5-ene-3-β-oxy)-3'-oxapentyloxy)-3-dimethyl-1-(cis,cis-9',12'-octadecadienyloxy)propane (CpLinDMA), N,N-dimethyl-3,4-dioleyloxybenzylamine (DMOBA), 1,2-N,N'-dioleylcarbamoyl-3-dimethylaminopropane (DOcarbDAP), 2,3-dilinoleoyloxy-N,N-dimethylpropylamine (DLinDAP), 1,2-N,N'-dilinoleylamino Formyl-3-dimethylaminopropane (DLincarbDAP), 1,2-dilinoleoylcarbamoyl-3-dimethylaminopropane (DLinCDAP), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA), 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-K-XTC2-DMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA), heptahexaenoic acid-6,9,28,31-tetraen-19-yl-4-(dimethylamino)butyrate (DLin-MC3-DMA A), 2-({8-[(3β)-cholesterol-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-octadec-9,12-dien-1-yloxy]propane-1-amine (octyl-CLinDMA), 1,2-dimyristoyl-3-dimethylammonium-propane (DMDAP), 1,2-dipalmitoyl-3-dimethylammonium-propane (DPDAP), N1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[bis(3-amino-propyl)amino]butylcarboxamido)ethyl]-3,4-di[oleyloxy]-benzamide (MVL5), di((Z)-non-2-en-1-yl)8,8'-((((2-(dimethylamino)ethyl)thio)carbonyl)azadiyl)dioctanoate (ATX), N,N-dimethyl-2,3-bis(dodecyloxy)propane-1-amine (DLDMA), N,N-dimethyl-2,3-bis(tetradecyloxy)propane-1-amine (DMDMA), di((Z)-non-2-en-1-yl)-9-((4-(dimethylaminobutyryl)oxy)heptadecanedioate (L319), N-dodecyl-3-((2-dodecylcarbamoyl)oxy)heptadecanoate -ethyl)-{2-[(2-dodecylcarbamoyl-ethyl)-2-{(2-dodecylcarbamoyl-ethyl)-[2-(2-dodecylcarbamoyl-ethylamino)-ethyl]-amino}-ethylamino)propionamide (lipid 98N12-5), 1-[2-[bis(2-hydroxydodecyl)amino]ethyl-[2-[4-[2-[bis(2-hydroxydodecyl)amino]ethyl]piperazin-1-yl]ethyl]amino]dodecan-2-ol (lipid C12-200).

[0288] In certain embodiments, the cationic ionizable lipid is or includes X-3.

[0289] In certain embodiments, the cationic ionizable lipid is or includes X-45.

[0290] In some embodiments, the cationic lipid used herein is or includes DPL-14. As used herein, "DPL-14" is a lipid including the following general formula:

[0291]

[0292] In some embodiments, the cationic lipid used herein is or includes EA-2. As used herein, "EA-2" is a lipid including the following general formula:

[0293]

[0294] It will be understood that any reference to a cationic or cationically ionizable lipid disclosed herein also includes salts (particularly pharmaceutically acceptable salts), tautomers, stereoisomers, solvates (eg, hydrates), and isotopically labeled forms thereof.

[0295] In some embodiments, the cations / cationically ionizable lipids may constitute from about 10 mol% to about 100 mol%, from about 20 mol% to about 100 mol%, from about 30 mol% to about 100 mol%, from about 40 mol% to about 100 mol%, or from about 50 mol% to about 100 mol% of the total lipids present in the composition / particle. In some embodiments, the cations / cationically ionizable lipids constitute from about 40 mol% to about 75 mol%, preferably from about 40 mol% to about 70 mol%, more preferably from about 45 mol% to about 65 mol% of the total lipids present in the composition / particle.

[0296] In some embodiments, wherein the nucleic acid compositions described herein (particularly DNA or RNA compositions) comprise a cationic or cationically ionizable lipid and one or more additional lipids, the cationic or cationically ionizable lipid constitutes about 10 mol% to about 80 mol%, about 20 mol% to about 75 mol%, about 20 mol% to about 70 mol%, about 20 mol% to about 60 mol%, about 25 mol% to about 55 mol%, about 30 mol% to about 50 mol%, about 35 mol% to about 45 mol%, or about 40 mol% to about 55 mol% of the total lipids present in the composition.

[0297] In some embodiments of the nucleic acid (such as DNA or RNA) compositions described herein, particularly mRNA compositions, in which (i) the nucleic acid and (ii) at least a portion of the cation or cation-ionizable lipid form a particle (e.g., LNP), the cation or cation-ionizable lipid may constitute from about 10 mol% to about 80 mol%, from about 20 mol% to about 75 mol%, from about 20 mol% to about 70 mol%, from about 20 mol% to about 60 mol%, from about 25 mol% to about 55 mol%, from about 30 mol% to about 50 mol%, from about 35 mol% to about 45 mol%, or from about 40 mol% to about 55 mol% of the total lipid present in the particle.

[0298] Helper lipids

[0299] As described herein, LNP of the present disclosure includes helper lipid.In some embodiments, helper lipid is phospholipid.In some embodiments, helper lipid is or includes 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), phosphatidylethanolamine such as 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), sphingomyelin (SM), 1,2-diacylglycerol-3-O-4'-(N,N,N-trimethyl)-homoserine (DGTS), ceramide, cholesterol, steroid such as sterol and derivatives thereof.

[0300] In some embodiments, the helper lipid is or includes phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine or sphingomyelin. In some embodiments, the helper lipid is or includes diacylphosphatidylcholine, such as distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), diarachidonoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC), dioctanoylphosphatidylcholine (DP ... (Tricosyl) phosphatidylcholine (DTPC), di(tetracosyl) phosphatidylcholine (DLPC), palmitoyloleoylphosphatidylcholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 diether PC), 1-oleoyl-2-cholestyrene hemisuccinyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Phosphatidylethanolamines such as dioleoylphosphatidylethanolamine (DOPE), distearoylphosphatidylethanolamine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphatidylethanolamine (DMPE), dilauroylphosphatidylethanolamine (DLPE), diphytylphosphatidylethanolamine (DPyPE), 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine (DOPG), 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), N-palmitoyl-D-erythro-sphingosinephosphatidylcholine (SM). In some embodiments, the helper lipid is selected from the group consisting of DSPC, DOPC, DMPC, DPPC, POPC, DOPE, DOPG, DPPG, POPE, DPPE, DMPE, DSPE and SM. In some embodiments, the neutral lipid is selected from the group consisting of DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM. In some embodiments, the neutral lipid is DSPC.

[0301] The helper lipids may be synthetic or naturally derived. Other helper lipids suitable for use in lipid nanoparticles are described in WO 2021 / 026358, WO 2017 / 075531 and WO 2018 / 081480, the entire contents of each of which are incorporated herein by reference in their entirety.

[0302] In some embodiments, the lipid nanoparticles comprise about 5 to about 15 mol% phospholipids. In some embodiments, the lipid nanoparticles comprise about 8 to about 12 mol% phospholipids. In some embodiments, the lipid nanoparticles comprise about 10 mol% phospholipids. In some embodiments, the lipid nanoparticles comprise about 5 to about 15 mol% DSPC. In some embodiments, the lipid nanoparticles comprise about 8 to about 12 mol% DSPC. In some embodiments, the lipid nanoparticles comprise about 10 mol% DSPC.

[0303] polymer-conjugated lipids

[0304] As described herein, LNP of the present disclosure includes polymer conjugated lipids. In some embodiments, polymer conjugated lipids are lipids (PEG-lipids) conjugated to polyethylene glycol. In some embodiments, PEG lipids are selected from PEGylated diacylglycerols (PEG-DAG) such as 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoyl glycerol (PEG-DMG) (for example, 1,2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol-2000 (PEG2000-DMG)), PEGylated phosphatidylethanolamine (PEG-PE), PEG succinic acid diacylglycerols (PEG-S-DAG) such as 4-O-(2', 3'-di-tetradecanoyloxy) propyl-1-O-(ω -methoxy(polyethoxy)ethyl)succinate (PEG-S-DMG), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000 amine), PEGylated ceramide (PEG-cer), or PEG dialkoxypropyl carbamates such as ω-methoxy(polyethoxy)ethyl-N-(2,3-di(tetradecyloxy)propyl)carbamate and 2,3-di(tetradecyloxy)propyl-N-(ωmethoxy(polyethoxy)ethyl)carbamate.

[0305] In some embodiments, the PEG-lipid is PEG2000-DMG:

[0306]

[0307] In some embodiments, the PEG-lipid is DMG-PEG.

[0308] In some embodiments, the PEG-lipids are provided in WO 2021 / 026358, WO 2017 / 075531, or WO 2018 / 081480, each of which is incorporated by reference in its entirety.

[0309] In some embodiments, the PEG lipid is a compound of Formula II:

[0310]

[0311] or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 Each is independently C 10 -C 30 aliphatic, optionally interrupted by one or more ester bonds, and w is an integer from 30 to 60.

[0312] As described in this article, R 8 and R 9 Each is independently C 10 -C 30 aliphatic, optionally interrupted by one or more ester bonds. 8 and R 9 Each is independently C 10 -C 30 In some embodiments, R 8 and R 9 Each independently selected from C 12 -C 16 In some embodiments, R 8 and R 9 Each independently selected from C 12 -C 16 In some embodiments, R 8 and R 9 Each independently selected from a linear C 12 -C 16 In some embodiments, w is an integer from 40 to 50. In some embodiments, w is from 45 to 47. In some embodiments, w is 45.

[0313] In some embodiments, the compound of Formula II is 2-[(polyethylene glycol)-2000]-N,N-di(tetradecyl)acetamide (ALC-0159). In some embodiments, the compound of Formula II is:

[0314]

[0315] or a pharmaceutically acceptable salt thereof, wherein n′ is an integer from about 45 to about 50.

[0316] In some embodiments, the PEG-lipid has the following structure:

[0317]

[0318] wherein the average value of n ranges from 30 to 60, such as about 50. In one embodiment, the PEG-conjugated lipid (PEGylated lipid) is PEG 2000 -C-DMA, which preferably refers to 3-N-[(ω-methoxypoly(ethylene glycol) 2000)carbamoyl]-1,2-dimyristyloxy-propylamine (MPEG-(2kDa)-C-DMA) or methoxy-polyethylene glycol-2,3-bis(tetradecyloxy)propylcarbamate (2000).

[0319] In some embodiments, the PEG-lipid is selected from PEG-DAG, PEG-PE, PEG-S-DAG, PEG2000-DMG, PEG-S-DMG, PEG-cer, PEG dialkoxypropyl carbamate (e.g., ω-methoxy(polyethoxy)ethyl-N-(2,3-di-tetradecyloxy)propyl)carbamate or 2,3-di-tetradecyloxy)propyl-N-(ω-methoxy(polyethoxy)ethyl)carbamate), ALC-0159, and combinations thereof. In some embodiments, the PEG-lipid is ALC-0159 or PEG2000-DMG. In some embodiments, the PEG-lipid is ALC-0159. In some embodiments, the PEG-lipid is PEG2000-DMG. In some embodiments, the PEG-lipid is PEG-DAG. In some embodiments, the PEG-lipid is PEG-PE. In some embodiments, the PEG-lipid is PEG-S-DAG. In some embodiments, the PEG-lipid is PEG-cer. In some embodiments, the PEG-lipid is PEG dialkoxypropyl carbamate.

[0320] In some embodiments, the PEG group that is part of the PEG-lipid has an average number average molecular weight (M) of about 2000 g / mol in a composition comprising one or more PEG-lipid molecules. n ).

[0321] In some embodiments, the polymer-conjugated lipid is a polysarcosine-conjugated lipid, also referred to herein as a sarcosinate lipid or pSar-lipid. The term "sarcosinate lipid" refers to a molecule comprising a lipid portion and a polysarcosine (poly(N-methylglycine)) portion.

[0322] In some embodiments, the polymer-conjugated lipid is a polyoxazoline (POX)-conjugated lipid and / or a polyoxazine (POZ)-conjugated lipid, also referred to herein as a conjugate of a POX and / or POZ polymer with one or more hydrophobic chains or an oxazolinylated and / or oxazinylated lipid or a POX-lipid and / or POZ-lipid. The term "oxazolinylated lipid" or "POX-lipid" refers to a molecule comprising a lipid portion and a polyoxazoline portion. The term "oxazinylated lipid" or "POZ-lipid" refers to a molecule comprising a lipid portion and a polyoxazine portion. The term "oxazolinylated / oxazinylated lipid" or "POX / POZ-lipid" or "POXZ-lipid" refers to a molecule comprising a lipid portion and a copolymer portion of a polyoxazoline and a polyoxazine.

[0323] In some embodiments, LNP as described herein may comprise sarcosinate lipids.In some embodiments, nucleic acid compositions as described herein (such as DNA or RNA compositions, especially mRNA compositions) comprise sarcosinate lipids and are substantially free of PEGylated lipids (or free of PEGylated lipids).

[0324] In some embodiments, nucleic acid compositions described herein (such as DNA or RNA compositions, especially mRNA compositions) comprise cations / cationic ionizable lipids and sarcosinate lipids (pSAR conjugated lipids) as described herein. In some embodiments, nucleic acid compositions described herein (such as DNA or RNA compositions, especially mRNA compositions) may also comprise neutral lipids (e.g., phospholipids, cholesterol, or derivatives thereof) or a combination of neutral lipids (e.g., phospholipids and cholesterol, or derivatives thereof). In some embodiments, nucleic acid compositions described herein (such as DNA or RNA compositions, especially mRNA compositions) comprise cations / cationic ionizable lipids, sarcosinate lipids, neutral lipids (e.g., phospholipids), and cholesterol, or derivatives thereof, as described herein. In some embodiments, the phospholipid is DSPC. In some embodiments, the cation / cationic ionizable lipid is a cationic ionizable lipid of formula (X) (such as a cationic ionizable lipid of formula (X-3) or (X-45)). In some embodiments, the cation / cationically ionizable lipid is a cationically ionizable lipid of formula (XI) (such as a cationically ionizable lipid of formula (XIV-1), (XIV-2), or (XIV-3). In some embodiments, the cation / cationically ionizable lipid is DPL14, EA-2, or 3D-P-DMA.

[0325] In some embodiments of the nucleic acid compositions described herein (such as DNA or RNA compositions, particularly mRNA compositions) that comprise sarcosinated lipids, the compositions are substantially free of PEGylated lipids (or contain no PEGylated lipids).

[0326] In some embodiments, the sarcosinated lipid comprises between 2 and 200 sarcosine units, such as between 5 and 100 sarcosine units, between 10 and 50 sarcosine units, between 15 and 40 sarcosine units, for example about 23 sarcosine units.

[0327] In some embodiments, the sarcosinated lipid comprises the following structure of Formula (XVII):

[0328]

[0329] where s is the number of sarcosine units.

[0330] In some embodiments, the sarcosinated lipid comprises the following structure of Formula (XVIII):

[0331]

[0332] where R 21 and R 22 One of them comprises a hydrophobic group, while the other is H, a hydrophilic group, or optionally comprises a functional group of a targeting moiety; and x is the number of sarcosine units.

[0333] In some embodiments of Formula (XVIII), R 21 is H, a hydrophilic group or a functional group optionally comprising a targeting moiety; and R 22 In some embodiments, R comprises one or two straight chain alkyl or alkenyl groups, each having at least 12 carbon atoms, such as at least 14 carbon atoms. In some embodiments, each of the straight chain alkyl and alkenyl groups has up to 30 carbon atoms, such as up to 28, up to 26, up to 24, up to 22, up to 20, or up to 18 carbon atoms. 22 Contains one or two straight-chain alkyl or alkenyl groups, each having 12 to 30 carbon atoms (such as 12 to 28 carbon atoms, 12 to 26 carbon atoms, 12 to 24 carbon atoms, 12 to 22 carbon atoms, 12 to 20 carbon atoms, or 12 to 18 carbon atoms).

[0334] In some embodiments, the sarcosinated lipid has the structure of the following general formula (IXX):

[0335]

[0336] wherein R is H, a hydrophilic group, or a functional group optionally comprising a targeting moiety; and s is the number of sarcosine units.

[0337] In some embodiments, the sarcosinated lipid has the structure of the following formula (IXX-1):

[0338]

[0339] wherein s1 is 23. The sarcosinated lipid of formula (IXX-1) is also referred to herein as "C14pSar23."

[0340] In some embodiments, the LNP herein may comprise oxazolinyl and / or oxazinyl lipids. In some embodiments, nucleic acid compositions as described herein (such as DNA or RNA compositions, especially mRNA compositions) comprise oxazolinyl and / or oxazinyl lipids and are substantially free of PEGylated lipids (or free of PEGylated lipids).

[0341] In some embodiments, nucleic acid compositions described herein (such as DNA or RNA compositions, especially mRNA compositions) comprise cations / cationic ionizable lipids and oxazolinyl and / or oxazinyl lipids (POX and / or POZ-conjugated lipids) as described herein. In some embodiments, nucleic acid compositions described herein (such as DNA or RNA compositions, especially mRNA compositions) may also comprise neutral lipids (e.g., phospholipids, cholesterol, or derivatives thereof) or a combination of neutral lipids (e.g., phospholipids and cholesterol, or derivatives thereof). In some embodiments, nucleic acid compositions described herein (such as DNA or RNA compositions, especially mRNA compositions) comprise cations / cationic ionizable lipids, oxazolinyl and / or oxazinyl lipids, neutral lipids (e.g., phospholipids), and cholesterol, or derivatives thereof, as described herein. In some embodiments, the phospholipid is DSPC. In some embodiments, the cation / cationic ionizable lipid is a cation ionizable lipid of formula (X) (such as a cation ionizable lipid of formula (X-3) or (X-45)). In some embodiments, the cation / cationically ionizable lipid is a cationically ionizable lipid of formula (XI) (such as a cationically ionizable lipid of formula (XIV-1), (XIV-2), or (XIV-3)). In some embodiments, the cation / cationically ionizable lipid is DPL14, EA-2, or 3D-P-DMA. In some embodiments of the nucleic acid compositions described herein (such as DNA or RNA compositions, particularly mRNA compositions) comprising oxazolinylated and / or oxazinylated lipids, the composition is substantially free of PEGylated lipids (or free of PEGylated lipids).

[0342] In some embodiments, in the oxazolinylated and / or oxazinylated lipids (i.e., conjugates comprising (i) a POX and / or POZ polymer and (ii) one or more hydrophobic chains), components (i) and (ii) are linked to each other via a linker comprising at least one functional moiety. In some embodiments, the linker comprises an alkylene moiety substituted with at least one monovalent functional moiety. In some embodiments, the linker comprises an alkylene moiety and a divalent functional moiety, wherein the divalent functional moiety links the alkylene to the one or more hydrophobic chains, and the alkylene is linked to the POX and / or POZ polymer. In some embodiments, the linker comprises an alkylene moiety and a divalent functional moiety, wherein the divalent functional moiety links the alkylene to the one or more hydrophobic chains, the alkylene is substituted with at least one monovalent functional moiety, and the alkylene is linked to the POX and / or POZ polymer.

[0343] In some embodiments of the oxazolinylated and / or oxazinylated lipids, each monovalent functional moiety is independently selected from hydroxyl, ether, halogen, cyano, azide, nitro, amino, ammonium, ester, carboxyl, thiol (sulfanyl), disulfanyl, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfenamide, sulfonamide, sulfamate, diselenide, sulfurous acid diamide, diamide), sulfuric acid diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioester, dithioester, imidoester, imino, iminothioester, sulfonamido, carbonate, thiocarbonate, dithiocarbonate, trithiocarbonate, guanidino (imino), carbamimidate, carbonimidate, carbamate, dithiocarbamate, carbonodithioimidate, carbamimidothioester, thiocarbamate, carbonimidothioester, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imide, and amide moieties.

[0344] In some embodiments of the oxazolinylated and / or oxazinylated lipids, each divalent functional moiety is independently selected from an ether, an amino, an ester, a sulfide, a disulfide, a sulfoxide, a sulfone, a sulfite, a sulfate, a phosphate, a sulfenamide, a sulfonamide, a sulfamate, a diselenide, a sulfenamide, a sulfenamide, a urea, a thiourea, a carbonyl, a thiocarbonyl, an orthoester, a thioester, a dithioester, an imidoester, an imino, an iminothioester, a sulfinamido, a carbonate, a thiocarbonate, a dithiocarbonate, a trithiocarbonate, a guanidino(imino), a carbamidoester, a carbamidoester, a carbamate, a dithiocarbamate, a carbodithioimide ester, a carbamidothioester, a thiocarbamate, a carbodithioimide ester, a carbamidothioester, a thiocarbamate, a carbomidothioester, an acylhydrazone, a hydrazine, an oxime, an acetal, a hemiacetal, a ketal, a hemiketal, an imine, an imide, and an amide moiety.

[0345] In some embodiments, the oxazolinylated and / or oxazinylated lipid comprises one of the following structures (particularly if one or more hydrophobic chains are attached to the N-terminus (i.e., the terminal N atom) of the POX and / or POZ polymer, for example as shown herein in Formula (XXI)):

[0346] (Hydrophobic chain) 1-2 -(alkylene moiety substituted with at least one monovalent functional moiety)-(POX and / or POZ polymer)

[0347] [(Hydrophobic chain)-(Divalent functional part)] 1-2 -(alkylene moiety)-(POX and / or POZ polymer).

[0348] In some embodiments, the oxazolinylated and / or oxazinylated lipid has one of the following formulae (particularly if one or more hydrophobic chains are attached to the N-terminus (i.e., the terminal N atom) of the POX and / or POZ polymer, e.g., as shown herein below in Formula (XXI)):

[0349] (Hydrophobic chain) 1-2 -(alkylene moiety substituted with at least one monovalent functional moiety)-(POX and / or POZ polymer)-(terminal group)

[0350] [(Hydrophobic chain)-(Divalent functional part)] 1-2 -(alkylene moiety)-(POX and / or POZ polymer)-(terminal group).

