Sphingolipid-loaded nanobiologics for immune modulation

Abstract

Provided herein are sphingolipid-loaded nanobiological agents and their uses, for example, in innate immune modulation and cancer treatment.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 326,191, filed March 31, 2022, the contents of which are incorporated by reference in their entirety for all purposes.

[0002] Statement of Government Interest This invention was made in part with Government support under Grant Nos. R01 CA220234, R01 HL144072, and P01 HL131478 awarded by the National Institutes of Health. The U.S. Government has certain rights in this invention.

[0003] Description of electronically submitted text files This application contains a Sequence Listing that has been submitted electronically as an XML file named 27527-0207WO1_SL_ST26.xml. The size of the XML file, created on Mar. 30, 2023, is 490,269 bytes. The material in the XML file is incorporated herein by reference in its entirety. [Background technology]

[0