[0351] In some embodiments of the oxazolinylated and / or oxazinylated lipids, the alkylene moiety substituted with at least one monovalent functional moiety is substituted with one or more (such as from 1 to the maximum number of hydrogen atoms bound to the alkylene moiety, e.g., 1, 2, 3, 4, 5, or 6, such as from 1 to 5, from 1 to 4, or from 1 to 3, or from 1 to 2) independently selected monovalent functional moieties.

[0352] In some embodiments of the oxazolinylated and / or oxazinylated lipids, the alkylene moiety is C 1-6 Alkylene, such as C 1-3 Alkylene, such as methylene, ethylene or trimethylene.

[0353] In some embodiments (particularly those in which the one or more hydrophobic chains are attached to the C-terminus (i.e., the terminal C atom) of the POX and / or POZ polymer, such as those depicted herein as Formula (XXI'), the linker comprises at least one bifunctional moiety through which the one or more hydrophobic chains are attached to the POX and / or POZ polymer. In some embodiments, the linker may further comprise an alkylene moiety (such as a C 1-6 Alkylene moieties, such as C 1-3 Alkylene moiety), cycloalkylene moiety (preferably C 3-8 -cycloalkylene, such as C 3-6 -cycloalkylene moiety), or cycloalkenylene moiety (preferably C 3-8 -cycloalkenylene, such as C 3-6-cycloalkenylene moieties), each of which links a bifunctional moiety to the POX and / or POZ polymer (directly to a terminus of the POX and / or POZ polymer or, preferably, through another bifunctional moiety). For example, one hydrophobic chain can be linked to the terminus of the POX and / or POZ polymer via one bifunctional moiety (directly or via an alkylene, cycloalkylene, or cycloalkenylene moiety or via an alkylene, cycloalkylene, or cycloalkenylene moiety with another bifunctional moiety); two hydrophobic chains can be linked to the terminus of the POX and / or POZ polymer via two bifunctional moieties (which in turn are preferably linked to an alkylene, cycloalkylene, or cycloalkenylene moiety or to an alkylene, cycloalkylene, or cycloalkenylene moiety with another bifunctional moiety); or two hydrophobic chains can be linked to the terminus of the POX and / or POZ polymer via the same bifunctional moiety (which is then followed by a trifunctional moiety and can be linked to the terminus of the POX and / or POZ polymer directly or via an alkylene, cycloalkylene, or cycloalkenylene moiety or to an alkylene, cycloalkylene, or cycloalkenylene moiety with another bifunctional moiety). In some embodiments, each divalent functional moiety is independently selected from ether, amino, ester, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfenamide, sulfonamide, sulfamate, diselenide, sulfurous acid diamide, sulfurous acid diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioester, dithioester, imidoester, imino, iminothioester, sulfonamido, carbonate, thiocarbonate, dithiocarbonate, trithiocarbonate, guanidino (imino), carbamoyl ester, carbomiyl ester, carbamate, dithiocarbamate, carbodithioimide ester, carbamoyl thioester, thiocarbamate, carbomiyl thioester, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imine, imide, and amide moieties.

[0354] In some embodiments of the oxazolinylated and / or oxazinylated lipids, the cycloalkylene moiety is C 3-8 -cycloalkylene, such as C 3-6 Cycloalkylene, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, wherein the cycloalkylene portion is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents (e.g., independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl) substituted.

[0355] In some embodiments of the oxazolinylated and / or oxazinylated lipids, the cycloalkenylene moiety is C 3-8 -cycloalkenylene, such as C 3-6-cycloalkenylene, such as cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, wherein the cycloalkenylene portion is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents (e.g., independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl) substituted.

[0356] In some embodiments of the oxazolinylated and / or oxazinylated lipids, the alkylene moiety is C 1-6 -alkylene, such as C 1-3 -alkylene, such as methylene, ethylene or trimethylene, or C 2-3 Alkylene.

[0357] In some embodiments (particularly those in which one or more hydrophobic chains are attached to the C-terminus (i.e., the terminal C atom) of the POX and / or POZ polymer, such as those shown herein below in Formula (XXI'), the oxazolinylated and / or oxazinylated lipid comprises one of the following structures (and may have the general formula (XXI')):

[0358] (Hydrophobic chain)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0359] [(Hydrophobic chain)-(Divalent functional part)] 1-2 -(Alkylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0360] (Hydrophobic chain)-(Divalent functional moiety)-(Cycloalkylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0361] (Hydrophobic chain)-(Divalent functional moiety)-(Cycloalkenylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0362] (Hydrophobic chain)-(Divalent functional moiety)-(Alkylene moiety)-(POX and / or POZ polymer)

[0363] [(Hydrophobic chain)2-(Trivalent functional moiety)]-(Alkylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0364] In some embodiments (particularly those in which one or more hydrophobic chains are attached to the C-terminus (i.e., the terminal C atom) of the POX and / or POZ polymer, such as those shown herein below in Formula (XXI'), the oxazolinylated and / or oxazinylated lipid has one of the following formulae (and may be of the general formula (XXI')):

[0365] (Hydrophobic chain)-(Divalent functional moiety)-(POX and / or POZ polymer)-(Terminal group)

[0366] [(Hydrophobic chain)-(Divalent functional part)] 1-2 -(Alkylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)-(Terminal group)

[0367] (Hydrophobic chain)-(Divalent functional moiety)-(Cycloalkylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)-(Terminal group)

[0368] (Hydrophobic chain)-(Divalent functional moiety)-(Cycloalkenylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)-(Terminal group)

[0369] (Hydrophobic chain)-(Divalent functional moiety)-(Alkylene moiety)-(POX and / or POZ polymer)-(Terminal group)

[0370] [(Hydrophobic chain)2-(Trivalent functional moiety)]-(Alkylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)-(Terminal group)

[0371] The POX and / or POZ polymers may comprise neutral end groups (such as H, alkyl, alkoxy, ester or amide end groups) or functionalized end groups (e.g., hydroxyl, thiol, cyano, azido or amino end groups). In the case of nucleic acid-lipid particles, the POX and / or POZ polymers are conjugated to (preferably covalently bound to) one or more hydrophobic chains.

[0372] In certain embodiments of oxazolinylated and / or oxazinylated lipids, the terminal groups of the POX and / or POZ polymers can be functionalized with one or more molecular moieties that impart certain properties (such as positive or negative charge) or targeting agents that direct the particle to a specific cell type, cell collection, or tissue.

[0373] A variety of suitable targeting agents are known in the art. Non-limiting examples of targeting agents include peptides, proteins, enzymes, nucleic acids, fatty acids, hormones, antibodies, carbohydrates, monosaccharides, oligosaccharides or polysaccharides, peptidoglycans, glycopeptides, and the like. In some embodiments, the targeting agent includes a targeting pair, such as the following pairs: antigen-antibody specific for the antigen; avidin-streptavidin; folate-folate receptor; transferrin-transferrin receptor; aptamer-molecule to which the aptamer is specific (e.g., pegaptanib-VEGF receptor); arginine-glycine-aspartic acid (RGD) peptide-α vβ3 integrin; asparagine-glycine-arginine (NGR) peptide-aminopeptidase N; galactose-asialoglycoprotein receptor. For example, any of a variety of different materials that bind to antigens on the surface of target cells can be used. Antibodies to target cell surface antigens will generally exhibit the necessary specificity for the target. In addition to antibodies, suitable immunoreactive fragments such as Fab, Fab', F(ab')2 or scFv fragments or single domain antibodies (e.g., Camelidae V H H fragments). Many antibody fragments suitable for forming targeting mechanisms exist in the art. Similarly, any ligand for a receptor on the target cell surface can be suitably used as a targeting agent. These include any natural or synthetic small molecule or biomolecule that specifically binds to a cell surface receptor, protein or glycoprotein present on the desired target cell surface.

[0374] In certain embodiments of the oxazolinylated and / or oxazinylated lipids, the POX and / or POZ polymer comprises between 2 and 200, between 2 and 190, between 2 and 180, between 2 and 170, between 2 and 160, between 2 and 150, between 2 and 140, between 2 and 130, between 2 and 120, between 2 and 110, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 5 and 200, between 5 and 190, between 5 and 180, between 5 and 170, between 5 and 160, between 5 and 150, between 5 and 140, between 2 and 130, between 2 and 120, between 2 and 110, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 5 and 200, between 5 and 190, between 5 and 180, between 5 and 170, between 5 and 160, between 5 and 150, between 5 and 1 In some embodiments, the present invention comprises between 10 to 40, 10 to 130, 10 to 120, 10 to 110, 10 to 100, 10 to 90, 10 to 80, 10 to 70, 10 to 200, 10 to 190, 10 to 180, 10 to 170, 10 to 160, 10 to 150, 10 to 140, 10 to 130, 10 to 120, 10 to 110, 10 to 100, 10 to 90, 10 to 80 or 10 to 70 POX and / or POZ repeating units.

[0375] In some embodiments, the POX and / or POZ polymer in the oxazolinylated and / or oxazinylated lipid comprises the following general formula (XX):

[0376]

[0377] Where a is an integer between 1 and 2; R 11 is an alkyl group, especially C 1-3 Alkyl, such as methyl, ethyl, isopropyl or n-propyl, is independently selected for each repeat unit; and m refers to the number of POX and / or POZ repeat units.

[0378] In some embodiments of the oxazolinylated and / or oxazinylated lipids, the POX and / or POZ polymer is a polymer of POX and comprises repeating units of the following general formula (XXa):

[0379]

[0380] In some embodiments of the oxazolinylated and / or oxazinylated lipids, the POX and / or POZ polymer is a polymer of POZ and comprises repeating units of the following general formula (XXb):

[0381]

[0382] In any of the above embodiments of formula (XX), (XXa) and (XXb), m (i.e., the number of repeating units of formula (XXa) or formula (XXb) in the polymer) is preferably between 2 and 190, such as between 2 and 180, between 2 and 170, between 2 and 160, between 2 and 150, between 2 and 140, between 2 and 130, between 2 and 120, between 2 and 110, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 5 and 200, between 5 and 190, between 5 and 180, between 5 and 170, between 5 and 180, between 5 and 190, between 5 and 20 ... between 5 and 160, between 5 and 150, between 5 and 140, between 5 and 130, between 5 and 120, between 5 and 110, between 5 and 100, between 5 and 90, between 5 and 80, between 5 and 70, between 10 and 200, between 10 and 190, between 10 and 180, between 10 and 170, between 10 and 160, between 10 and 150, between 10 and 140, between 10 and 130, between 10 and 120, between 10 and 110, between 10 and 100, between 10 and 90, between 10 and 80, or between 10 and 70. In certain embodiments of any of the above embodiments of formulae (XX), (XXa), and (XXb), m is 2 to 180, such as 4 to 160, 6 to 140, 8 to 120, or 10 to 100, e.g., 20 to 80, 30 to 70, or 40 to 50.

[0383] In some embodiments of the oxazolinylated and / or oxazinylated lipids, the POX and / or POZ polymer is a polymer comprising repeating units of the following general formulae (XXa) and (XXb):

[0384]

[0385] wherein the number of repeating units of formula (XXa) in the copolymer is 1 to 199; the number of repeating units of formula (XXb) in the copolymer is 1 to 199; and the sum of the number of repeating units of formula (XXa) and the number of repeating units of formula (XXb) in the copolymer is 2 to 200.

[0386] In some embodiments of the oxazolinated and / or oxazinated lipids, the number of repeating units of formula (XXa) in the copolymer is 1 to 179, such as 1 to 159, 1 to 139, 1 to 119 or 1 to 99; the number of repeating units of formula (XXb) in the copolymer is 1 to 179, such as 1 to 159, 1 to 139, 1 to 119 or 1 to 99; and the sum of the number of repeating units of formula (XXa) and the number of repeating units of formula (XXb) in the copolymer is 2 to 180, such as 4 to 160, 6 to 140, 8 to 120 or 10 to 100, for example 20 to 80, 30 to 70 or 40 to 50.

[0387] In some of the above embodiments of Formulas (XX), (XXa), and (XXb), R 11 The alkyl group may be the same at each occurrence (ie, in each repeat unit) (eg, R 11 In some alternative embodiments of formula (XX), (XXa) and (XXb), R in at least one repeating unit may be methyl. 11 With another repeating unit R 11 different (e.g., for at least one repeating unit, R 11 is a specific alkyl group (such as ethyl), and for at least one different repeating unit, R 11 are different specific alkyl groups (such as methyl). For example, each R 11 can be selected from two different alkyl groups (such as methyl and ethyl), and not all R 11 All are the same alkyl group.

[0388] In any of the above embodiments of Formula (XX), (XXa), and (XXb), R 11 Preferably, it is methyl or ethyl, more preferably methyl. Thus, in some embodiments of formula (XX), (XXa) and (XXb), each R 11 are all methyl or each R 11 In some alternative embodiments of formula (XX), (XXa) and (XXb), for each repeating unit, R 11 are independently selected from methyl and ethyl, wherein in at least one repeating unit, R 11 is methyl, and in at least one repeating unit, R 11 It's ethyl.

[0389] In some embodiments, the oxazolinylated and / or oxazinylated lipid has the following general formula (XXI) or (XXI'):

[0390]

[0391] in:

[0392] a is an integer between 1 and 2;

[0393] R 11 is an alkyl group, especially C 1-3 Alkyl, such as methyl, ethyl, isopropyl, or n-propyl, and is independently selected for each repeating unit;

[0394] m is 2 to 200;

[0395] R 12 It is R 14 or -L 11 (R 14 ) p , where each R 14 are independently hydrocarbon groups; L 11 is a linker; and p is 1 or 2; and

[0396] R 13 Selected from the group consisting of: H, C 1-6 Alkyl, C 2-6 Alkynyl, -OR 20 、-SR 20 、Halogen、-CN、-N3、-OC(O)R 21 、-C(O)R 21 、-NR 22 R 23 、-COOH、-C(O)NR 22 R 23 、-NR 22 C(O)R 21 , sugars, amino acids, peptides, and members of targeting pairs, wherein C 1-6 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NR 22 R 23 、-C(O)NR 22 R 23 、-NR 22 C(O)R 21 , sugars, amino acids, peptides, and members of targeting pairs; R 20 Selected from the group consisting of: H, C 1-3 Alkyl and 3 to 6 membered heterocyclic groups, wherein C 1-3Each of the alkyl and 3 to 6 membered heterocyclic groups is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NR 22 R 23 , sugars, amino acids, peptides, and members of targeting pairs; R 21 Choose from C 1-6 The group consisting of an alkyl group and a 3- to 6-membered heterocyclic group, wherein C 1-6 Each of the alkyl and 3 to 6 membered heterocyclic groups is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NR 22 R 23 , sugars, amino acids, peptides, and members of targeting pairs; and R 22 and R 23 Each of R is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R 22 and R 23 can be joined together with the nitrogen atom to which they are attached to form a heterocyclic group, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl) 2, sugars, amino acids, peptides and members of targeting pairs. In formula (XXI), R 12 is attached to the N-terminus (ie, the terminal N atom) of the POX and / or POZ polymer, and R 13 is connected to the C-terminus (ie, the terminal C atom) of the POX and / or POZ polymer, and in Formula (XXI'), R 12 is attached to the C-terminus (ie, the terminal C atom) of the POX and / or POZ polymer, and R 13 Attached to the N-terminus (ie, the terminal N atom) of the POX and / or POZ polymer.

[0397] In some embodiments (particularly embodiments of oxazolinylated and / or oxazinylated lipids of formula (XXI) and (XXI')), the targeting pair is selected from the following pairs: antigen-antibody specific for the antigen; avidin-streptavidin; folate-folate receptor; transferrin-transferrin receptor; aptamer-molecule for which the aptamer is specific; arginine-glycine-aspartic acid (RGD) peptide-α vβ3 integrin; asparagine-glycine-arginine (NGR) peptide-aminopeptidase N; galactose-asialoglycoprotein receptor. Thus, in some embodiments, the members of the targeting pair include one of the following: antigen, antibody, avidin, streptavidin, folic acid, transferrin, aptamer; RGD peptide; NGR peptide; and galactose.

[0398] In some embodiments of Formula (XXI), a is 1, ie, the oxazolinated and / or oxazinated lipid has the following general formula (XXIa) or (XXIa'):

[0399]

[0400] In some embodiments of Formula (XXI), a is 2, ie, the oxazolinated and / or oxazinated lipid has the following general formula (XXIb) or (XXIb'):

[0401]

[0402] In any of the above embodiments of Formula (XXIa), (XXIa'), (XXIb), and (XXIb'), R 11 、R 12 、R 13 and m are as defined for formula (XXI) / (XXI').

[0403] In some of the above embodiments of Formula (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), and (XXIb'), R 11 The alkyl group may be the same at each occurrence (ie, in each repeat unit) (eg, R 11 In some alternative embodiments of Formulas (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), and (XXIb'), R in at least one repeating unit is 11 With another repeating unit R 11 different (e.g., for at least one repeating unit, R 11 is a specific alkyl group (such as ethyl), and for at least one different repeating unit, R 11 are different specific alkyl groups (such as methyl). For example, each R 11 can be selected from two different alkyl groups (such as methyl and ethyl), and not all R 11 All are the same alkyl group.

[0404] In any of the above embodiments of Formula (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), and (XXIb'), R 11Preferably, it is methyl or ethyl, more preferably methyl. Thus, in some embodiments of Formula (XXI), (XXI'), (XXIa), (XXIa'), (XXIb) and (XXIb'), each R 11 are all methyl or each R 11 In some alternative embodiments of Formulas (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), and (XXIb'), for each repeating unit, R 11 are independently selected from methyl and ethyl, wherein in at least one repeating unit, R 11 is methyl, and in at least one repeating unit, R 11 It's ethyl.

[0405] In any of the above embodiments of Formula (XXI), (XXI'), (XXIa), (XXIa'), (XXIb) and (XXIb'), m is preferably between 2 and 190, such as between 2 and 180, between 2 and 170, between 2 and 160, between 2 and 150, between 2 and 140, between 2 and 130, between 2 and 120, between 2 and 110, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 5 and 200, between 5 and 190, between 5 and 180, between 5 and 170, between 5 and 1 between 5 and 150, between 5 and 140, between 5 and 130, between 5 and 120, between 5 and 110, between 5 and 100, between 5 and 90, between 5 and 80, between 5 and 70, between 10 and 200, between 10 and 190, between 10 and 180, between 10 and 170, between 10 and 160, between 10 and 150, between 10 and 140, between 10 and 130, between 10 and 120, between 10 and 110, between 10 and 100, between 10 and 90, between 10 and 80, or between 10 and 70. In certain embodiments of Formula (XXI), (XXI′), (XXIa), (XXIa′), (XXIb), and (XXIb′), m is 2 to 180, such as 4 to 160, 6 to 140, 8 to 120, or 10 to 100, for example 20 to 80, 30 to 70, or 40 to 50.

[0406] In some embodiments of Formula (XXI), (XXI'), (XXIIa), (XXIa'), (XXIb), and (XXIb'), L 11 Contains at least one functional moiety, such as substituted with at least one monovalent functional moiety and / or in an alkylene group and R 14The terminal end of the linkage is connected to an alkylene moiety of a divalent functional moiety, wherein preferably each monovalent functional moiety is independently selected from hydroxy, ether, halogen, cyano, azide, nitro, amino, ammonium, ester, carboxyl, thiol (sulfanyl), disulfanyl, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfenamide, sulfonamide, sulfamate, diselenide, sulfurous acid diamide (sulfurous acid diamide), diamide), sulfuric acid diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioester, dithioester, imidoester, imino, iminothioester, sulfinamido, carbonate, thiocarbonate, dithiocarbonate, trithiocarbonate, guanidino (imino), carbamoyl ester, carbamoyl ester, carbamate, dithiocarbamate, carbodithioimino ester, carbamoylthioester, thiocarbamate, carbodithioimino ester, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imide and amide; and / or each divalent functional moiety is independently selected from ether, amino, ester, sulfide, disulfide, sulfoxide, Sulfone, sulfite, sulfate, phosphate, sulfenamide, sulfonamide, sulfamate, diselenide, sulfodiamide, sulfuric acid diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioester, dithioester, imidoester, imino, iminothioester, sulfonamido, carbonate, thiocarbonate, dithiocarbonate, trithiocarbonate, guanidino (imino), carbamoyl ester, carbomilide ester, carbamate, dithiocarbamate, carbodithioimide ester, carbamoyl thioester, thiocarbamate, carbomilide thioester, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imine, imide and amide.

[0407] In some embodiments of Formula (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), and (XXIb'), L 11 comprising an alkylene moiety substituted with at least one monovalent functional moiety as specified above. Thus, in some embodiments, the oxazolinylated and / or oxazinylated lipid may comprise the following structure (particularly if one or more hydrophobic chains are attached to the N-terminus (i.e., the terminal N atom) of the POX and / or POZ polymer, for example as shown in formula (XXI)):

[0408] (Hydrophobic chain) 1-2 -(alkylene moiety substituted with at least one monovalent functional moiety)-(POX and / or POZ polymer),

[0409] Wherein "hydrophobic chain" represents R 14 ; "alkylene moiety substituted with at least one monovalent functional moiety" means L 11; and "POX and / or POZ polymer" means the polymer specified in formula (XX).

[0410] In some embodiments, the oxazolinylated and / or oxazinylated lipid has the following formula (XXIc) (particularly if one or more hydrophobic chains are attached to the N-terminus (i.e., the terminal N atom) of the POX and / or POZ polymer, for example as shown in formula (XXI)):

[0411] (Hydrophobic chain) 1-2 -(alkylene moiety substituted with at least one monovalent functional moiety)-(POX and / or POZ polymer)-R 13

[0412] In some embodiments (particularly embodiments of oxazolinylated and / or oxazinylated lipids of formula (XXIc)), at least one monovalent functional moiety can be any of the monovalent functional moieties specified herein, for example, selected from the group consisting of: hydroxyl, ether, halogen, cyano, azido, nitro, amino, ammonium, ester, carboxyl, thiol (sulfanyl), disulfanyl, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfenamide, sulfonamide, sulfamate, diselenide, disulfide, sulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfenamide, sulfonamide, sulfamate, diselenide, disulfide, sulfonamide, diselenide ... Amide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioester, dithioester, imidoester, imino, iminothioester, sulfinamido, carbonate, thiocarbonate, dithiocarbonate, trithiocarbonate, guanidino (imino), carbamoyl ester, carbonamido ester, carbamate, dithiocarbamate, carbodithioimide ester, carbamoyl thioester, thiocarbamate, carbonamidothioester, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imide and amide.

[0413] In some embodiments (particularly embodiments of oxazolinylated and / or oxazinylated lipids of Formula (XXIc)), the alkylene moiety substituted with at least one monovalent functional moiety is C 1-6 -alkylene, such as C 1-3 - an alkylene group, such as a methylene group, an ethylene group or a trimethylene group.

[0414] In some embodiments (particularly embodiments of oxazolinylated and / or oxazinylated lipids of Formula (XXIc)), the alkylene moiety substituted with at least one monovalent functional moiety is substituted with one or more (such as from 1 to the maximum number of hydrogen atoms bound to the alkylene moiety, e.g., 1, 2, 3, 4, 5, or 6, such as between 1 and 5, between 1 and 4, or between 1 and 3, or between 1 or 2) independently selected monovalent functional moieties.

[0415] In some embodiments (particularly embodiments of oxazolinylated and / or oxazinylated lipids of Formula (XXIc)), the alkylene moiety substituted with at least one monovalent functional moiety is C 1-6 -alkylene, such as C 1-3 -alkylene, such as methylene, ethylene or trimethylene, and substituted with one or more (such as from 1 to the maximum number of hydrogen atoms bound to the alkylene moiety, for example 1, 2, 3, 4, 5 or 6, such as from 1 to 5, from 1 to 4, or from 1 to 3, or from 1 or 2) independently selected monovalent functional moieties.

[0416] In some embodiments of Formula (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), and (XXIb'), L 11 comprising an alkylene moiety linked to a divalent functional moiety as specified above, said alkylene being linked via a terminal end to R 14 Thus, in some embodiments, the oxazolinylated and / or oxazinylated lipids may include the following structures (particularly if one or more hydrophobic chains are attached to the N-terminus (i.e., the terminal N atom) of the POX and / or POZ polymer, for example as shown in Formula (XXI)):

[0417] [(Hydrophobic chain)-(Divalent functional part)] 1-2 -(alkylene moiety)-(POX and / or POZ polymer),

[0418] Wherein "hydrophobic chain" represents R 14 ; "-(divalent functional moiety)] 1-2 -(alkylene moiety)" represents L 11 ; and "POX and / or POZ polymer" means the polymer specified in formula (XX).

[0419] In some embodiments, the oxazolinylated and / or oxazinylated lipid has the following formula (XXId) (particularly if one or more hydrophobic chains are attached to the N-terminus (i.e., the terminal N atom) of the POX and / or POZ polymer, for example as shown in formula (XXI)):

[0420] [(Hydrophobic chain)-(Divalent functional part)] 1-2 -(alkylene moiety)-(POX and / or POZ polymer)-R 13

[0421] In some embodiments (particularly embodiments of oxazolinylated and / or oxazinylated lipids of formula (XXId)), the divalent functional moiety can be any of the divalent functional moieties specified herein, for example, selected from the group consisting of ether, amino, ester, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfenamide, sulfonamide, sulfamate, diselenide, sulfonamide, sulfuramide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, Thioester, dithioester, imidoester, imino, iminothioester, sulfonamido, carbonate, thiocarbonate, dithiocarbonate, trithiocarbonate, guanidine (imino), carbamoyl ester, carbonimido ester, carbamate, dithiocarbamate, carbondithioimino ester, carbamoyl thioester, thiocarbamate, carbonimidothioester, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imine, imide and amide. In some embodiments, the linker comprises at least one divalent functional part selected from the group consisting of: ester, sulfide, disulfide, sulfone, orthoester, acylhydrazone, hydrazine, oxime, acetal, ketal, amino and amide moiety. In some embodiments, the linker comprises at least one divalent functional part selected from the group consisting of: ester, sulfide, sulfone, amino and amide moiety.

[0422] In some embodiments (particularly embodiments of oxazolinylated and / or oxazinylated lipids of Formula (XXId)), the alkylene moiety is C 1-6 Alkylene, such as C 1-3 Alkylene, such as methylene, ethylene or trimethylene.

[0423] In some embodiments of Formulas (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), (XXIb'), (XXIc), and (XXId), particularly those in which one or more hydrophobic chains are attached to the N-terminus (i.e., the terminal N atom) of the POX and / or POZ polymers, such as those shown in Formula (XXI), L 11 Contains at least one ester, sulfide, disulfide, sulfone, orthoester, acylhydrazone, hydrazine, oxime, acetal, ketal, or amide moiety. In certain embodiments, L 11 Selected from the group consisting of: [*-NHC(O)] p (C 1-6 -alkylene), [*-C(O)NH] p (C 1-6 -alkylene)-, [*-C(O)O] p (C 1-6 -alkylene)-, [*-OC(O)] p -(C 1-6 -alkylene)-, [*-S]p (C 1-6 -alkylene)-, [*-SS] p (C 1-6 -alkylene)-, [*-S(O)2] p (C 1-6 -alkylene)-, [(*-O) r C(OR 25 ) 3-r ](C 1-6 -alkylene)-, [*-C(OR 25 )2O] p (C 1-6 -alkylene)-, [*-C(R 25 )(=NN(R 26 )C(O)-)] p (C 1-6 -alkylene)-, [*-C(O)(N(R 26 )-N=)C(R 25 )-] p (C 1-6 -alkylene)-, [*=C(=NN(R 26 )C(O)(R 25 ))] p (C 1-6 -alkylene)-, [*N(R 26 )N(R 26 )] p (C 1-6 -alkylene)-, [*=C(=N(OH))] p (C 1-6 -alkylene)- and [*-OC(R 25 )(R 26 )O] p (C 1-6 -alkylene)-, where * represents 14的 Connection point; p is 1 or 2; C 1-6 - alkylene is divalent (if p is 1) or trivalent (if p is 2); R 25 Choose from C 1-6 Alkyl, aryl and aryl-(C 1-6 alkyl) group; R 26 Choose from H, C 1-6 Alkyl, aryl and aryl (C 1-6 and r is an integer between 1 and 2. For example, L 11 Can be selected from the group consisting of: [*-NHC(O)] p (C 1-3 -alkylene)-, [*-C(O)NH] p (C1-3 -alkylene)-, [*-C(O)O] p (C 1-3 -alkylene)-, [*-OC(O)] p (C 1-3 -alkylene)-, [*-S] p (C 1-3 -alkylene)-, [*-SS] p (C 1-3 -alkylene)-, [*-S(O)2] p (C 1-3 -alkylene)-, [(*-O) r C(OR 25 ) 3-r ](C 1-3 -alkylene)-, [*-C(OR 25 )2O] p (C 1-3 -alkylene)-, [*-C(R 25 )(=NN(R 26 )C(O)-)] p (C 1-3 -alkylene)-, [*-C(O)(N(R 26 )-N=)C(R 25 )-] p (C 1-3 -alkylene)-, [*=C(=NN(R 26 )C(O)(R 25 ))] p (C 1-3 -alkylene)-, [*N(R 26 )N(R 26 )] p (C 1-3 -alkylene)-, [*=C(=N(OH))] p (C 1-3 -alkylene)- and [*-OC(R 25 )(R 26 )O] p (C 1-3 -alkylene)-, where * represents 14的 Connection point; p is 1 or 2; C 1-3 - alkylene is divalent (if p is 1) or trivalent (if p is 2); R 25 Choose from C 1-6 Alkyl, aryl and aryl (C 1-6 alkyl) group; R 26 Choose from H, C 1-6 Alkyl, aryl and aryl (C 1-6and r is an integer between 1 and 2.

[0424] In some embodiments, R 25 Choose from C 1-3 Alkyl, phenyl and phenyl (C 1-3 alkyl), such as selected from the group consisting of methyl, ethyl, phenyl, benzyl and phenethyl.

[0425] In some embodiments, R 26 Choose from H, C 1-3 Alkyl, phenyl and phenyl (C 13 alkyl), such as selected from the group consisting of H, methyl, ethyl, phenyl, benzyl and phenethyl.

[0426] In some embodiments of Formulas (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), (XXIb'), (XXIc), and (XXId), particularly those in which one or more hydrophobic chains are attached to the N-terminus (i.e., the terminal N atom) of the POX and / or POZ polymers (as shown, for example, in Formula (XXI)), L 11 Selected from the group consisting of: [*-NHC(O)] p (C 1-6 -alkylene)-, [*-C(O)NH] p (C 1-6 -alkylene)-, [*-C(O)O] p (C 1-6 -alkylene)-, [*-OC(O)] p (C 1-6 -alkylene)-, [*-S] p (C 1-6 -alkylene)- and [*-S(O)2] p (C 1-6 -alkylene)-, preferably selected from the group consisting of: [*-NHC(O)] p (C 1-6 -alkylene)-, [*-C(O)O] p (C 1-6 -alkylene)-, [*-OC(O)] p (C 1-6 -alkylene)-, [*-S] p (C 1-6 -alkylene)- and [*-S(O)2] p (C 1-6 -alkylene)-, more preferably selected from the group consisting of: [*-NHC(O)] p (C 1-6-alkylene)- and [*-C(O)O] p (C 1-6 -alkylene)-, where * represents 14 connection point; p is 1 or 2; and C 1-6 -Alkylene is divalent (if p is 1) or trivalent (if p is 2).

[0427] In some embodiments of Formulas (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), (XXIb'), (XXIc), and (XXId), particularly those in which one or more hydrophobic chains are attached to the N-terminus (i.e., the terminal N atom) of the POX and / or POZ polymers (as shown, for example, in Formula (XXI)), L 11 Selected from the group consisting of: [*-NHC(O)] p (C 1-3 -alkylene)-, [*-C(O)NH] p (C 1-3 -alkylene)-, [*-C(O)O] p (C 1-3 -alkylene)-, [*-OC(O)] p (C 1-3 -alkylene)-, [*-S] p (C 1-3 -alkylene)- and [*-S(O)2] p (C 1-3 -alkylene)-, preferably selected from the group consisting of: [*-NHC(O)] p (C 1-3 -alkylene)-, [*-C(O)O] p (C 1-3 -alkylene)-, [*-OC(O)] p (C 1-3 -alkylene)-, [*-S] p (C 1-3 -alkylene)- and [*-S(O)2] p (C 1-3 -alkylene)-, more preferably selected from the group consisting of: [*-NHC(O)] p (C 1-3 -alkylene)- and [*-C(O)O] p (C 1-3 -alkylene)-, where * represents 14 connection point; p is 1 or 2; and C 1-3 -Alkylene is divalent (if p is 1) or trivalent (if p is 2).

[0428] In some embodiments of Formulas (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), (XXIb'), (XXIc), and (XXId), particularly those in which one or more hydrophobic chains are attached to the N-terminus (i.e., the terminal N atom) of the POX and / or POZ polymers (as shown, for example, in Formula (XXI)), L 11 Selected from the group consisting of: *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)-, *-C(O)NH-(CH2)2-, -(CH2)-CH(OC(O)-*)-(CH2OC(O)-*), -(CH2)-CH(S-*)2, -(CH2)-CH(S-*)-CH2(S-*), *-S-(CH2)3-, *-S(O)2-(CH2)3- and *-OC(O)-(CH2)-, wherein * represents the 14 Therefore, R 12 Can be selected from the group consisting of: R 14 、-L 11 R 14 、-(CH2)-CH(OC(O)R 14 )(CH2OC(O)R 14 )、-(CH2)-CH(SR 14 )2 and -(CH2)-CH(SR 14 )-CH2(SR 14 ); and L 11 Selected from the group consisting of *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)-, *-C(O)NH-(CH2)2-, *-S-(CH2)3-, *-S(O)2-(CH2)3- and *-OC(O)-(CH2)-, preferably L 11 It is *-NHC(O)-(CH2)- or *-NHC(O)-(CH2)2-, where * represents the 14 connection point.

[0429] In some embodiments of Formula (XXI), (XXIa), and (XXIb), R 12 Yes-L 11 (R 14 ) p , that is, the POX and / or POZ polymers are connected via the linker L 11 Conjugated to one or more hydrophobic chains (ie, R 14 ).

[0430] In some embodiments of Formula (XXI'), (XXIa'), and (XXIb'), the linker comprises at least one bifunctional moiety, one or more hydrophobic chains (R 14 ) is connected to the C-terminus of the POX and / or POZ polymer via the bifunctional moiety. In some embodiments, the linker may additionally comprise an alkylene moiety (such as C 1-6 Alkylene moieties, such as C 1-3 Alkylene moiety), cycloalkylene moiety (preferably C 3-8 -cycloalkylene, such as C 3-6 -cycloalkylene moiety), or cycloalkenylene moiety (preferably C 3-8 -cycloalkenylene, such as C 3-6 -cycloalkenylene moieties), each of which links a bifunctional moiety to the C-terminus of the POX and / or POZ polymer (directly to the C-terminus or preferably through another bifunctional moiety). For example, a hydrophobic chain (R 14 ) can be linked to the C-terminus of the POX and / or POZ polymer via a bifunctional moiety (directly or via an alkylene, cycloalkylene or cycloalkenylene moiety or via an alkylene, cycloalkylene or cycloalkenylene moiety with another bifunctional moiety); two hydrophobic chains (R 14 ) can be linked to the C-terminus of the POX and / or POZ polymers via two bifunctional moieties (which in turn are preferably linked to an alkylene, cycloalkylene or cycloalkenylene moiety or to an alkylene, cycloalkylene or cycloalkenylene moiety bearing another bifunctional moiety); or two hydrophobic chains (R 14) can be linked to the C-terminus of the POX and / or POZ polymer through the same bifunctional moiety (which is then followed by a trifunctional moiety and can be linked to the C-terminus of the POX and / or POZ polymer directly or through an alkylene, cycloalkylene or cycloalkenylene moiety, or to an alkylene, cycloalkylene or cycloalkenylene moiety bearing another bifunctional moiety). In some embodiments, each divalent functional moiety is independently selected from ether, amino, ester, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfenamide, sulfonamide, sulfamate, diselenide, sulfurous acid diamide, sulfurous acid diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioester, dithioester, imidoester, imino, iminothioester, sulfonamido, carbonate, thiocarbonate, dithiocarbonate, trithiocarbonate, guanidino (imino), carbamoyl ester, carbomiyl ester, carbamate, dithiocarbamate, carbodithioimide ester, carbamoyl thioester, thiocarbamate, carbomiyl thioester, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imine, imide, and amide moieties. In some preferred embodiments of Formulas (XXI'), (XXIa'), and (XXIb'), the linker comprises at least one divalent functional moiety selected from the group consisting of amide, sulfide, sulfone, and amino moieties.

[0431] In some embodiments of Formula (XXI'), (XXIa'), and (XXIb'), the cycloalkylene moiety is C 3-8 -cycloalkylene, such as C 3-6 -cycloalkylene, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, wherein the cycloalkylene portion is optionally substituted, such as optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl.

[0432] In some embodiments of Formulas (XXI'), (XXIa'), and (XXIb'), the cycloalkenylene moiety is C 3-8 -cycloalkenylene, such as C 3-6 -cycloalkenylene, such as cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, wherein the cycloalkenylene portion is optionally substituted, such as optionally with one or more (e.g., 1, 2, 3, or 4) substituents (e.g., independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl) substituted.

[0433] In some embodiments of Formulas (XXI'), (XXIa'), and (XXIb'), the alkylene moiety is C 1-6Alkylene, such as C 1-3 Alkylene, such as methylene, ethylene or trimethylene, or C 2-3 Alkylene.

[0434] In some embodiments of Formula (XXI'), (XXIa'), and (XXIb'), the oxazolinylated and / or oxazinylated lipid comprises one of the following structures:

[0435] (Hydrophobic chain)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0436] [(Hydrophobic chain)-(Divalent functional part)] 1-2 -(Alkylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0437] (Hydrophobic chain)-(Divalent functional moiety)-(Cycloalkylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0438] (Hydrophobic chain)-(Divalent functional moiety)-(Cycloalkenylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0439] (Hydrophobic chain)-(Divalent functional moiety)-(Alkylene moiety)-(POX and / or POZ polymer)

[0440] [(Hydrophobic chain)2-(Trivalent functional moiety)]-(Alkylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0441] In some embodiments of Formula (XXI'), (XXIa'), and (XXIb'), the oxazolinated and / or oxazinated lipid has one of the following structures (XXIe') to (XXIj'):

[0442] (Hydrophobic chain)-(divalent functional moiety)-(POX and / or POZ polymer)-R 13 (XXIe')

[0443] [(Hydrophobic chain)-(Divalent functional part)] 1-2 -(alkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)-R 13 (XXIf')

[0444] (Hydrophobic chain)-(divalent functional moiety)-(cycloalkylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)-R 13 (XXIg')

[0445] (Hydrophobic chain)-(divalent functional moiety)-(cycloalkenylene moiety)-(divalent functional moiety)-(POX and / or POZ polymer)-R 13 (XXIh')

[0446] (Hydrophobic chain)-(divalent functional moiety)-(alkylene moiety)-(POX and / or POZ polymer)-R 13 (XXIi')

[0447] [(Hydrophobic chain)2-(Trivalent functional moiety)]-(Alkylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)-R 13 (XXIj')

[0448] In some embodiments of Formula (XXI'), (XXIa'), (XXIb'), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), and (XXIj'), L 11 Select from the group consisting of: [*-Z] p (C 1-6 -alkylene)-Z-, *-Z-(C 3-8 -cycloalkylene)-Z-, *-Z-(C 3-8 -cycloalkenylene)-Z-, (*=N)(C 1-6 -alkylene)-Z-, *-Z-(C 1-6 -alkylene)- and *-Z-, wherein * represents 14 The connection point; p is 1 or 2; C 1-3 - alkylene is divalent (if p is 1) or trivalent (if p is 2); C 3-8 -cycloalkylene and C 3-8 Each of the -cycloalkenylene groups is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and each Z is independently selected from the group consisting of: -OP(O)2O(C 1-3 -alkylene)NH-, -NH(C 1-3 -alkylene)OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NR 22 -, where R 22 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl. For example, the linker can be selected from the group consisting of: [*-C(O)O] p (C1-6 -alkylene)-Z-, (*-NH)(C 1-6 -alkylene)-Z-, (*=N)(C 1-6 -alkylene)-Z-, (*-NH)C(O)(C 1-6 -alkylene)-Z-, (*-C(O)NH(C 1-6 -alkylene)-Z-, (*-NH)C(O)(C 1-6 -alkylene)-, (*-C(O)NH(C 1-6 -alkylene)-, (*-NH)C(O)-, *-C(O)NH-, *-Z-(C 3-8 -cycloalkenyl)-Z-, -S- and -S(O)2-, where * represents the same as R 14 The connection point; p is 1 or 2; C 1-6 - alkylene is divalent (if p is 1) or trivalent (if p is 2); C 3-8 -cycloalkenylene is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and Z is selected from the group consisting of: -OP(O)2O(C 1-3 -alkylene)NH-, -NH(C 1-3 -alkylene)OP(O)2O-, -OC(O)NH-, -NHC(O)O-, -O-, -S- and -NH-.

[0449] In some embodiments of Formula (XXI'), (XXIa'), (XXIb'), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), and (XXIj'), L 11 Select from the group consisting of: [*-Z] p (C 1-3 -alkylene)-Z-, *-Z-(C 3-6 -cycloalkylene)-Z-, *-Z-(C 3-6 -cycloalkenylene)-Z-, (*=N)(C 1-3 -alkylene)-Z-, *-Z(C 1-3 -alkylene)- and *-Z-, wherein * represents 14 The connection point; p is 1 or 2; C 1-3 - alkylene is divalent (if p is 1) or trivalent (if p is 2); C 3-6 -cycloalkylene and C 3-6Each of the -cycloalkenylene groups is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and each Z is independently selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, -N(C 1-3 -alkyl)- and -NH-. For example, the linker may be selected from the group consisting of: [*-C(O)O] p (C 1-3 -alkylene)-Z-, (*-NH)(C 1-3 -alkylene)-Z-, (*=N)(C 1-3 -alkylene)-Z-, (*-NH)C(O)(C 1-3 -alkylene)-Z-, (*-C(O)NH(C 1-3 -alkylene)-Z-, (*-NH)C(O)(C 1-3 -alkylene)-, (*-C(O)NH(C 1-3 -alkylene)-, (*-NH)C(O)-, *-C(O)NH-, *-Z-(C 3-6 -cycloalkenyl)-Z-, -S- and -S(O)2-, where * represents the same as R 14 The connection point; p is 1 or 2; C 1-3 - alkylene is divalent (if p is 1) or trivalent (if p is 2); C 3-6 -cycloalkenylene is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and Z is selected from the group consisting of: -OP(O)2O(C 1-2 -alkylene)NH-, -NH(C 1-2 -alkylene)OP(O)2O-, -OC(O)NH-, -NHC(O)O-, -O-, -S- and -NH-.

[0450] In some embodiments of Formula (XXI'), (XXIa'), (XXIb'), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), and (XXIj'), L 11 Select from the group consisting of: [*-Z] p (C 1-3-alkylene)-Z-, *-Z-(C 3-6 -cycloalkylene)-Z-, *-Z-(C 3-6 -cycloalkenylene)-Z-, (*=N)(C 1-3 -alkylene)-Z-, *-Z(C 1-3 -alkylene)- and *-Z-, wherein * represents 14 connection; p is 1 or 2; C 1-3 - alkylene is divalent (if p is 1) or trivalent (if p is 2); C 3-6 -cycloalkylene and C 3-6 Each of the -cycloalkenylene groups is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and each Z is independently selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, -N(C 1-3 -alkyl)- and -NH-. For example, the linker may be selected from the group consisting of: [*-C(O)O] p (C 1-3 -alkylene)-Z-, (*-NH)(C 1-3 -alkylene)-Z-, (*=N)(C 1-3 -alkylene)-Z-, (*-NH)C(O)(C 1-3 -alkylene)-Z-, (*-C(O)NH(C 1-3 -alkylene)-Z-, (*-NH)C(O)(C 1-3 -alkylene)-, (*-C(O)NH(C 1-3 -alkylene)-, (*-NH)C(O)-, *-C(O)NH-, *-Z-(C 3-6 -cycloalkenyl)-Z-, -S- and -S(O)2-, where * represents the same as R 14 The connection point; p is 1 or 2; C 1-3 - alkylene is divalent (if p is 1) or trivalent (if p is 2); C 3-6 -cycloalkenylene is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3-alkyl; and Z is selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -OC(O)NH-, -NHC(O)O-, -O-, -S- and -NH-.

[0451] In some embodiments of Formula (XXI'), (XXIa'), (XXIb'), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), and (XXIj'), L 11 Selected from the group consisting of: (*-C(O)O)(CH(OC(O)-*))(CH2)-Z-, (*=N)(C 1-3 -alkylene)-NHC(O)-, (*-Z)(C 1-3 -alkylene)-Z-, *-Z-(C 3-6 -cycloalkenylene)-Z- and *-Z-, wherein * represents the same as R 14 The connection point of C 3-6 -cycloalkenylene is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and each Z is independently selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NH-. For example, the linker may be selected from the group consisting of: (*-C(O)O)(CH(OC(O)-*))(CH2)-Z-, (*=N)(C 1-3 -alkylene)-NHC(O)-, (*-NH)(C 1-3 -alkylene)-NHC(O)-, *-C(O)NH-, (*-NH)C(O)-, *-Z-(C 3-6 -cycloalkenyl)-Z-, -S- and -S(O)2-, where * represents the same as R 14 The connection point of C 3-6 -cycloalkenylene is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and Z is selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -OC(O)NH-, -NHC(O)O-, -O-, -S- and -NH.

[0452] In some embodiments of Formula (XXI'), (XXIa'), (XXIb'), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), and (XXIj'), R 12 Selected from the group consisting of: (R 14 C(O)O)(CH(OC(O)R 14 ))(CH2)-Z-、(R 14 )2N(C 1-3 -alkylene)-NHC(O)-, R 14 Z(C 1-3 -alkylene)-Z-, R 14 Z-(C 3-6 -cycloalkenylene)-Z- and R 14 Z-, where C 3-6 -cycloalkenylene is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and each Z is independently selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NH-. For example, the linker may be selected from the group consisting of: (R 14 C(O)O)(CH(OC(O)R 14 ))(CH2)-Z-、(R 14 )2N(C 1-3 -alkylene)-NHC(O)-, R 14 NH(C 1-3 -alkylene)-NHC(O)-, R 14 C(O)NH-、(R 14 NH)C(O)-、R 14 Z-(C 3-6 -cycloalkenylene)-Z-, R 14 S- and R 14 S(O)2-, where C 3-6 -cycloalkenylene is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3-alkyl; and Z is selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -OC(O)NH, -NHC(O)O-, -O-, -S-, -S(O)2- and -NH-.

[0453] In some embodiments of Formula (XXI'), (XXIa'), (XXIb'), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), and (XXIj'), R 12 Yes-L 11 (R 14 ) p , that is, the POX and / or POZ polymers are connected via the linker L 11 Conjugated to one or more hydrophobic chains (ie, R 14 ).

[0454] In any of the above embodiments of Formula (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), (XXIb'), (XXIc), (XXId), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), and (XXIj'), each R 14 Preferably, each R is independently acyclic, more preferably a straight chain hydrocarbon group. 14 is independently a hydrocarbyl group having at least 8 carbon atoms, such as at least 10 carbon atoms, preferably up to 30 carbon atoms, such as up to 28, 26, 24, 22, or 20 carbon atoms, or up to 16 carbon atoms, such as up to 15, 14, 13, 12, 11, or 10 carbon atoms. 14 is a hydrocarbon group having 10 to 16 carbon atoms, such as 10 to 15 or 10 to 14 carbon atoms. 14 is a straight chain hydrocarbon group having 10 to 16 carbon atoms, such as 10 to 15 or 10 to 14 carbon atoms.

[0455] In any of the above embodiments of Formula (XXI'), (XXIa'), (XXIb'), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), and (XXIj'), each R 14Preferred are hydrocarbon groups having 10 to 18 carbon atoms, such as straight-chain alkyl groups having 10 to 18 carbon atoms or straight-chain alkenyl groups having 10 to 18 carbon atoms. For example, the straight-chain alkyl group may have 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbon atoms; and / or the straight-chain alkenyl group may have 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbon atoms and 1, 2, or 3 carbon-carbon double bonds.

[0456] In any of the above embodiments of Formula (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), (XXIb'), (XXIc), (XXId), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), and (XXIj'), R 13 Preferably selected from the group consisting of: H, C 1-3 Alkyl, -OR 20 、-N3、C 2-6 Alkynyl, -OC(O)R 21 、-C(O)R 21 、-NR 22 R 23 、-COOH、-C(O)NR 22 R 23 、-NR 22 C(O)R 21 and members of a targeting pair, where C 1-3 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NR 22 R 23 、-C(O)NR 22 R 23 、-NR 22 C(O)R 21 and a member of a targeting pair; R 20 Choose from H, C 1-3 The group consisting of an alkyl group and a 3- to 6-membered heterocyclic group, wherein C 1-3 Each of the alkyl and 3 to 6 membered heterocyclic groups is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NR 22 R 23 and a member of a targeting pair; R 21 Choose from C 1-3 The group consisting of an alkyl group and a 3- to 6-membered heterocyclic group, wherein C 1-6The alkyl and 3 to 6 membered heterocyclic groups are optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NR 22 R 23 and a member of a targeting pair; and R 22 and R 23 Each of which is independently selected from the group consisting of: H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, or R 22 and R 23 may be joined together with the nitrogen atom to which they are attached to form a heterocyclic group, wherein C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each of the alkynyl groups is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 and a member of a targeting pair.

[0457] In any of the above embodiments of Formula (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), (XXIb'), (XXIc), (XXId), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), and (XXIj'), R 13 Preferably selected from the group consisting of: H, C 1-3 Alkyl, -OR 20 、-N3、C 2-6 Alkynyl, -OC(O)R 21 、-C(O)R 21 、-NR 22 R 23 、-COOH、-C(O)NR 22 R 23 、-NR 22 C(O)R 21 and members of a targeting pair, where C 1-3 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NR 22 R 23 、-NR 22 C(O)R 21and a member of a targeting pair; R 20 Selected from H and C 1-3 A group consisting of an alkyl group; R 21 It is C 1-3 Alkyl, optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NR 22 R 23 and a member of a targeting pair; and R 22 and R 23 Each of which is independently selected from the group consisting of: H, C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, where C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Each of the alkynyl groups is optionally substituted with one or more (such as 1, 2, 3 or 4) substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 and a member of a targeting pair, or R 22 and R 23 They may be joined together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic group.

[0458] In any of the above embodiments of Formula (XXI), (XXI'), (XXIa), (XXIa'), (XXIb), (XXIb'), (XXIc), (XXId), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), and (XXIj'), R 13 Preferably selected from the group consisting of: H, C 1-3 Alkyl, -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and members of the targeted pair, wherein C 1-3 The alkyl group is optionally substituted with one or more (such as 1 or 2) substituents independently selected from the group consisting of: -OH, -N3, C 2-6Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and members of a targeting pair.

[0459] In some embodiments of Formula (XXI), (XXIa), (XXIb), (XXIc), and (XXId), R 13 Selected from the group consisting of: H, -OH, -N3, C 2-6 alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and members of the targeting pair. In some embodiments of Formulas (XXI), (XXIa), (XXIb), (XXIc), and (XXId), R 13 Selected from the group consisting of: -OH, -N3, C 2-6 alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and members of the targeting pair. In some embodiments of Formulas (XXI), (XXIa), (XXIb), (XXIc), and (XXId), R 13 Selected from the group consisting of: -OH, -N3, C 2-6 alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), -OC(O)(CH2)2COOH, and members of the targeting pair. In some embodiments of Formulas (XXI), (XXIa), (XXIb), (XXIc), and (XXId), R 13 Selected from the group consisting of: -OH, -N3, -NH2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3) and -OC(O)(CH2)2COOH.

[0460] In some embodiments of Formula (XXI'), (XXIa'), (XXIb'), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), and (XXIj'), R 13 It is C 1-3 Alkyl, which is optionally substituted by one or two substituents independently selected from the group consisting of: -OH, -N3, C 2-6 alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and members of the targeting pair. In some embodiments of Formula (XXI'), (XXIa'), (XXIb'), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), and (XXIj'), R 13 It is C 1-3 Alkyl, which is optionally substituted with a substituent selected from the group consisting of -COOH and -C(O)NH(CH2)2NH2.

[0461] In certain embodiments, the oxazolinylated and / or oxazinylated lipid has the following general formula (XXII) or (XXII'):

[0462]

[0463] in:

[0464] a is an integer between 1 and 2;

[0465] R 11 is methyl or ethyl and is independently selected for each repeat unit;

[0466] m is 10 to 100 (preferably 20 to 80, 30 to 70 or 40 to 50);

[0467] For formula (XXII), R 12 Selected from the group consisting of: -L 11 R 14 、-(CH2)-CH(OC(O)R 14 )(CH2OC(O)R 14 )、-(CH2)-CH(SR 14 )2, and -(CH2)-CH(SR 14 )-CH2(SR 14 ), where each R 14 is independently a straight chain hydrocarbon group having at least 10 carbon atoms (preferably having 10 to 16 carbon atoms); and L 11Selected from the group consisting of: *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)-, *-C(O)NH-(CH2)2-, *-S-(CH2)3-, *-S(O)2-(CH2)3- and *-OC(O)-(CH2)- (preferably, L 11 Selected from the group consisting of: *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)- and *-C(O)NH-(CH2)2-, such as *-NHC(O)-(CH2)- or *-NHC(O)-(CH2)2-), wherein * represents the 14 or for Formula (XXII'), R 12 Selected from the group consisting of: (R 14 C(O)O)(CH(OC(O)R 14 ))(CH2)-Z-、(R 14 )2N(C 1-3 -alkylene)-Z-, R 14 Z(C 1-3 -alkylene)-Z-, R 14 Z-(C 3-6 -cycloalkenylene)-Z- and R 14 Z-, where C 3-6 -cycloalkenylene is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and each Z is independently selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NH-; and

[0468] R 13 Selected from the group consisting of: H, C 1-3 Alkyl, -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and members of the targeted pair, wherein C 1-3The alkyl group is optionally substituted with one or more (such as one or two) substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and members of a targeting pair.

[0469] In some embodiments of Formula (XXII) or (XXII'), a is 1, ie, the oxazolinated and / or oxazinated lipid has the following general formula (XXIIa) or (XXIIa'):

[0470]

[0471] In some embodiments of Formula (XXII) or (XXII'), a is 2, ie, the oxazolinated and / or oxazinated lipid has the following general formula (XXIIb) or (XXIIb'):

[0472]

[0473] In any of the above embodiments of Formula (XXIIa), (XXIIa'), (XXIIb), and (XXIIb'), R 11 、R 12 、R 13 and m are as defined for formula (XXII) / (XXII').

[0474] In some embodiments of Formula (XXII), (XXII'), (XXIIa), (XXIIa'), (XXIIb), and (XXIIb'), each R 11 are all methyl or each R 11 In some alternative embodiments of formula (XXII), (XXII'), (XXIIa), (XXIIa'), (XXIIb) and (XXIIb'), for each repeating unit, R 11 are independently selected from methyl and ethyl, wherein in at least one repeating unit, R 11 is methyl, and in at least one repeating unit, R 11 It's ethyl.

[0475] In some embodiments of Formula (XXII), (XXIIa), and (XXIIb), R 12 Selected from the group consisting of: R 14 -NHC(O)-(CH2)-、R 14 -NHC(O)-(CH2)2-, -(CH2)-CH(OC(O)R 14)(CH2OC(O)R 14 )、-(CH2)-CH(SR 14 )-CH2(SR 14 ), R 14 S-(CH2)3-、R 14 S(O)2-(CH2)3- and R 14 -OC(O)-(CH2)-; and / or R 13 Selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), -OC(O)(CH2)2COOH, and members of the targeting pair (e.g., R 13 Selected from the group consisting of: -OH, -N3, -NH2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3) and -OC(O)(CH2)2COOH).

[0476] In some embodiments of Formula (XXII'), (XXIIa') and (XXIIb'), R 12 Selected from the group consisting of: R 14 C(O)NH-、R 14 S-、R 14 S(O)2- and R 14 NH-(3,4-dioxocyclobut-1-ene-1,2-diyl)-NH-; and / or R 13 It is C 1-3 Alkyl, which is optionally substituted by one or two substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2 and members of the targeting pair (e.g., R 13 It is C 1-3 alkyl, which is optionally substituted with one substituent selected from the group consisting of -COOH and -C(O)NH(CH2)2NH2).

[0477] In some embodiments, the oxazolinylated and / or oxazinylated lipid has the following general formula or (XXIII):

[0478] R 15 -POXZ-R16

[0479] in:

[0480] R 15 It is R 17 or -L 12 (R 17 ) q , where each R 17 are independently hydrocarbon groups; L 12 is a linker; and q is 1 or 2;

[0481] POXZ is a copolymer containing repeating units of the following general formulae (XXa) and (XXb):

[0482]

[0483] where R 11 Each of which is independently an alkyl group, particularly C 1-3 an alkyl group, such as a methyl group, an ethyl group, an isopropyl group, or an n-propyl group, and is independently selected for each repeating unit; the number of repeating units of formula (XXa) in the copolymer is 1 to 199; the number of repeating units of formula (XXb) in the copolymer is 1 to 199; the sum of the number of repeating units of formula (XXa) and the number of repeating units of formula (XXb) in the copolymer is 2 to 200; and the repeating units of formula (XXa) and (XXb) are arranged in a random, periodic, alternating, or blockwise manner; and

[0484] R 16 Selected from the group consisting of: H, C 1-6 Alkyl, C 2-6 Alkynyl, -OR 20 、-SR 20 、Halogen、-CN、-N3、-OC(O)R 21 、-C(O)R 21 、-NR 22 R 23 、-COOH、-C(O)NR 22 R 23 、-NR 22 C(O)R 21 , sugars, amino acids, peptides, and members of targeting pairs, wherein C 1-6 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NR 22 R 23 、-C(O)NR 22 R 23 、-NR 22 C(O)R 21, sugars, amino acids, peptides, and members of targeting pairs; R 20 Selected from the group consisting of: H, C 1-3 Alkyl and 3 to 6 membered heterocyclic groups, wherein C 1-3 Each of the alkyl and 3 to 6 membered heterocyclic groups is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NR 22 R 23 , sugars, amino acids, peptides, and members of targeting pairs; R 21 Choose from C 1-6 The group consisting of an alkyl group and a 3- to 6-membered heterocyclic group, wherein C 1-6 Each of the alkyl and 3 to 6 membered heterocyclic groups is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NR 22 R 23 , sugars, amino acids, peptides, and members of targeting pairs; and R 22 and R 23 Each of R is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R 22 and R 23 can be joined together with the nitrogen atom to which they are attached to form a heterocyclic group, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl) 2', sugars, amino acids, peptides, and members of targeting pairs.

[0485] In some embodiments of Formula (XXIII), the targeting pair is selected from the following pairs: antigen-antibody specific for the antigen; avidin-streptavidin; folate-folate receptor; transferrin-transferrin receptor; aptamer-molecule for which the aptamer is specific; arginine-glycine-aspartic acid (RGD) peptide-α v β3 integrin; asparagine-glycine-arginine (NGR) peptide-aminopeptidase N; galactose-asialoglycoprotein receptor. Therefore, in some embodiments of formula (XXIII), the members of the targeting pair include one of the following: antigen, antibody, avidin, streptavidin, folic acid, transferrin, aptamer; RGD peptide; NGR peptide; and galactose.

[0486] In some of the above embodiments of Formula (XXIII), R 11 The alkyl group may be the same at each occurrence (ie, in each repeat unit) (eg, R 11 In some alternative embodiments of Formula (XXIII), R in at least one repeating unit may be methyl. 11 With another repeating unit R 11 different (e.g., for at least one repeating unit, R 11 is a specific alkyl group (such as ethyl), and for at least one different repeating unit, R 11 are different specific alkyl groups (such as methyl). For example, each R 11 can be selected from two different alkyl groups (such as methyl and ethyl), and not all R 1 All are the same alkyl group.

[0487] In some embodiments of Formula (XXIII), R 11 Each of R is independently methyl or ethyl, preferably methyl. Thus, in some embodiments of formula (XXIII), each R 11 are all methyl or each R 11 In some alternative embodiments of formula (XXIII), for each repeating unit, R 11 are independently selected from methyl and ethyl, wherein in at least one repeating unit, R 11 is methyl, and in at least one repeating unit, R 11 It's ethyl.

[0488] In some embodiments of formula (XXIII), the sum of the number of repeating units of formula (XXa) and the number of repeating units of formula (XXb) in the copolymer is preferably between 2 and 190, such as between 2 and 180, between 2 and 170, between 2 and 160, between 2 and 150, between 2 and 140, between 2 and 130, between 2 and 120, between 2 and 110, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 4 and 200, between 4 and 190, between 4 and 180, between 4 and 170, between 4 and 160 between 4 and 150, between 4 and 140, between 4 and 130, between 4 and 120, between 4 and 110, between 4 and 100, between 4 and 90, between 4 and 80, between 4 and 70, between 10 and 200, between 10 and 190, between 10 and 180, between 10 and 170, between 10 and 160, between 10 and 150, between 10 and 140, between 10 and 130, between 10 and 120, between 10 and 110, between 10 and 100, between 10 and 90, between 10 and 80, or between 10 and 70. In certain embodiments of formula (XXIII), the sum of the number of repeating units of formula (XXa) and the number of repeating units of formula (XXb) in the copolymer is 2 to 180, such as 4 to 160, 6 to 140, 8 to 120 or 10 to 100, for example 20 to 80, 30 to 70 or 40 to 50.

[0489] Thus, in some embodiments of Formula (XXIII), the number of repeating units of formula (XXa) in the copolymer is 1 to 179, such as 1 to 159, 1 to 139, 1 to 119, or 1 to 99; the number of repeating units of formula (XXb) in the copolymer is 1 to 179, such as 1 to 159, 1 to 139, 1 to 119, or 1 to 99; and the sum of the number of repeating units of formula (XXa) and the number of repeating units of formula (XXb) in the copolymer is 2 to 180, such as 4 to 160, 6 to 140, 8 to 120, or 10 to 100.

[0490] In some embodiments of Formula (XXIII), L 12 Contains at least one functional moiety, such as substituted with at least one monovalent functional moiety and / or in an alkylene group and R 17The terminal end of the linkage is connected to an alkylene moiety of a divalent functional moiety, wherein preferably each monovalent functional moiety is independently selected from hydroxy, ether, halogen, cyano, azide, nitro, amino, ammonium, ester, carboxyl, thiol (sulfanyl), disulfanyl, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfenamide, sulfonamide, sulfamate, diselenide, sulfurous acid diamide (sulfurous acid diamide), diamide), sulfuric acid diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioester, dithioester, imidoester, imino, iminothioester, sulfinamido, carbonate, thiocarbonate, dithiocarbonate, trithiocarbonate, guanidino (imino), carbamoyl ester, carbamoyl ester, carbamate, dithiocarbamate, carbodithioimino ester, carbamoylthioester, thiocarbamate, carbodithioimino ester, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imide and amide; and / or each divalent functional moiety is independently selected from ether, amino, ester, sulfide, disulfide, sulfoxide , sulfone, sulfite, sulfate, phosphate, sulfenamide, sulfonamide, sulfamate, diselenide, sulfodiamide, sulfuric acid diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioester, dithioester, imidoester, imino, iminothioester, sulfonamido, carbonate, thiocarbonate, dithiocarbonate, trithiocarbonate, guanidino (imino), carbamoyl ester, carbamoyl ester, dithiocarbamate, carbodithioimide ester, carbamoyl thioester, thiocarbamate, carbodithioimide ester, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imide and amide.

[0491] In some embodiments of Formula (XXIII), R 15 is attached to the N-terminus (ie, the terminal N atom) of the POXZ copolymer, and R 16 is connected to the C-terminus (ie, the terminal C atom) of the POXZ copolymer. In some alternative embodiments of Formula (XXIII), R 15 is attached to the C-terminus (ie, the terminal C atom) of the POXZ copolymer, and R 16 is attached to the N-terminus (ie, the terminal N atom) of the POXZ copolymer. Subsequent alternative embodiments of formula (XXIII) (ie, at R 15 is attached to the C-terminus (ie, the terminal C atom) of the POXZ copolymer and R 16 Where attached to the N-terminus (ie, the terminal N atom) of the POXZ copolymer, it is designated herein as Formula (XXIII').

[0492] In some embodiments of Formula (XXIII), L 12

[0014] ... 16 Connected to the terminal C atom of the POXZ copolymer):

[0493] (Hydrophobic chain) 1-2 -(alkylene moiety substituted with at least one monovalent functional moiety)-(POXZ copolymer),

[0494] Wherein "hydrophobic chain" represents R 17 ; "alkylene moiety substituted with at least one monovalent functional moiety" means L 12 ; and "POXZ copolymer" means the copolymer specified in formula (XXIII).

[0495] In some embodiments, the oxazolinylated and / or oxazinylated lipid has the following formula (XXIIIa) (optionally, R 16 Connected to the terminal C atom of the POXZ copolymer):

[0496] (Hydrophobic chain) 1-2 -(alkylene moiety substituted with at least one monovalent functional moiety)-(POXZ copolymer)-R 16

[0497] In some embodiments of formula (XXIII) and (XXIIIa), at least one monovalent functional moiety can be any of the monovalent functional moieties specified herein, for example, selected from the group consisting of hydroxyl, ether, halogen, cyano, azido, nitro, amino, ammonium, ester, carboxyl, thiol (sulfanyl), disulfanyl, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfenamide, sulfonamide, sulfamate, diselenide, sulfur diamide, sulfur diamide, urea, Thiourea, carbonyl, thiocarbonyl, orthoester, thioester, dithioester, imidoester, imino, iminothioester, sulfinamido, carbonate, thiocarbonate, dithiocarbonate, trithiocarbonate, guanidino (imino), carbamoyl ester, carbonamido ester, carbamate, dithiocarbamate, carbodithioimide ester, carbamoylthioester, thiocarbamate, carbonamidothioester, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imide and amide.

[0498] In some embodiments of formula (XXIII) and (XXIIIa), the alkylene moiety substituted with at least one monovalent functional moiety is C 1-6 -alkylene, such as C 1-3 - an alkylene group, such as a methylene group, an ethylene group or a trimethylene group.

[0499] In some embodiments of Formulas (XXIII) and (XXIIIa), the alkylene moiety substituted with at least one monovalent functional moiety is substituted with one or more (such as from 1 to the maximum number of hydrogen atoms bound to the alkylene moiety, e.g., 1, 2, 3, 4, 5, or 6, such as from 1 to 5, from 1 to 4, or from 1 to 3, or from 1 to 2) independently selected monovalent functional moieties.

[0500] In some embodiments, the alkylene moiety substituted with at least one monovalent functional moiety is C 1-6 -alkylene, such as C 1-3 -alkylene, such as methylene, ethylene or trimethylene, and substituted with one or more (such as from 1 to the maximum number of hydrogen atoms bound to the alkylene moiety, for example 1, 2, 3, 4, 5 or 6, such as from 1 to 5, from 1 to 4, or from 1 to 3, or from 1 or 2) independently selected monovalent functional moieties.

[0501] In some embodiments of Formula (XXIII) (particularly wherein R 16 connected to the terminal C atom of the POXZ copolymer), L 12 comprising an alkylene moiety linked to a divalent functional moiety as specified above, said alkylene being linked via a terminal end to R 17 Thus, in some embodiments (particularly where R 16 In those embodiments where the lipid is attached to a terminal C atom of the POXZ copolymer, the oxazolinylated and / or oxazinylated lipid may comprise the following structure:

[0502] [(Hydrophobic chain)-(Divalent functional part)] 1-2 -(alkylene moiety)-(POXZ copolymer),

[0503] Wherein "hydrophobic chain" represents R 17 ; "-(divalent functional moiety)] 1-2 -(alkylene moiety)" represents L 12 ; and "POXZ copolymer" means the copolymer specified in formula (XXIII).

[0504] In some embodiments (particularly where R 16 In those embodiments where the lipid is attached to a terminal C atom of the POXZ copolymer, the oxazolinylated and / or oxazinylated lipid has the following formula (XXIIIb):

[0505] [(Hydrophobic chain)-(Divalent functional part)] 1-2 -(alkylene moiety)-(POXZ copolymer)-R 16

[0506] In some embodiments of formula (XXIII) and (XXIIIb), the divalent functional moiety can be any of the divalent functional moieties specified herein, for example, selected from the group consisting of ether, amino, ester, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfenamide, sulfonamide, sulfamate, diselenide, sulfonamide, sulfuramide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioester, disulfide, sulfonamide, sulfonamide, diselenide, sulfonamide, sulfuramide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioester, disulfide, sulfonamide, sulfonamide, diselenide, sulfonamide, sulfuramide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioester, disulfide, sulfonamide, sulfonamide, diselenide, sulfonamide, sulfonamide, diselenide, sulfonamide, sulfuramide, urea, thiourea, carbonyl, thiocarbonyl, sulfoester, sulfoester, disulfide, sulfoester ... Thioester, imidoester, imino, iminothioester, sulfinamido, carbonate, thiocarbonate, dithiocarbonate, trithiocarbonate, guanidino (imino), carbamoyl ester, carbonimido ester, carbamate, dithiocarbamate, carbodithioimino ester, carbamoyl thioester, thiocarbamate, carbonimidothioester, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imine, imide and amide.

[0507] In some embodiments of Formulas (XXIII) and (XXIIIb), the alkylene moiety is C 1-6 Alkylene, such as C 1-3 Alkylene, such as methylene, ethylene or trimethylene.

[0508] In some embodiments of Formula (XXIII), wherein R 16 Attached to the terminal N atom of the POXZ copolymer (ie, in the embodiment of formula (XXIII')), L 12 Contains at least one bifunctional moiety, one or more hydrophobic chains (R 17 ) is connected to the POXZ copolymer via the bifunctional moiety. In some embodiments, L 12 May additionally contain an alkylene moiety (such as C 1-6 Alkylene moieties, such as C 1-3 Alkylene moiety), cycloalkylene moiety (preferably C 3-8 -cycloalkylene, such as C 3-6 -cycloalkylene moiety), or cycloalkenylene moiety (preferably C 3-8 -cycloalkenylene, such as C 3-6-cycloalkenylene moiety), each of which connects a bifunctional moiety to the POXZ copolymer (directly to a terminus of the POXZ copolymer or, preferably, through another bifunctional moiety). For example, one hydrophobic chain can be connected to a terminus of the POXZ copolymer through one bifunctional moiety (directly or through an alkylene, cycloalkylene, or cycloalkenylene moiety or through an alkylene, cycloalkylene, or cycloalkenylene moiety with another bifunctional moiety); two hydrophobic chains can be connected to a terminus of the POXZ copolymer through two bifunctional moieties (which in turn are preferably connected to an alkylene, cycloalkylene, or cycloalkenylene moiety or to an alkylene, cycloalkylene, or cycloalkenylene moiety with another bifunctional moiety); or two hydrophobic chains can be connected to a terminus of the POXZ copolymer through the same bifunctional moiety (which is then a trifunctional moiety and can be connected to a terminus of the POXZ copolymer directly or through an alkylene, cycloalkylene, or cycloalkenylene moiety or to an alkylene, cycloalkylene, or cycloalkenylene moiety with another bifunctional moiety). In some embodiments, each divalent functional moiety is independently selected from ether, amino, ester, sulfide, disulfide, sulfoxide, sulfone, sulfite, sulfate, phosphate, sulfenamide, sulfonamide, sulfamate, diselenide, sulfurous acid diamide, sulfurous acid diamide, urea, thiourea, carbonyl, thiocarbonyl, orthoester, thioester, dithioester, imidoester, imino, iminothioester, sulfonamido, carbonate, thiocarbonate, dithiocarbonate, trithiocarbonate, guanidino (imino), carbamoyl ester, carbomiyl ester, carbamate, dithiocarbamate, carbodithioimide ester, carbamoyl thioester, thiocarbamate, carbomiyl thioester, acylhydrazone, hydrazine, oxime, acetal, hemiacetal, ketal, hemiketal, imine, imide, and amide moieties.

[0509] In some embodiments of Formula (XXIII'), the cycloalkylene moiety is C 3-8 -cycloalkylene, such as C 3-6 Cycloalkylene, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, wherein the cycloalkylene portion is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents (e.g., independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl) substituted.

[0510] In some embodiments of Formula (XXIII'), the cycloalkenylene moiety is C 3-8 -cycloalkenylene, such as C 3-6-cycloalkenylene, such as cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, wherein the cycloalkenylene portion is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents (e.g., independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl) substituted.

[0511] In some embodiments of Formula (XXIII'), the alkylene moiety is C 1-6 Alkylene, such as C 1-3 Alkylene, such as methylene, ethylene or trimethylene, or C 2-3 Alkylene.

[0512] In some embodiments of Formula (XXIII'), the oxazolinylated and / or oxazinylated lipid comprises one of the following structures:

[0513] (Hydrophobic chain)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0514] [(Hydrophobic chain)-(Divalent functional part)] 1-2 -(Alkylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0515] (Hydrophobic chain)-(Divalent functional moiety)-(Cycloalkylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0516] (Hydrophobic chain)-(Divalent functional moiety)-(Cycloalkenylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0517] (Hydrophobic chain)-(Divalent functional moiety)-(Alkylene moiety)-(POX and / or POZ polymer)

[0518] [(Hydrophobic chain)2-(Trivalent functional moiety)]-(Alkylene moiety)-(Divalent functional moiety)-(POX and / or POZ polymer)

[0519] In some embodiments of Formula (XXIII'), the oxazolinylated and / or oxazinylated lipid has one of the following Formulas (XXIIIc') to (XXIIIh'):

[0520] (Hydrophobic chain)-(Divalent functional part)-(POXZ copolymer)-R 16 (XXIIIc')

[0521] [(Hydrophobic chain)-(Divalent functional part)] 1-2 -(alkylene moiety)-(divalent functional moiety)-(POXZ copolymer)-R 16(XXIIId')

[0522] (Hydrophobic chain)-(divalent functional moiety)-(cycloalkylene moiety)-(divalent functional moiety)-(POXZ copolymer)-R 16 (XXIIIe')

[0523] (Hydrophobic chain)-(Divalent functional moiety)-(Cycloalkenylene moiety)-(Divalent functional moiety)-(POXZ copolymer)-R 16 (XXIIIf')

[0524] (Hydrophobic chain)-(Divalent functional moiety)-(Alkylene moiety)-(POXZ copolymer)-R 16 (XXIIIg')

[0525] [(Hydrophobic chain)2-(Trivalent functional part)]-(Alkylene part)-(Divalent functional part)-(POXZ copolymer)-R 16 (XXIIIh')

[0526] In some embodiments of Formulas (XXIII), (XXIIIa), and (XXIIIb), L 12 Contains at least one ester, sulfide, disulfide, sulfone, orthoester, acylhydrazone, hydrazine, oxime, acetal, ketal, or amide moiety. In some embodiments, L 12 Selected from the group consisting of: [*-NHC(O)] q (C 1-6 -alkylene)-, [*-C(O)NH] q (C 1-6 -alkylene)-, [*-C(O)O] q (C 1-6 -alkylene)-, [*-OC(O)] q (C 1-6 -alkylene)-, [*-S] q (C 1-6 -alkylene)-, [*-SS] q (C 1-6 -alkylene)-, [*-S(O)2] p (C 1-6 -alkylene)-, [(*-O) s C(OR 25 ) 3-s ](C 1-6 -alkylene)-, [*-C(OR 25 )2O] q (C 1-6 -alkylene)-, [*-C(R 25 )(=NN(R 26)C(O)-)] q (C 1-3 -alkylene)-, [*-C(O)(N(R 26 )-N=)C(R 25 )-] q (C 1-3 -alkylene)-, [*=C(=NN(R 26 )C(O)(R 25 ))] q (C 1-3 -alkylene)-, [*N(R 26 )N(R 26 )] q -(C 1-6 -alkylene)-, [*=C(=N(OH))] q (C 1-6 -alkylene)- and [*-OC(R 25 )(R 26 )O] q (C 1-6 -alkylene)-, where * represents 17 The connection point; q is 1 or 2; C 1-6 - alkylene is divalent (if q is 1) or trivalent (if q is 2); R 25 Choose from C 1-6 Alkyl, aryl and aryl (C 1-6 alkyl) group; R 26 Choose from H, C 1-6 Alkyl, aryl and aryl (C 1-6 and s is an integer between 1 and 2. For example, L 12 Can be selected from the group consisting of: [*-NHC(O)] q (C 1-3 -alkylene)-, [*-C(O)NH] q (C 1-3 -alkylene)-, [*-C(O)O] q (C 1-3 -alkylene)-, [*-OC(O)] q (C 1-3 -alkylene)-, [*-S] q (C 1-3 -alkylene)-, [*-SS] q (C 1-3 -alkylene)-, [*-S(O)2] p (C 1-3 -alkylene)-, [(*-O) s C(OR 25 ) 3-s ](C1-3 -alkylene)-, [*-C(OR 25 )2O] q (C 1-3 -alkylene)-, [*-C(R 25 )(=NN(R 26 )C(O)-)] q (C 1-3 -alkylene)-, [*-C(O)(N(R 26 )-N=)C(R 25 )-] q (C 1-3 -alkylene)-, [*=C(=NN(R 26 )C(O)(R 25 ))] q (C 1-3 -alkylene)-, [*N(R 26 )N(R 26 )] q -(C 1-3 -alkylene)-, [*=C(=N(OH))] q (C 1-3 -alkylene)- and [*-OC(R 25 )(R 26 )O] q (C 1-3 -alkylene)-, where * represents 17 The connection point; q is 1 or 2; C 1-3 - alkylene is divalent (if q is 1) or trivalent (if q is 2); R 25 Choose from C 1-6 Alkyl, aryl and aryl (C 1-6 alkyl) group; R 26 Choose from H, C 1-6 Alkyl, aryl and aryl (C 1-6 alkyl); and s is an integer between 1 and 2.

[0527] In some embodiments of Formula (XXIII), (XXIIIa), and (XXIIIb), R 25 Choose from C 1-3 Alkyl, phenyl and phenyl (C 1-3 alkyl), such as selected from the group consisting of methyl, ethyl, phenyl, benzyl and phenethyl.

[0528] In some embodiments of Formula (XXIII), (XXIIIa), and (XXIIIb), R 26 Choose from H, C 1-3 Alkyl, phenyl and phenyl (C 13alkyl), such as selected from the group consisting of H, methyl, ethyl, phenyl, benzyl and phenethyl.

[0529] In some embodiments of Formulas (XXIII), (XXIIIa), and (XXIIIb), L 12 Selected from the group consisting of: [*-NHC(O)] q (C 1-6 -alkylene)-, [*-C(O)NH] q (C 1-6 -alkylene)-, [*-C(O)O] q (C 1-6 -alkylene)-, [*-OC(O)] q (C 1-6 -alkylene)-, [*-S] q (C 1-6 -alkylene)- and [*-S(O)2] p (C 1-6 -alkylene)-, preferably selected from the group consisting of: [*-NHC(O)] q (C 1-6 -alkylene)-, [*-C(O)O] q (C 1-6 -alkylene)-, [*-OC(O)] q (C 1-6 -alkylene)-, [*-S] q (C 1-6 -alkylene)- and [*-S(O)2] p (C 1-6 -alkylene)-, more preferably selected from the group consisting of: [*-NHC(O)] q (C 1-6 -alkylene)- and [*-C(O)O] q (C 1-6 -alkylene)-, where * represents 17 The connection point of ; q is 1 or 2; and C 1-6 -Alkylene is divalent (if q is 1) or trivalent (if q is 2).

[0530] In some embodiments of Formulas (XXIII), (XXIIIa), and (XXIIIb), L 12 Selected from the group consisting of: [*-NHC(O)] q (C 1-3 -alkylene)-, [*-C(O)NH] q (C 1-3 -alkylene)-, [*-C(O)O] q (C 1-3-alkylene)-, [*-OC(O)] q (C 1-3 -alkylene)-, [*-S] q (C 1-3 -alkylene)- and [*-S(O)2] p (C 1-3 -alkylene)-, preferably selected from the group consisting of: [*-NHC(O)] q (C 1-3 -alkylene)-, [*-C(O)O] q (C 1-3 -alkylene)-, [*-OC(O)] q (C 1-3 -alkylene)-, [*-S] q (C 1-3 -alkylene)- and [*-S(O)2] p (C 1-3 -alkylene)-, more preferably selected from the group consisting of: [*-NHC(O)] q (C 1-3 -alkylene)- and [*-C(O)O] q (C 1-3 -alkylene)-, where * represents 17 The connection point of ; q is 1 or 2; and C 1-3 -Alkylene is divalent (if q is 1) or trivalent (if q is 2).

[0531] In some embodiments of Formulas (XXIII), (XXIIIa), and (XXIIIb), L 12 Selected from the group consisting of: *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)-, *-C(O)NH-(CH2)2-, -(CH2)-CH(OC(O)-*)(CH2OC(O)-*), -(CH2)-CH(S-*)2, -(CH2)-CH(S-*)-CH2(S-*), *-S-(CH2)3-, *-S(O)2-(CH2)3- and *-OC(O)-(CH2)-, wherein * represents the 17 Therefore, R 15 Can be selected from the group consisting of: R 17 、-L 12 R 17 、-(CH2)-CH(OC(O)R 17 )(CH2OC(O)R 17 )、-(CH2)-CH(SR 17 )2 and -(CH2)-CH(SR17 )-CH2(SR 17 ); and L 12 Selected from the group consisting of *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)-, *-C(O)NH-(CH2)2-, *-S-(CH2)3-, *-S(O)2-(CH2)3- and *-OC(O)-(CH2)-, preferably L 12 Selected from the group consisting of: *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)- and *-C(O)NH-(CH2)2-, such as -NHC(O)-(CH2)- or *-NHC(O)-(CH2)2-, wherein * represents the residue with R 17 connection point.

[0532] In some embodiments of Formula (XXIII), (XXIIIa), and (XXIIIb), R 15 Yes-L 12 (R 15 ) q , that is, the POXZ copolymer is connected by the linker L 12 Conjugated to one or more hydrophobic chains (ie, R 17 ).

[0533] In some embodiments of Formula (XXIII'), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), and (XXIIIh'), L 12 Select from the group consisting of: [*-Z1] q (C 1-6 -alkylene)-Z1-, *-Z1-(C 3-8 -cycloalkylene)-Z1-, *-Z1-(C 3-8 -cycloalkenylene)-Z1-, (*=N)(C 1-6 -alkylene)-Z1-, *-Z1(C 1-6 -alkylene)- and *-Z1-, wherein * represents 17 The connection point; q is 1 or 2; C 1-6 -alkylene is divalent (if q is 1) or trivalent (if q is 2); C 3-8 -cycloalkylene and C 3-8 Each of the -cycloalkenylene groups is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3-alkyl; and each Z1 is independently selected from the group consisting of: -OP(O)2O(C 1-3 -alkylene)NH-, -NH(C 1-3 -alkylene)OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NR 22 For example, L 12 Can be selected from the group consisting of: [*-C(O)O] q (C 1-6 -alkylene)-Z1-, (*-NH)(C 1-6 -alkylene)-Z1-, (*=N)(C 1-6 -alkylene)-Z1-, (*-NH)C(O)(C 1-6 -alkylene)-Z1-, (*-C(O)NH(C 1-6 -alkylene)-Z1-, (*-NH)C(O)(C 1-6 -alkylene)-, (*-C(O)NH(C 1-6 -alkylene)-, *-Z1-(C 3-8 -cycloalkenylene)-Z1-, *-S-, *-S(O)2-, (*-NH)C(O)- and *-C(O)NH-, wherein * represents the same as R 17 The connection point; q is 1 or 2; C 1-6 -alkylene is divalent (if q is 1) or trivalent (if q is 2); and Z1 is selected from the group consisting of: -OP(O)2O(C 1-3 -alkylene)NH-, -NH(C 1-3 -alkylene)OP(O)2O-, -OC(O)NH-, -NHC(O)O-, -O-, -S- and -NH-.

[0534] In some embodiments of Formula (XXIII'), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), and (XXIIIh'), L 12 Select from the group consisting of: [*-Z1] q (C 1-3 -alkylene)-Z1-, *-Z1-(C 3-6 -cycloalkylene)-Z1-, *-Z1-(C 3-6 -cycloalkenylene)-Z1-, (*=N)(C 1-3 -alkylene)-Z1-, *-Z1(C 1-3 -alkylene)- and *-Z1-, wherein * represents17 The connection point; q is 1 or 2; C 1-3 -alkylene is divalent (if q is 1) or trivalent (if q is 2); C 3-6 -cycloalkylene and C 3-6 Each of the -cycloalkenylene groups is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and each Z1 is independently selected from the group consisting of: -OP(O)2O(C 1-2 -alkylene)NH-, -NH(C 1-2 -alkylene)OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NR 22 For example, L 12 Can be selected from the group consisting of: [*-C(O)O] q (C 1-3 -alkylene)-Z1-, (*-NH)(C 1-3 -alkylene)-Z1-, (*=N)(C 1-3 -alkylene)-Z1-, (*-NH)C(O)(C 1-3 -alkylene)-Z1-, (*-C(O)NH(C 1-3 -alkylene)-Z1-, (*-NH)C(O)(C 1-3 -alkylene)-, (*-C(O)NH(C 1-3 -alkylene)-, *-Z1-(C 3-6 -cycloalkenylene)-Z1-, *-S-, *-S(O)2-, (*-NH)C(O)- and *-C(O)NH-, wherein * represents the same as R 17 The connection point; q is 1 or 2; C 1-3 -alkylene is divalent (if q is 1) or trivalent (if q is 2); and Z1 is selected from the group consisting of: -OP(O)2O(C 1-2 -alkylene)NH-, -NH(C 1-2 -alkylene)OP(O)2O-, -OC(O)NH-, -NHC(O)O-, -O-, -S- and -NH-.

[0535] In some embodiments of Formula (XXIII'), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), and (XXIIIh'), L 12Select from the group consisting of: [*-Z1] q (C 1-3 -alkylene)-Z1-, *-Z1-(C 3-6 -cycloalkylene)-Z1-, *-Z1-(C 3-6 -cycloalkenylene)-Z1-, (*=N)(C 1-3 -alkylene)-Z1-, *-Z1(C 1-3 -alkylene)- and *-Z1-, wherein * represents 17 The connection point; p is 1 or 2; C 1-3 -alkylene is divalent (if q is 1) or trivalent (if q is 2); C 3-6 -cycloalkylene and C 3-6 Each of the -cycloalkenylene groups is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and each Z1 is independently selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, -N(C 1-3 -alkyl)- and -NH-. For example, L 12 Can be selected from the group consisting of: [*-C(O)O] q (C 1-3 -alkylene)-Z1-, (*-NH)(C 1-3 -alkylene)-Z1-, (*=N)(C 1-3 -alkylene)-Z1-, (*-NH)C(O)(C 1-3 -alkylene)-Z1-, (*-C(O)NH(C 1-3 -alkylene)-Z1-, (*-NH)C(O)(C 1-3 -alkylene)-, (*-C(O)NH(C 1-3 -alkylene)-, *-Z1-(C 3-6 -cycloalkenylene)-Z1-, *-S-, *-S(O)2-, (*-NH)C(O)- and *-C(O)NH-, wherein * represents the same as R 17 The connection point; p is 1 or 2; C 1-3-Alkylene is divalent (if q is 1) or trivalent (if q is 2); and Z1 is selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -OC(O)NH-, -NHC(O)O-, -O-, -S- and -NH-.

[0536] In some embodiments of Formula (XXIII'), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), and (XXIIIh'), L 12 Selected from the group consisting of: (*-C(O)O)(CH(OC(O)-*))(CH2)-Z1-, (*=N)(C 1-3 -alkylene)-NHC(O)-, (*-Z1(C 1-3 -alkylene)-Z1-, *-Z1-(C 3-6 -cycloalkenylene)-Z1- and *-Z1-, wherein * represents the same as R 17 The connection point of C 3-6 -cycloalkenylene is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and each Z1 is independently selected from the group consisting of: -OP(O)2O(CH2)2-NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NH-. For example, L 12 Can be selected from the group consisting of: (*-C(O)O)(CH(OC(O)-*))(CH2)-Z1-, (*=N)(C 1-3 -alkylene)-NHC(O)-, (*-NH)(C 1-3 -alkylene)-NHC(O)-, *-Z1-(C 3-6 -cycloalkenyl)-Z1-, *-S-, *-S(O)2- and *-C(O)NH-, wherein * represents the same 17 and Z1 is selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2-O-, -OC(O)NH-, -NHC(O)O-, -O-, -S-, and -NH-. In some embodiments of Formulas (XXIII'), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), and (XXIIIh'), R15 Selected from the group consisting of: (R 17 C(O)O)(CH(OC(O)R 17 ))(CH2)-Z1-、(R 17 )2N(C 1-3 -alkylene)-Z1-, R 17 Z1(C 1-3 -alkylene)-Z1-, R 17 Z1-(C 3-6 -cycloalkenylene)-Z1- and R 17 Z1-, where C 3-6 -cycloalkenylene is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and each Z1 is independently selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NH-. For example, R 15 Can be selected from the group consisting of: (R 17 C(O)O)(CH(OC(O)R 17 ))(CH2)-Z1-、(R 17 )2N(C 1-3 -alkylene)-NHC(O)-, R 17 NH(C 1-3 -alkylene)NHC(O)-, R 17 Z1-(C 3-6 -cycloalkenylene)-Z1-, R 17 S-、R 17 S(O)2- and R 17 C(O)NH-, wherein Z1 is selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2- and -NH-.

[0537] In some embodiments of Formula (XXIII'), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), and (XXIIIh'), R 15 Yes-L 12 (R15 ) q , that is, the POXZ copolymer is connected by the linker L 12 Conjugated to one or more hydrophobic chains (ie, R 17 ).

[0538] In any of the above embodiments of Formula (XXIII), (XXIIIa), (XXIIIb), (XXIII'), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), and (XXIIIh'), R 17 Preferably, each R is independently acyclic, more preferably a straight chain hydrocarbon group. 17 is preferably independently a hydrocarbyl group having at least 8 carbon atoms, such as at least 10 carbon atoms, preferably up to 30 carbon atoms, such as up to 28, 26, 24, 22, or 20 carbon atoms, or up to 16 carbon atoms, such as up to 15, 14, 13, 12, 11, or 10 carbon atoms. 17 is a hydrocarbon group having 10 to 16 carbon atoms, such as 10 to 15 or 10 to 14 carbon atoms. 17 is a straight chain hydrocarbon group having 10 to 16 carbon atoms, such as 10 to 15 or 10 to 14 carbon atoms.

[0539] In any of the above embodiments of Formula (XXIII'), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), and (XXIIIh'), each R 17 Preferred are hydrocarbon groups having 10 to 18 carbon atoms, such as straight-chain alkyl groups having 10 to 18 carbon atoms or straight-chain alkenyl groups having 10 to 18 carbon atoms. For example, the straight-chain alkenyl group may have 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms and 1, 2 or 3 carbon-carbon double bonds.

[0540] In any of the above embodiments of Formula (XXIII), (XXIIIa), (XXIIIb), (XXIII'), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), and (XXIIIh'), R 16 Preferably selected from the group consisting of: H, C 1-3 Alkyl, -OR 20 、-N3、C 2-6 Alkynyl, -OC(O)R 21 、-C(O)R 21 、-NR 22 R23 、-COOH、-C(O)NR 22 R 23 、-NR 22 C(O)R 21 and members of a targeting pair, where C 1-3 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NR 22 R 23 、-C(O)NR 22 R 23 、-NR 22 C(O)R 21 and a member of a targeting pair; R 20 Choose from H, C 1-3 The group consisting of an alkyl group and a 3- to 6-membered heterocyclic group, wherein C 1-3 Each of the alkyl and 3 to 6 membered heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, -COOH, -NR 22 R 23 and a member of a targeting pair; R 21 Choose from C 1-3 The group consisting of an alkyl group and a 3- to 6-membered heterocyclic group, wherein C 1-6 The alkyl and 3 to 6 membered heterocyclic groups are optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NR 22 R 23 and a member of a targeting pair; and R 22 and R 23 Each of which is independently selected from the group consisting of: H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, or R 22 and R 23 may be joined together with the nitrogen atom to which they are attached to form a heterocyclic group, wherein C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each of the alkynyl groups is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 and a member of a targeting pair.

[0541] In any of the above embodiments of Formula (XXIII), (XXIIIa), (XXIIIb), (XXIII'), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), and (XXIIIh'), R 16 Preferably selected from the group consisting of: H, C 1-3 Alkyl, -OR 20 、-N3、C 2-6 Alkynyl, -OC(O)R 21 、-C(O)R 21 、-NR 22 R 23 、-COOH、-C(O)NR 22 R 23 、-NR 22 C(O)R 21 and members of a targeting pair, where C 1-3 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NR 22 R 23 、-NR 22 C(O)R 21 and a member of a targeting pair; R 20 Selected from H and C 1-3 A group consisting of an alkyl group; R 21 It is C 1-3 Alkyl, optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NR 22 R 23 and a member of a targeting pair; and R 22 and R 23 Each of which is independently selected from the group consisting of: H, C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, where C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Each of the alkynyl groups is optionally substituted with one or more substituents independently selected from the group consisting of: -OH, SH, halogen, -CN, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NH(C 13 Alkyl), -N(C 1-3 alkyl)2 and a member of a targeting pair, or R 22 and R23 They may be joined together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic group.

[0542] In any of the above embodiments of Formula (XXIII), (XXIIIa), (XXIIIb), (XXIII'), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), and (XXIIIh'), R 16 Preferably selected from the group consisting of: H, C 1-3 Alkyl, -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -C(O)NH2, -C(O)NHCH3 and members of the targeted pair, wherein C 1-3 The alkyl group is optionally substituted with one or more (such as one or two) substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and members of a targeting pair.

[0543] In some embodiments of Formula (XXIII), (XXIIIa), and (XXIIIb), R 16 Selected from the group consisting of: H, -OH, -N3, C 2-6 alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and members of the targeting pair. In some embodiments of Formulas (XXIII), (XXIIIa), and (XXIIIb), R 16 Selected from the group consisting of: -OH, -N3, C 2-6alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and members of the targeting pair. In some embodiments of Formulas (XXIII), (XXIIIa), and (XXIIIb), R 16 Selected from the group consisting of: -OH, -N3, C 2-6 alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), -OC(O)(CH2)2COOH, and members of the targeting pair. In some embodiments of Formulas (XXIII), (XXIIIa), and (XXIIIb), R 16 Selected from the group consisting of: -OH, -N3, -NH2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3) and -OC(O)(CH2)2COOH.

[0544] In some embodiments of Formula (XXIII'), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), and (XXIIIh'), R 16 It is C 1-3 Alkyl, which is optionally substituted by one or two substituents independently selected from the group consisting of: -OH, -N3, C 2-6 alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and members of the targeting pair. In some embodiments of Formula (XXIII'), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), and (XXIIIh'), R 16 It is C 1-3 Alkyl, which is optionally substituted with a substituent selected from the group consisting of -COOH and -C(O)NH(CH2)2NH2.

[0545] In certain embodiments, the oxazolinylated and / or oxazinylated lipid has the following general formula or (XXIV):

[0546] R 15 -POXZ-R 16

[0547] in:

[0548] When attached to the N-terminus of the POXZ copolymer, R 15 Selected from the group consisting of: -L 12 R 17 、-(CH2)-CH(OC(O)R 17 )(CH2OC(O)R 17 )、-(CH2)-CH(SR 17 )2, and -(CH2)-CH(SR 17 )-CH2(SR 17 ), where each R 17 is independently a straight chain hydrocarbon group having at least 10 carbon atoms (preferably having 10 to 15 carbon atoms); and L 12 Selected from the group consisting of: *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)-, *-C(O)NH-(CH2)2-, *-S-(CH2)3-, *-S(O)2-(CH2)3- and *-OC(O)-(CH2)- (preferably, L 12 Selected from the group consisting of: *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)- and *-C(O)NH-(CH2)2-, such as *-NHC(O)-(CH2)- or *-NHC(O)-(CH2)2-), wherein * represents the 17 or when attached to the C-terminus of the POXZ copolymer, R 15 Selected from the group consisting of: (R 17 C(O)O)(CH(OC(O)R 17 ))(CH2)-Z1-、(R 17 )2N(C 1-3 -alkylene)-Z1-, R 17 Z1(C 1-3 -alkylene)-Z1-, R 17 Z1-(C 3-6 -cycloalkenylene)-Z1- and R 17 Z1-, where C 3-6 -cycloalkenylene is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3-alkyl; and each Z1 is independently selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2- and -NH-;

[0549] POXZ is a copolymer containing repeating units of the following general formulae (XXa) and (XXb):

[0550]

[0551] where R 11 each of which is independently methyl or ethyl and is independently selected for each repeating unit; the number of repeating units of formula (XXa) in the copolymer is 1 to 99 (preferably 1 to 79, 1 to 69 or 1 to 49); the number of repeating units of formula (XXb) in the copolymer is 1 to 99 (preferably 1 to 79, 1 to 69 or 1 to 49); the sum of the number of repeating units of formula (XXa) and the number of repeating units of formula (XXb) in the copolymer is 10 to 100 (preferably 20 to 80, 30 to 70 or 40 to 50); and the repeating units of formula (XXa) and (XXb) are arranged in a random, periodic, alternating or blockwise manner; and

[0552] R 16 Selected from the group consisting of: H, C 1-3 Alkyl, -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and members of the targeted pair, wherein C 1-3 The alkyl group is optionally substituted with one or more (such as one or two) substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and members of a targeting pair.

[0553] In R 15 is attached to the C-terminus (ie, the terminal C atom) of the POXZ copolymer and R 16When attached to the N-terminus (ie, the terminal N atom) of the POXZ copolymer, these embodiments of Formula (XXIV) are designated herein as Formula (XXIV').

[0554] In some embodiments of Formula (XXIV) or (XXIV'), each R 11 are all methyl or each R 11 In some alternative embodiments of formula (XXIV) or (XXIV'), for each repeating unit, R 11 are independently selected from methyl and ethyl, wherein in at least one repeating unit, R 11 is methyl, and in at least one repeating unit, R 11 It's ethyl.

[0555] In some embodiments of Formula (XXIV), wherein R 15 Connected to the N-terminus of the POXZ copolymer, R 15 Selected from the group consisting of: R 17 -NHC(O)-(CH2)-、R 17 -NHC(O)-(CH2)2-, -(CH2)-CH(OC(O)R 17 )(CH2OC(O)R 17 )、-(CH2)-CH(SR 17 )-CH2(SR 17 ), R 17 S-(CH2)3-、R 17 S(O)2-(CH2)3- and R 17 -OC(O)-(CH2)-; and / or R 16 Selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), -OC(O)(CH2)2COOH, and members of the targeting pair (e.g., R 16 Selected from the group consisting of: -OH, -N3, -NH2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3) and -OC(O)(CH2)2COOH).

[0556] In some embodiments of Formula (XXIV') (ie, R 15 connected to the C-terminus of the POXZ copolymer), R15 Selected from the group consisting of: R 17 C(O)NH-、R 17 S-、R 17 S(O)2- and R 17 NH-(3,4-dioxocyclobut-1-ene-1,2-diyl)-NH-; and / or R 16 It is C 1-3 Alkyl, which is optionally substituted by one or two substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2 and members of the targeting pair (e.g., R 16 It is C 1-3 alkyl, which is optionally substituted with one substituent selected from the group consisting of -COOH and -C(O)NH(CH2)2NH2).

[0557] In some embodiments, the oxazolinylated and / or oxazinylated lipid has one of the following formulas (XXV), (XXV'), (XXVI), or (XXVI'):

[0558]

[0559] where R 12 、R 13 and m are as specified above, in particular for any of formulae (XXI), (XXI′), (XXIa), (XXIa′), (XXIc), (XXId), (XXIe′), (XXIf′), (XXIg′), (XXIh′), (XXIi′), (XXIj′), (XXII), (XXII′), (XXIIa) and (XXIIa′).

[0560] In any of the above embodiments of formulae (XXV), (XXV'), (XXVI) and (XXVI'), m is preferably 10 to 100, such as 20 to 80, 30 to 70, or 40 to 50, for example 20 to 25 or 45 to 50.

[0561] In some embodiments, the oxazolinylated and / or oxazinylated lipid has one of the following formulas (XXVa), (XXVa'), (XXVIa), or (XXVIa'):

[0562]

[0563] wherein m is 20 to 25 or 45 to 50; and R 12 and R 13As specified above, in particular for any of formulae (XXI), (XXI′), (XXIa), (XXIa′), (XXIc), (XXId), (XXIe′), (XXIf′), (XXIg′), (XXIh′), (XXIi′), (XXIj′), (XXII), (XXII′), (XXIIa) and (XXIIa′).

[0564] In any of the above embodiments of Formulae (XXV), (XXVa), (XXVI), and (XXVIa), R 12 Preferably selected from the group consisting of: -L 11 R 14 、-(CH2)-CH(OC(O)R 14 )(CH2OC(O)R 14 )、-(CH2)-CH(SR 14 )2, and -(CH2)-CH(SR 14 )-CH2(SR 14 ), where each R 14 is independently a straight chain hydrocarbon group having at least 10 carbon atoms (and preferably up to 30 carbon atoms, such as up to 24 carbon atoms, for example having 10 to 16 carbon atoms, such as 10 to 14 carbon atoms); and L 11 Selected from the group consisting of: *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)-, *-C(O)NH-(CH2)2-, *-S-(CH2)3-, *-S(O)2-(CH2)3- and *-OC(O)-(CH2)- (preferably, L 11 Selected from the group consisting of: *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)- and *-C(O)NH-(CH2)2-, such as *-NHC(O)-(CH2)- or *-NHC(O)-(CH2)2-), wherein * represents the 14 Thus, in any of the above embodiments of Formulae (XXV), (XXVa), (XXVI), and (XXVIa), R 12 Can be selected from the group consisting of: R 14 -NHC(O)-(CH2)-、R 14 -NHC(O)-(CH2)2-, -(CH2)-CH(OC(O)R 14 )(CH2OC(O)R 14 )、-(CH2)-CH(SR 14 )-CH2(SR 14), R 14 S-(CH2)3-、R 14 S(O)2-(CH2)3- and R 14 -OC(O)-(CH2)-.

[0565] In any of the above embodiments of Formula (XXV'), (XXVa'), (XXVI'), and (XXVIa'), R 12 Preferably selected from the group consisting of: (R 14 C(O)O)(CH(OC(O)R 14 ))(CH2)-Z-、(R 14 )2N(C 1-3 -alkylene)-Z-, R 14 Z(C 1-3 -alkylene)-Z-, R 14 Z-(C 3-6 -cycloalkenylene)-Z- and R 14 Z-, where each R 14 is independently a straight chain hydrocarbon group having at least 10 carbon atoms (and preferably up to 30 carbon atoms, such as up to 24 carbon atoms, for example having 10 to 16 carbon atoms, such as 10 to 14 carbon atoms); C 3-6 -cycloalkenylene is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and each Z is independently selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NH-. Thus, in any of the above embodiments of Formulas (XXV'), (XXVa'), (XXVI'), and (XXVIa'), R 12 Can be selected from the group consisting of: R 14 C(O)NH-、R 14 S-、R 14 S(O)2- and R 14 NH-(3,4-dioxocyclobut-1-ene-1,2-diyl)-NH-.

[0566] In any of the above embodiments of Formula (XXV), (XXV'), (XXVa), (XXVa'), (XXVI), (XXVI'), (XXVIa), and (XXVIa'), R 13 Preferably selected from the group consisting of: H, C1-3 Alkyl, -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and members of the targeted pair, wherein C 1-3 The alkyl group is optionally substituted with one or more (such as one or two) substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and members of a targeting pair.

[0567] In any of the above embodiments of Formulae (XXV), (XXVa), (XXVI), and (XXVIa), R 13 Preferably selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), -OC(O)(CH2)2COOH, and members of a targeting pair such as selected from the group consisting of: -OH, -N3, -NH2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), and -OC(O)(CH2)2COOH.

[0568] In any of the above embodiments of Formula (XXV'), (XXVa'), (XXVI'), and (XXVIa'), R 13 C is preferred 1-3 Alkyl, which is optionally substituted by one or two substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2 and members of the targeting pair, more preferably, R 13 It is C 1-3 Alkyl, which is optionally substituted with a substituent selected from the group consisting of -COOH and -C(O)NH(CH2)2NH2.

[0569] In any of the above embodiments of formulae (XXV), (XXVa), (XXVI) and (XXVIa), preferred are:

[0570] R 12 Selected from the group consisting of: -L 11 R 14 、-(CH2)-CH(OC(O)R 14 )(CH2OC(O)R 14 )、-(CH2)-CH(SR 14 )2 and -(CH2)-CH(SR 14 )-CH2(SR 14 ), where each R 14 is independently a straight chain hydrocarbon group having at least 10 carbon atoms (and preferably up to 30 carbon atoms, such as up to 24 carbon atoms, or up to 16 carbon atoms, such as up to 15, 14, 13, 12, 11 or 10 carbon atoms, for example having 10 to 16 carbon atoms, such as 10 to 15 or 10 to 14 carbon atoms); and L 11 Selected from the group consisting of: *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)-, *-C(O)NH-(CH2)2-, *-S-(CH2)3-, *-S(O)2-(CH2)3- and *-OC(O)-(CH2)- (preferably, L 11 Selected from the group consisting of: *-NHC(O)-(CH2)-, *-NHC(O)-(CH2)2-, *-C(O)NH-(CH2)- and *-C(O)NH-(CH2)2-, such as *-NHC(O)-(CH2)- or *-NHC(O)-(CH2)2-), wherein * represents the 14 connection point; and

[0571] R 13 Selected from the group consisting of: -OH, -N3, C 2-6Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), -OC(O)(CH2)2COOH, and members of a targeting pair such as selected from the group consisting of: -OH, -N3, -NH2, -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -NH(CH2CH3), and -OC(O)(CH2)2COOH.

[0572] In any of the above embodiments of formula (XXV'), (XXVa'), (XXVI') and (XXVIa'), preferred are:

[0573] R 12 Selected from the group consisting of: (R 14 C(O)O)(CH(OC(O)R 14 ))(CH2)-Z-、(R 14 )2N(C 1-3 -alkylene)-Z-, R 14 Z(C 1-3 -alkylene)-Z-, R 14 Z-(C 3-6 -cycloalkenylene)-Z- and R 14 Z-, where each R 14 is independently a straight chain hydrocarbon group having at least 10 carbon atoms (and preferably up to 30 carbon atoms, such as up to 24 carbon atoms, for example having 10 to 16 carbon atoms, such as 10 to 14 carbon atoms); C 3-6 -cycloalkenylene is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: -OH, =O, -SH, halogen, -CN, -N3, and C 1-3 -alkyl; and each Z is independently selected from the group consisting of: -OP(O)2O(CH2)2NH-, -NH(CH2)2OP(O)2O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -O-, -C(O)O-, -OC(O)-, -S-, -S(O)2-, and -NH-; and

[0574] R 13 It is C 1-3 Alkyl, which is optionally substituted by one or two substituents independently selected from the group consisting of: -OH, -N3, C 2-6Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2 and members of the targeting pair, preferably, R 13 It is C 1-3 Alkyl, which is optionally substituted with a substituent selected from the group consisting of -COOH and -C(O)NH(CH2)2NH2.

[0575] In some embodiments, the oxazolinylated and / or oxazinylated lipid has one of the following formulas (XXVII), (XXVII'), (XXVIII), or (XXVIII'):

[0576]

[0577] where R 13 、R 14 and m are as specified above, particularly for any of Formulae (XXI), (XXI'), (XXIa), (XXIa'), (XXII), (XXII'), (XXIIa) and (XXIIa'). In some embodiments of Formulae (XXVII) or (XXVII'), R 14 is a straight chain hydrocarbon group having at least 10 carbon atoms and up to 16 carbon atoms (such as up to 15, 14, 13, 12, 11 or 10 carbon atoms, for example, having 10 to 16 carbon atoms, such as 10 to 15 or 10 to 14 carbon atoms). In some embodiments of Formula (XXVIII) or (XXVIII'), R 14 Independently is a straight chain hydrocarbon group having at least 10 carbons and up to 30 carbon atoms, such as up to 24, 22 or 20 carbon atoms, for example having 10 to 16 carbon atoms, such as 10 to 15 or 10 to 14 carbon atoms.

[0578] In any of the above embodiments of formula (XXVII), (XXVII'), (XXVIII) or (XXVIII'), m is preferably 10 to 100, such as 20 to 80, 30 to 70, or 40 to 50, for example 20 to 25 or 45 to 50.

[0579] In some embodiments, the oxazolinylated and / or oxazinylated lipid has one of the following formulas (XXVIIa) or (XXVIIIa):

[0580]

[0581] where R 13 、R 14and m are as specified above, in particular for any of formulae (XXI), (XXI′), (XXIa), (XXIa′), (XXII), (XXII′), (XXIIa) and (XXIIa′).

[0582] In any of the above embodiments of Formulae (XXVII), (XXVII'), (XXVIIa), (XXVIII), (XXVIII'), and (XXVIIIa), each R 14 is preferably independently a straight chain hydrocarbon group having at least 10 carbon atoms (and preferably up to 30 carbon atoms, such as up to 24 carbon atoms, for example having 10 to 16 carbon atoms). In some embodiments of Formulas (XXVII), (XXVII') and (XXVIIa), R 14 is a straight chain hydrocarbon group having at least 10 carbon atoms and up to 16 carbon atoms (such as up to 15, 14, 13, 12, 11 or 10 carbon atoms, for example, having 10 to 16 carbon atoms, such as 10 to 15 or 10 to 14 carbon atoms). In some embodiments of Formulas (XXVIII), (XXVIII') and (XXVIIIa), R 14 Independently is a straight chain hydrocarbon group having at least 10 carbons and up to 30 carbon atoms, such as up to 24, 22 or 20 carbon atoms, for example having 10 to 16 carbon atoms, such as 10 to 15 or 10 to 14 carbon atoms.

[0583] In any of the above embodiments of Formula (XXVII), (XXVII'), (XXVIIa), (XXVIII), (XXVIII'), and (XXVIIIa), R 13 Preferably selected from the group consisting of: H, C 1-3 Alkyl, -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and members of the targeted pair, wherein C 1-3 The alkyl group is optionally substituted with one or more (such as one or two) substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and members of a targeting pair.

[0584] In any of the above embodiments of formula (XXVII), (XXVII'), (XXVIIa), (XXVIII), (XXVIII') and (XXVIIIa), preferred are:

[0585] Each R 14 is independently a straight chain hydrocarbon group having at least 10 carbon atoms (and preferably up to 30 carbon atoms, such as up to 24 carbon atoms, for example having 10 to 16 carbon atoms, such as 10 to 14 carbon atoms); and

[0586] R 13 Selected from the group consisting of: H, C 1-3 Alkyl, -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and members of the targeted pair, wherein C 1-3 The alkyl group is optionally substituted with one or more (such as one or two) substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and members of a targeting pair.

[0587] In this regard, for formula (XXVII') and (XXVIII'), it is preferred that R 13 It is C 1-3 Alkyl, which is optionally substituted by one or two substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2 and members of the targeting pair, more preferably, R 13 It is C 1-3 Alkyl, which is optionally substituted with a substituent selected from the group consisting of -COOH and -C(O)NH(CH2)2NH2.

[0588] In any of the above embodiments of formula (XXVII), (XXVII') and (XXVIIa), preferred are:

[0589] Each R 14is independently a straight chain hydrocarbon group having at least 10 carbon atoms (and preferably up to 16 carbon atoms, such as up to 15, 14, 13, 12, 11 or 10 carbon atoms, for example having 10 to 16 carbon atoms, such as 10 to 15 or 10 to 14 carbon atoms); and

[0590] R 13 Selected from the group consisting of: H, C 1-3 Alkyl, -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and members of the targeted pair, wherein C 1-3 The alkyl group is optionally substituted with one or more (such as one or two) substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and members of a targeting pair.

[0591] In this respect, for formula (XXVII'), it is preferred that R 13 It is C 1-3 Alkyl, which is optionally substituted by one or two substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2 and members of the targeting pair, more preferably, R 13 It is C 1-3 Alkyl, which is optionally substituted with a substituent selected from the group consisting of -COOH and -C(O)NH(CH2)2NH2.

[0592] In any of the above embodiments of formula (XXVIII), (XXVIII') and (XXVIIIa), preferred are:

[0593] Each R 14 is independently a straight chain hydrocarbon group having at least 10 carbon atoms (and preferably up to 30 carbon atoms, such as up to 24 carbon atoms, for example having 10 to 15 carbon atoms); and

[0594] R 13 Selected from the group consisting of: H, C1-3 Alkyl, -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3), -NHC(O)(CH2)2COOH, -N(CH2CH3)C(O)(CH2)2COOH, -N(CH2CH3)C(O)CH3, -C(O)NH2, -C(O)NHCH3, -OC(O)(CH2)2COOH, and members of the targeted pair, wherein C 1-3 The alkyl group is optionally substituted with one or more (such as one or two) substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2, and members of a targeting pair.

[0595] In this respect, for formula (XXVIII'), it is preferred that R 13 It is C 1-3 Alkyl, which is optionally substituted by one or two substituents independently selected from the group consisting of: -OH, -N3, C 2-6 Alkynyl, -COOH, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)NH(CH2)2NH2 and members of the targeting pair, more preferably, R 13 It is C 1-3 Alkyl, which is optionally substituted with a substituent selected from the group consisting of -COOH and -C(O)NH(CH2)2NH2.

[0596] Specific examples of oxazolinated and / or oxazinated lipids are the following compounds (XXI-1) to (XXI-34) and (XXI'-35) to (XXI'-48):

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605] In each case, C 14 H 29 Refers to the part -(CH2) 13 CH3, and in each case C 13 H 27 Refers to the part -(CH2) 12 CH3.

[0606] In some embodiments, the oxazolinated and / or oxazinylated lipids are selected from any one of formulae (XXIa), (XXIa'), (XXIb), (XXIb'), (XXIc), (XXId), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), (XXIj'), (XXII), (XXII'), (XXIIa), (XXIIa'), (XXIIb), (XXIIb'), (XXIII), (XXIII'), (XXIIIa), (XXIIIb), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), (XXIIIh'), (XXIV), (XXIV'), (XXV), (XXV'), (XXVa), (XXVa'), (XXVI), (XXVI'), (XXVIa), (XXVIa'), (XXVII), (XXVII'), (XXVIIa), (XXVIII), (XXVIII'), (XXVIIIa), (XXI-1), (XXI-2), (XXI-3), (XXI-4), (XXI-5), (XXI-6), (XXI-7), (XXI-8), (XXI-9), (XXI-10), (XXI-11), (XXI-12), (XXI-13), (XXI-14), (XXI-15), (XXI-16), (XXI-17), (XXI-18), (XXI-19), (XXI-20), (XXI-21), (XXI-22), (XXI-23), (XXI-24), (XXI-25), (XXI-26), (XXI-27), (XXI-28), (XXI-29), (XXI-30), (XXI-31), (XXI-32), (XXI-33), (XXI-34), (XXI'-35), (XXI'-36), (XXI'-37), (XXI'-38), (XXI'-39), (XXI'-40), (XXI'-41), (XXI'-42), (XXI'-43), (XXI'-44), (XXI'-45), (XXI'-46), (XXI'-47), and (XXI'-48).

[0607] In some embodiments, the nucleic acid compositions described herein (such as DNA or RNA compositions, especially mRNA compositions) may comprise a cationic / cationically ionizable lipid as described herein (e.g., a cationic ionizable lipid of formula (I), (X) or (XI)), an oxazolinylated and / or oxazinylated lipid as described herein, a phospholipid as described herein, and cholesterol, wherein the oxazolinylated and / or oxazinylated lipid is preferably or includes any one of the following: Formula (XXIa), (XXIa'), (XXIb), (XXIb'), (XXIc), (XXId), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi' ), (XXIj'), (XXII), (XXII'), (XXIIa), (XXIIa'), (XXIIb), (XXIIb'), (XXIII), (XXIII'), (XXIIIa), (XXIIIb), (XXIIIc'), (XXIIId'), (XXIII e'), (XXIIIf'), (XXIIIg'), (XXIIIh'), (XXIV), (XXIV'), (XXV), (XXV'), (XXVa), (XXVa'), (XXVI), (XXVI'), (XXVIa), (XXVIa'), (XXVII), (XX VII'), (XXVIIa), (XXVIII), (XXVIII'), (XXVIIIa), (XXI-1), (XXI-2), (XXI-3), (XXI-4), (XXI-5), (XXI-6), (XXI-7), (XXI-8), (XXI-9), (XXI -10), (XXI-11), (XXI-12), (XXI-13), (XXI-14), (XXI-15), (XXI-16), (XXI-17), (XXI-18), (XXI-19), (XXI-20), (XXI-21), (XXI-22), (XXI-23 ), (XXI-24), (XXI-25), (XXI-26), (XXI-27), (XXI-28), (XXI-29), (XXI-30), (XXI-31), (XXI-32), (XXI-33), (XXI-34), (XXI'-35), (XXI'-36) , (XXI'-37), (XXI'-38), (XXI'-39), (XXI'-40), (XXI'-41), (XXI'-42), (XXI'-43), (XXI'-44), (XXI'-45), (XXI'-46), (XXI'-47) and (XXI'-48).

[0608] In some embodiments, the oxazolinylated and / or oxazinylated lipids constitute about 0.1 mol% to about 10 mol% of the total lipids present in the nucleic acid compositions described herein, such as DNA or RNA compositions, particularly mRNA compositions, such as about 0.2 mol% to about 9 mol%, about 0.5 mol% to about 8 mol%, about 1 mol% to about 7.5 mol%, about 1.5 mol% to about 7 mol%, about 2 mol% to about 6.5 mol%, about 2.5 mol% to about 6 mol%, or about 3 mol% to about 5 mol%.

[0609] In some embodiments, wherein at least a portion of (i) nucleic acid (such as DNA or RNA, particularly mRNA), (ii) cationic / cationically ionizable lipids, and (iii) oxazolinylated and / or oxazinylated lipids form particles (e.g., nanoparticles, such as LNPs), the oxazolinylated and / or oxazinylated lipids may constitute from about 0.1 mol% to about 10 mol%, such as from about 0.2 mol% to about 9 mol%, from about 0.5 mol% to about 8 mol%, from about 1 mol% to about 7.5 mol%, from about 1.5 mol% to about 7 mol%, from about 2 mol% to about 6.5 mol%, from about 2.5 mol% to about 6 mol%, or from about 3 mol% to about 5 mol% of the total lipids present in the particles.

[0610] In some embodiments, the nucleic acid compositions described herein (such as DNA or RNA compositions, particularly mRNA compositions) may comprise a cationic / cationically ionizable lipid as described herein (e.g., a cationic ionizable lipid of formula (X) or (XI)), an oxazolinylated and / or oxazinylated lipid as described herein, a phospholipid, and cholesterol, wherein the cationic / cationically ionizable lipid constitutes about 40 mol% to about 50 mol% of the total lipids present in the composition, the oxazolinylated and / or oxazinylated lipid constitutes about 0.5 mol% to about 10 mol% (such as about 2 mol% to about 5 mol%) of the total lipids present in the composition, the phospholipid constitutes about 5 mol% to about 15 mol% of the total lipids present in the composition, and cholesterol constitutes about 30 mol% to about 50 mol% of the total lipids present in the composition.In some embodiments, the oxazolinated and / or oxazinylated lipids have any one of formulae (XXIa), (XXIa'), (XXIb), (XXIb'), (XXIc), (XXId), (XXIe'), (XXIf'), (XXIg'), (XXIh'), (XXIi'), (XXIj'), (XXII), (XXII'), (XXIIa), (XXIIa'), (XXIIb), (XXIIb'), (XXIII), (XXIII'), (XXIIIa), (XXIIIb), (XXIIIc'), (XXIIId'), (XXIIIe'), (XXIIIf'), (XXIIIg'), (XXIIIh'), (XXIV), (XXIV'), (XXV), (XXV'), (XXVa), (XXVa'), (XXVI), (XXVI'), (XXVIa), (XXVIa'), (XXVII), (XXVII'), (XXVIIa), (XXVIII), (XXVIII'), (XXVIIIa), (XXI-1), (XXI-2), (XXI-3), (XXI-4), (XXI-5), (XXI-6), (XXI-7), (XXI-8), (XXI-9), (XXI-10), (XXI-11), (XXI-12), (XXI-13), (XXI-14), (XXI-15), (XXI-16), (XXI-17), (XXI-18), (XXI-19), (XXI-20), (XXI-21), (XXI-22), (XXI-23), (XXI-24), (XXI-25), (XXI-26), (XXI-27), (XXI-28), (XXI-29), (XXI-30), (XXI-31), (XXI-32), (XXI-33), (XXI-34), (XXI'-35), (XXI'-36), (XXI'-37), (XXI'-38), (XXI'-39), (XXI'-40), (XXI'-41), (XXI'-42), (XXI'-43), (XXI'-44), (XXI'-45), (XXI'-46), (XXI'-47), and (XXI'-48).

[0611] In some embodiments, the polymer-conjugated lipid is about 0.5 to about 5 mol% relative to the total lipid in the LNP. In some embodiments, the LNP comprises about 1.0 to about 2.5 mol% of polymer-conjugated lipid. In some embodiments, the LNP comprises about 1.5 to about 2.0 mol% of polymer-conjugated lipid. In some embodiments, the LNP comprises about 1.5 to about 1.8 mol% of polymer-conjugated lipid.

[0612] In some embodiments, the molar ratio of total cationic lipids to total polymer-conjugated lipids (e.g., PEG-conjugated lipids) is from about 100: 1 to about 20: 1. In some embodiments, the molar ratio of total cationic lipids to total polymer-conjugated lipids (e.g., PEG-conjugated lipids) is from about 50: 1 to about 20: 1. In some embodiments, the molar ratio of total cationic lipids to total polymer-conjugated lipids (e.g., PEG-conjugated lipids) is from about 40: 1 to about 20: 1. In some embodiments, the molar ratio of total cationic lipids to total polymer-conjugated lipids (e.g., PEG-conjugated lipids) is from about 35: 1 to about 25: 1.

[0613] Immunomodulators

[0614] As described herein, the lipid nanoparticles comprise an immunomodulator. In some embodiments, the immunomodulator is an immunosuppressant. In some embodiments, the immunomodulator is an immunostimulator. In some embodiments, the immunomodulator is an agent (e.g., a small molecule) that is an agonist or antagonist of a Toll-like receptor (e.g., TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10) or pattern recognition receptor (PRR). In some embodiments, the immunomodulator is a sp 2 -iminoglycolipids. In some embodiments, the immunomodulator is a small molecule downstream inhibitor of NF-κβ. In some embodiments, the immunomodulator is sp 2 -Iminosaccharide glycolipids. In some embodiments, the immunomodulator is an inflammasome inhibitor.

[0615] In some embodiments, the lipid nanoparticles described herein do not comprise dexamethasone or a dexamethasone prodrug (e.g., dexamethasone conjugated to a biodegradable linker).

[0616] In some embodiments, the immunomodulator is a TLR inhibitor. In some embodiments, the TLR inhibitor is an inhibitor of TLR2, TLR4, and / or TLR6. In some embodiments, the TLR inhibitor is an inhibitor of TLR2. In some embodiments, the immunomodulator is an inhibitor of TLR4. In some embodiments, the immunomodulator is an inhibitor of TLR6. In some embodiments, the inhibitor of TLR4 is TAK-242:

[0617]

[0618] or a pharmaceutically acceptable salt thereof.

[0619] In some embodiments, the immunomodulator is a terpenoid. In some embodiments, the terpenoid is a triterpenoid. In some embodiments, the immunomodulator is a triterpenoid. In some embodiments, the triterpenoid is a synthetic or natural derivative of amyl alcohol, betulinic acid, oleanolic acid, sterols, squalene, or ursolic acid.

[0620] In some embodiments, the immunomodulator is a corticosteroid. In some embodiments, the corticosteroid is a glucocorticoid. In some embodiments, the glucocorticoid is selected from: dexamethasone, prednisolone, fluticasone propionate, budesonide, or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid is dexamethasone or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid is prednisolone or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid is fluticasone or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid is propionate or a pharmaceutically acceptable salt thereof. In some embodiments, the glucocorticoid is budesonide or a pharmaceutically acceptable salt thereof.

[0621] In some embodiments, the immunomodulator is an inflammasome inhibitor. In some embodiments, the inflammasome inhibitor is an NLRP3 inflammasome inhibitor, an AIM2 inflammasome inhibitor, a caspase-1 inhibitor, or a pan-casase inhibitor. In some embodiments, the inflammasome inhibitor is selected from glyburide (i.e., glibenclamide), 5-chloro-2-methoxy-N-[2-(4-sulfamoylphenyl)-ethyl]-benzamide (i.e., 16673-34-0), JC124, FC11A-2, parthenolide, VX-740, VX-765, BAY 11-7082, BHB, MCC950, MNS, CY-09, tranilast, OLT1177, and Rubescensine A. In some embodiments, the inflammasome inhibitor is glyburide (i.e., glibenclamide).

[0622]

[0623] Glyburide

[0624] In some embodiments, the inflammasome inhibitor is 5-chloro-2-methoxy-N-[2-(4-sulfamoylphenyl)-ethyl]-benzamide (ie, 16673-34-0).

[0625]

[0626] In some embodiments, the inflammasome inhibitor is JC124.

[0627]

[0628] In some embodiments, the inflammasome inhibitor is FC11A-2.

[0629]

[0630] In some embodiments, the inflammasome inhibitor is parthenolide.

[0631]

[0632] Parthenolide

[0633] In some embodiments, the inflammasome inhibitor is VX-740.

[0634]

[0635]

[0636] In some embodiments, the inflammasome inhibitor is VX-765.

[0637]

[0638] In some embodiments, the inflammasome inhibitor is BAY 11-7082.

[0639]

[0640] In some embodiments, the inflammasome inhibitor is beta hydroxybutyrate (BHB).

[0641] In some embodiments, the inflammasome inhibitor is MCC950.

[0642]

[0643] In some embodiments, the inflammasome inhibitor is 3,4-methylenedioxy-β-nitrostyrene (MNS).

[0644] In some embodiments, the inflammasome inhibitor is CY-09.

[0645]

[0646] In some embodiments, the inflammasome inhibitor is tranilast.

[0647]

[0648] Tranilast

[0649] In some embodiments, the inflammasome inhibitor is OLT1177.

[0650]

[0651] In some embodiments, the inflammasome inhibitor is Rubescensine A.

[0652]

[0653] Rubescensine A

[0654] In some embodiments, lipid nanoparticles as described herein include more than one immunomodulator. In some embodiments, lipid nanoparticles include immunomodulators and one or more other immunomodulators. In some embodiments, lipid nanoparticles include terpenes (for example, corticosteroids or glucocorticoids, such as dexamethasone, prednisolone, fluticasone propionate, or budesonide, or inflammasome inhibitors) and one or more other immunomodulators (for example, another corticosteroid or glucocorticoid, such as dexamethasone, prednisolone, fluticasone propionate or budesonide, or TLR or PRR agonists or antagonists, or inflammasome inhibitors, as described herein). In some embodiments, lipid nanoparticles include terpenes (including any subclass as described herein) and TLR or PRR small molecule agonists or antagonists (including any subclass as described herein, such as TAK-242) immunomodulators.

[0655] In some embodiments, the lipid nanoparticles described herein comprise cationic lipids and immunomodulators, wherein the immunomodulator is a TLR inhibitor. In some embodiments, the lipid nanoparticles comprise cationic lipids and immunomodulators, wherein the immunomodulator is an inflammasome inhibitor. In some embodiments, the lipid nanoparticles comprise cationic lipids, RNA, and an immunomodulator selected from TAK-242, MCC950, and BAY 11-7082. In some embodiments, the lipid nanoparticles comprise cationic lipids, RNA, and TAK-242. In some embodiments, the lipid nanoparticles comprise cationic lipids, RNA, and MCC950. In some embodiments, the lipid nanoparticles comprise cationic lipids, RNA, and BAY 11-7082.

[0656] In some embodiments, the lipid nanoparticles comprise from about 0.1 to about 50 mol % of an immunomodulator (relative to the total amount of lipid and immunomodulator). In some embodiments, the lipid nanoparticles comprise from about 1 to about 50 mol % of an immunomodulator (relative to the total amount of lipid and immunomodulator). In some embodiments, the lipid nanoparticles comprise from about 30 to about 50 mol % of an immunomodulator (relative to the total amount of lipid and immunomodulator). In some embodiments, the lipid nanoparticles comprise from about 30 to about 50 mol % of an immunomodulator (relative to the total amount of lipid and immunomodulator). In some embodiments, the lipid nanoparticles comprise from about 30 to about 35 mol % of an immunomodulator (relative to the total amount of lipid and immunomodulator). In some embodiments, the lipid nanoparticles comprise from about 35 to about 45 mol % of an immunomodulator (relative to the total amount of lipid and immunomodulator). In some embodiments, the lipid nanoparticles comprise from about 40 to about 50 mol % of an immunomodulator (relative to the total amount of lipid and immunomodulator). In some embodiments, the lipid nanoparticle comprises about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mol% immunomodulator (relative to the total amount of lipid and immunomodulator).

[0657] In some embodiments, the nucleic acid particle comprises i) about 30 to about 50 mol% of a cationic lipid; ii) about 1 to about 5 mol% of a polymer-conjugated lipid; iii) about 5 to about 15 mol% of a helper lipid, and iv) an immunomodulator. In some embodiments, the nucleic acid particle comprises: i) about 30 to about 50 mol% of ALC-0315; ii) about 1 to about 5 mol% of ALC-0159; iii) about 5 to about 15 mol% of DSPC, and iv) an immunomodulator. In some embodiments, the nucleic acid particle comprises: i) about 30 to about 50 mol% of ALC366; ii) about 1 to about 5 mol% of ALC-0159; iii) about 5 to about 15 mol% of DSPC, and iv) an immunomodulator.

[0658] In some embodiments, the nucleic acid particle comprises: i) about 47.5 mol% ALC-0315; ii) about 1.8 mol% ALC-0159; and iii) about 10 mol% DSPC. In some embodiments, the nucleic acid particle comprises: i) about 47.5 mol% ALC366; ii) about 1.8 mol% ALC-0159; and iii) about 10 mol% DSPC.

[0659] In some embodiments, the nucleic acid particle comprises: i) about 30 to about 50 mol% SM-102; ii) about 1 to about 5 mol% PEG2000-DMG; iii) about 5 to about 15 mol% DSPC; and iv) an immunomodulator. In some embodiments, the nucleic acid particle comprises: i) about 50 mol% SM-102; ii) about 1.5 mol% PEG2000-DMG; iii) about 10 mol% DSPC; and iv) an immunomodulator. In some embodiments, the immunomodulator is TAK-242, MCC950, or BAY 11-7082. In some embodiments, the nucleic acid particle comprises: i) about 50 mol% SM-102; ii) about 1.5 mol% PEG2000-DMG; iii) about 10 mol% DSPC; and iv) TAK-242. In some embodiments, the nucleic acid particle comprises: i) about 50 mol% SM-102; ii) about 1.5 mol% PEG2000-DMG; iii) about 10 mol% DSPC; and iv) MCC950. In some embodiments, the nucleic acid particle comprises: i) about 50 mol% SM-102; ii) about 1.5 mol% PEG2000-DMG; iii) about 10 mol% DSPC; and iv) BAY 11-7082.

[0660] Terpenes

[0661] As described herein, in some embodiments, the nucleic acid particle further comprises a terpenoid. In some embodiments, the terpenoid is a triterpenoid. In some embodiments, the terpenoid is a steroid. In some embodiments, the steroid is a sterol. In some embodiments, the sterol is β-sitosterol, stigmasterol, cholesterol, cholecalciferol, ergocalciferol, calcipotriol, botulin, lupeol, ursolic acid, oleanolic acid, cycloartenol, lanosterol, or α-tocopherol. In some embodiments, the sterol is β-sitosterol. In some embodiments, the sterol is stigmasterol. In some embodiments, the sterol is cholesterol. In some embodiments, the sterol is cholecalciferol. In some embodiments, the sterol is ergocalciferol. In some embodiments, the sterol is calcipotriol. In some embodiments, the sterol is botulin. In some embodiments, the sterol is lupeol. In some embodiments, the sterol is ursolic acid. In some embodiments, the sterol is oleanolic acid. In some embodiments, the sterol is cycloartenol. In some embodiments, the sterol is lanosterol. In some embodiments, the sterol is alpha-tocopherol.

[0662] In some embodiments, the lipid nanoparticles comprise about 30 to about 50 mol% of the steroid. In some embodiments, the lipid nanoparticles comprise about 35 to about 45 mol% of the steroid. In some embodiments, the lipid nanoparticles comprise about 38 to about 40 mol% of the steroid. In some embodiments, the lipid nanoparticles comprise about 38.5 mol% of the steroid. In some embodiments, the lipid nanoparticles comprise about 40 mol% of the steroid.

[0663] In some embodiments, the lipid nanoparticles comprise about 30 to about 50 mol% cholesterol. In some embodiments, the lipid nanoparticles comprise about 35 to about 45 mol% cholesterol. In some embodiments, the lipid nanoparticles comprise about 38 to about 41 mol% cholesterol. In some embodiments, the lipid nanoparticles comprise about 38.5 mol% cholesterol. In some embodiments, the lipid nanoparticles comprise about 40.7 mol% cholesterol.

[0664] Method for preparing lipid nanoparticles

[0665] Lipids and lipid nanoparticles containing nucleic acids and methods for preparing the same are known in the art, including, for example, U.S. Patent Nos. 8,569,256, 5,965,542 and U.S. Patent Publication Nos. 2016 / 0199485, 2016 / 0009637, 2015 / 0273068, 2015 / 0265708, 2015 / 0203446, 2015 / 0005363, 2014 / 03 08304, 2014 / 0200257, 2013 / 086373, 2013 / 0338210, 2013 / 0323269, 2013 / 0245107, 2013 / 0195920, 2013 / 0123338, 2013 / 0022649, 2013 / 0017223, 2012 / 0295832, 2012 / 0183581, 201 2 / 0172411, 2012 / 0027803, 2012 / 0058188, 2011 / 0311583, 2011 / 0311582, 2011 / 0262527, 2011 / 0216622, 2011 / 0117125, 2011 / 0091525, 2011 / 0076335, 2011 / 0060032, 2010 / 013058 8, 2007 / 0042031, 2006 / 0240093, 2006 / 0083780, 2006 / 0008910, 2005 / 0175682, 2005 / 017054, 2005 / 0118253, 2005 / 0064595, 2004 / 0142025, 2007 / 0042031, 1999 / 009076 and PCT Publication No. WO 99 / 39741, WO 2018 / 081480, WO 2017 / 004143, WO 2017 / 075531, WO 2015 / 199952, WO 2014 / 008334, WO 2013 / 086373, WO 2013 / 086322, WO 2013 / 016058, WO 2013 / 086373, WO2011 / 141705 and WO 2001 / 07548, the complete disclosures of which are incorporated herein by reference in their entireties for the purposes described herein.

[0666] For example, in some embodiments, cationic lipids, helper lipids and immunomodulators are dissolved in ethanol with a predetermined weight or molar ratio / percentage (e.g., those described herein). In some embodiments, lipid nanoparticles (LNPs) are prepared with a total lipid and RNA weight ratio of approximately 10:1 to 30:1. In some embodiments, such RNA can be diluted to 0.2 mg / mL in acetate buffer.

[0667] In some embodiments, using the ethanol injection technique, colloidal lipid dispersions containing RNA can be formed by injecting an ethanol solution containing lipids (such as cationic lipids, helper lipids, immunomodulators, and polymer-conjugated lipids) into an aqueous solution containing RNA (e.g., those described herein).

[0668] In some embodiments, lipid and RNA solutions can be mixed at room temperature by pumping each solution (e.g., a lipid solution comprising a cationic lipid, a helper lipid, an immunomodulator, and any other additive) into a mixing unit (e.g., using a piston pump) at a controlled flow rate. In some embodiments, the flow rate at which the lipid solution and the RNA solution enter the mixing unit is maintained at a ratio of 1:3. After mixing, when the ethanol lipid solution is diluted with aqueous RNA, nucleic acid-lipid particles are formed. The lipid solubility decreases while the positively charged cationic lipid interacts with the negatively charged RNA.

[0669] In some embodiments, the solution comprising RNA-encapsulated lipid nanoparticles may be processed by one or more of concentration adjustment, buffer exchange, formulation, and / or filtration.

[0670] Polymer-based particles

[0671] In some embodiments, nucleic acid particles as described herein include cationic polymers, RNA and immunomodulators. Examples of nucleic acid particles suitable for RNA delivery are described in PCT Application Publication No. WO 2021 / 001417, which is incorporated herein by reference in its entirety. As generally described above, complexes as described herein include cationic polymers. In some embodiments, cationic polymers are polycationic polymers, such as polymers with one or more cations or ionizable groups. As described herein, a "cationic" group is a group with a net positive charge. As used herein, an "ionizable" group is a group that can have a neutral charge at a certain pH but can be changed to a charged (e.g., cationic) group at different pH values. For example, in some embodiments, an ionizable group becomes a cationic (i.e., positively charged) group at physiological pH (e.g., a pH of about 7.4). Therefore, it should be understood that reference to cationic polymers refers to neutral form and charged (i.e., ionic) form. It should also be understood by those skilled in the art that cationic groups as described herein can also exist as salts (e.g., pharmaceutically acceptable salts) comprising cationic groups and one or more suitable counterions. For example, in some embodiments, cationic groups as described herein include ammonium chloride. Suitable counterions include halogens (e.g., Br - 、Cl - , I - 、F - ), acetate (e.g., C(O)O -) etc. For additional examples, see the definition of pharmaceutically acceptable salts described herein.

[0672] In some embodiments, one or more cationic or ionizable groups comprises a nitrogen atom.Cationic polymers useful in preparing the complexes described herein can be homopolymers, heteropolymers, or block copolymers.

[0673] In some embodiments, the cationic polymer is poly(ethyleneimine), poly(propyleneimine), polybrene, polyallylamine, polyvinylamine, polyamidoamine, poly-L-lysine, poly-L-arginine, poly-L-histidine, and poly(2-aminoethyl methacrylate), or a pharmaceutically acceptable salt thereof.

[0674] In some embodiments, the cationic polymer is a homopolymer. In some embodiments, the cationic polymer is a homopolymer selected from the group consisting of poly(ethyleneimine), poly(propyleneimine), polybrene, polyallylamine, polyvinylamine, polyamidoamine, poly-L-lysine, poly-L-arginine, poly-L-histidine, and poly(2-aminoethyl methacrylate), or a pharmaceutically acceptable salt thereof.

[0675] It should be understood that the cationic polymers described herein can be linear or branched. In some embodiments, the cationic polymer is linear. In some embodiments, the cationic polymer is a linear polymer selected from poly (ethyleneimine), poly (propyleneimine), polybrene, polyallylamine, polyethyleneamine, polyamidoamine, poly-L-lysine, poly-L-arginine, poly-L-histidine and poly (2-aminoethyl methacrylate) or a pharmaceutically acceptable salt thereof. In some embodiments, the cationic polymer is a branched polymer selected from poly (ethyleneimine), poly (propyleneimine), polybrene, polyallylamine, polyethyleneamine, polyamidoamine, poly-L-lysine, poly-L-arginine, poly-L-histidine and poly (2-aminoethyl methacrylate) or a pharmaceutically acceptable salt thereof. In some embodiments, the cationic polymer is linear poly(ethyleneimine), poly(propyleneimine), polybrene, polyallylamine, polyvinylamine, polyamidoamine, poly-L-lysine, poly-L-arginine, poly-L-histidine, and poly(2-aminoethyl methacrylate), or a pharmaceuticall...

Claims

1. A nucleic acid particle comprising RNA, an immunomodulator and a cationic lipid or a cationic polymer.

2. The nucleic acid particle of claim 1, wherein the immunomodulator is not dexamethasone or a dexamethasone prodrug.

3. The nucleic acid particle of claim 1 or 2, wherein the immunomodulator is about 0.001 to about 50 mol % of the total amount of lipid or polymer and immunomodulator in the nucleic acid particle.

4. The nucleic acid particle of any one of claims 1-3, wherein the immunomodulator is about 0.01 to about 0.9 mol % of the total amount of lipid or polymer and immunomodulator in the nucleic acid particle.

5. The nucleic acid particle of any one of claims 1-4, wherein the immunomodulator is a small molecule agonist or antagonist of a TLR or PRR receptor.

6. The nucleic acid particle of any one of claims 1-4, wherein the immunomodulator is a small molecule downstream inhibitor of NF-κβ.

7. The nucleic acid particle of any one of claims 1 to 4, wherein the immunomodulator is sp 2 -Iminose glycolipid.

8. The nucleic acid particle of any one of claims 1-4, wherein the immunomodulator is a TLR inhibitor.

9. The nucleic acid particle of claim 8, wherein the TLR inhibitor is an inhibitor of TLR2, TLR4 and / or TLR6.

10. The nucleic acid particle of claim 9, wherein the TLR inhibitor is an inhibitor of TLR4. The nucleic acid particle of claim 10 , wherein the inhibitor of TLR4 is TAK-242.

12. The nucleic acid particle of any one of claims 1-4, wherein the immunomodulator is a terpenoid.

13. The nucleic acid particle of claim 12, wherein the terpenoid is a triterpene.

14. The nucleic acid particle of claim 13, wherein the triterpene is a synthetic or natural derivative of amyl alcohol, betulinic acid, oleanolic acid, sterols, squalene or ursolic acid.

15. The nucleic acid particle of claim 14, wherein the immunomodulator is a sterol.

16. The nucleic acid particle of claim 15, wherein the sterol is a corticosteroid.

17. The nucleic acid particle of claim 16, wherein the corticosteroid is a glucocorticoid.

18. The nucleic acid particle of claim 17, wherein the glucocorticoid is prednisolone, fluticasone propionate, budesonide, or a pharmaceutically acceptable salt thereof.

19. The nucleic acid particle of any one of claims 1-4, wherein the immunomodulator is an inflammasome inhibitor.

20. The nucleic acid particle of claim 19, wherein the inflammasome inhibitor is a NLRP3 inflammasome inhibitor, an AIM2 inflammasome inhibitor, a caspase-1 inhibitor, or a pan-casase inhibitor.

21. The nucleic acid particle of claim 20, wherein the inflammasome inhibitor is selected from glyburide (e.g., glibenclamide), 5-chloro-2-methoxy-N-[2-(4-sulfamoylphenyl)-ethyl]-benzamide (e.g., 16673-34-0), JC124, FC11A-2, parthenolide, VX-740, VX-765, BAY 11-7082, BHB, MCC950, MNS, CY-09, tranilast, OLT1177, and oridonin.

22. The nucleic acid particle of claim 20 or 21, wherein the inflammasome inhibitor is MCC950 or BAY 11-7082.

23. The nucleic acid particle of any one of claims 1-22, wherein the lipid nanoparticle further comprises one or more additional immunomodulators.

24. The nucleic acid particle of claim 23, wherein the one or more additional immunomodulators is or comprises a small molecule agonist or antagonist of a TLR or PRR receptor.

25. The nucleic acid particle of claim 23, wherein the one or more additional immunomodulators is or comprises an inflammasome inhibitor.

26. The nucleic acid particle of any one of claims 1-25, wherein the nucleic acid particle comprises the immunomodulator, a cationic lipid, and RNA.

27. The nucleic acid particle of claim 26, wherein the nucleic acid particle is in the form of a lipid nanoparticle.

28. The nucleic acid particle of any one of claims 1-27, wherein the cationic lipid is a lipid comprising one or more nitrogen atoms that are cationic or ionizable at physiological pH (e.g., about 7.4).

29. The nucleic acid particle of any one of claims 1-28, wherein the cationic lipid is selected from Table 1 and / or Table 2.

30. The nucleic acid particle of claim 29, wherein the cationic lipid is ALC-0315, SM-102, ALC366, DODMA or HY-501.

31. The nucleic acid particle of any one of claims 27-30, wherein the cationic lipid is about 30 to about 50 mol% of the total amount of lipid and immunomodulator in the lipid nanoparticle.

32. The nucleic acid particle of any one of claims 27-31, further comprising a helper lipid.

33. The nucleic acid particle of claim 32, wherein the helper lipid is a phospholipid.

34. The nucleic acid particle of claim 33, wherein the helper lipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine and sphingomyelin, more preferably selected from the group consisting of distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), diarachidonoylphosphatidylcholine (DAPPC), dioctano ... C), dibehenylphosphatidylcholine (DBPC), di(tricosyl)phosphatidylcholine (DTPC), di(tetracosyl)phosphatidylcholine (DLPC), palmitoyloleoyl-phosphatidylcholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 diether PC), 1-oleoyl-2-cholesteryl hemisuccinyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), dioleoylphosphatidylethanolamine (DOPE), distearoyl-phosphatidylethanolamine (DSPE), dipalmitoyl-phosphatidylethanolamine (DPPE), dimyristoyl-phosphatidylethanolamine (DMPE), dilauroyl-phosphatidylethanolamine (DLPE), diphytyl-phosphatidylethanolamine (DPyPE), and combinations thereof.

35. The nucleic acid particle of claim 34, wherein the helper lipid is DSPC.

36. The nucleic acid particle of any one of claims 32-34, wherein the lipid nanoparticle comprises about 5 to about 15 mol % of the helper lipid relative to the total amount of lipid and immunomodulator.

37. The nucleic acid particle of any one of claims 27-36, further comprising a polymer-conjugated lipid.

38. The nucleic acid particle of claim 37, wherein the polymer-conjugated lipid is a PEG-lipid selected from the group consisting of PEG-DAG, PEG-PE, PEG-S-DAG, PEG2000-DMG, PEG-cer, PEG dialkoxypropylcarbamate, ALC-0159, and combinations thereof.

39. The nucleic acid particle of claim 38, wherein the PEG-lipid is ALC-0159 or PEG2000-DMG.

40. The nucleic acid particle of claim 39, wherein the PEG-lipid is ALC-0159.

41. The nucleic acid particle of claim 39, wherein the PEG-lipid is PEG2000-DMG.

42. The nucleic acid particle of any one of claims 38-41, wherein the lipid nanoparticle comprises about 1 to about 5 mol % of the PEG-lipid relative to the total amount of lipid and immunomodulator.

43. The nucleic acid particle of claim 27, wherein the cationic lipid is ALC-0315 and the lipid nanoparticle further comprises a helper lipid that is DSPC and a PEG-lipid that is ALC-0159.

44. The nucleic acid particle of claim 27, wherein the cationic lipid is SM-102, and the lipid nanoparticle further comprises a helper lipid that is DSPC and a PEG-lipid that is PEG2000-DMG.

45. The nucleic acid particle of claim 27, wherein the cationic lipid is HY-501 and the lipid nanoparticle further comprises a helper lipid that is DSPC.

46. ​​The nucleic acid particle of any one of claims 27-45, further comprising an additional terpenoid.

47. The nucleic acid particle of claim 46, wherein the additional terpenoid is a triterpene.

48. The nucleic acid particle of claim 47, wherein the triterpene is a sterol.

49. The nucleic acid particle of claim 48, wherein the sterol is selected from β-sitosterol, stigmasterol, cholesterol, cholecalciferol, ergocalciferol, calcipotriol, botulinum toxin, lupeol, ursolic acid, oleanolic acid, cycloartenol, lanosterol, or α-tocopherol.

50. The nucleic acid particle of any one of claims 27-49, wherein the lipid nanoparticle further comprises a surfactant, the surfactant being or comprising a polysorbate, a poloxamer and / or a compound comprising an amphiphilic moiety selected from polyalkylene glycol (e.g., polyethylene glycol), poly(2-oxazoline), poly(2-oxazine), polysarcosine, polyvinylpyrrolidone, and poly[N-(2-hydroxypropyl)methacrylamide], wherein the amphiphilic moiety is conjugated to one or more C 12 -C 20 Aliphatic bonding.

51. The nucleic acid particle of claim 50, wherein the surfactant is or comprises a polysorbate selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and combinations thereof.

52. The nucleic acid particle of claim 27, wherein the lipid nanoparticle comprises: i) about 30 to about 50 mol % of said cationic lipid; ii) about 1 to about 5 mol % PEG-lipid; and iii) about 5 to about 15 mol % of a helper lipid.

53. The nucleic acid particle of claim 52, wherein the lipid nanoparticle comprises: i) about 30 to about 50 mol % of ALC-0315; ii) about 1 to about 5 mol% ALC-0159; and iii) about 5 to about 15 mol % DSPC.

54. The nucleic acid particle of claim 53, wherein the lipid nanoparticle comprises: i) about 47.5 mol% ALC-0315; ii) about 1.8 mol% ALC-0159; and iii) about 10 mol% DSPC.

55. The nucleic acid particle of claim 27, wherein the lipid nanoparticle comprises: i) about 30 to about 50 mol % of SM-102; ii) about 1 to about 5 mol % PEG2000-DMG; and iii) about 5 to about 15 mol % DSPC.

56. The nucleic acid particle of claim 55, wherein the lipid nanoparticle comprises: i) about 50 mol% of SM-102; ii) about 1.5 mol% PEG2000-DMG; and iii) about 10 mol% DSPC.

57. The nucleic acid particle of any one of claims 27-56, wherein the lipid nanoparticle is characterized by an N / P ratio of about 4:1 to about 12:

1.

58. The nucleic acid particle of claim 57, wherein the lipid nanoparticle is characterized by an N / P ratio of about 6:

1.

59. The nucleic acid particle of any one of claims 27-58, wherein the lipid nanoparticle has a diameter of about 50 nm to about 150 nm.

60. The nucleic acid particle of claims 1-25, wherein the nucleic acid particle comprises the immunomodulator, the cationic polymer, and RNA.

61. The nucleic acid particle of claim 60, wherein the cationic polymer is poly(ethyleneimine) or poly(propyleneimine).

62. The nucleic acid particle of claim 60 or 61, wherein the nucleic acid particle further comprises a secondary polymer.

63. The nucleic acid particle of claim 62, wherein the secondary polymer is polysarcosine.

64. The nucleic acid particle of any one of claims 1-63, wherein the RNA is mRNA.

65. nucleic acid particles as described in claim 64, wherein the RNA is modRNA, circRNA, saRNA, taRNA or uRNA.

66. A method of increasing or causing an increase in RNA expression in a target in a subject, the method comprising administering to the subject a nucleic acid particle as described in any one of claims 1-65.

67. The method of claim 66, wherein the target is selected from the group consisting of lung, liver, spleen, heart, brain, lymph node, bladder, kidney, and pancreas.

68. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject the nucleic acid particle of any one of claims 1-65.

69. The method of claim 68, wherein the disease, disorder or condition is an infectious disease, cancer, a genetic disorder, an autoimmune disease, or a rare disease.

70. The method of any one of claims 66-69, wherein the nucleic acid particle is administered parenterally or intranasally.

71. The method of claim 70, wherein the nucleic acid particles are administered intramuscularly, subcutaneously, intradermally, or intravenously.

72. The nucleic acid particle of any one of claims 1-65 for use as a medicament.

73. The nucleic acid particle of any one of claims 1-65, for use in treating and / or preventing a disease or disorder, wherein the disease or disorder is an infectious disease, cancer, a genetic disorder, an autoimmune disease or a rare disease.

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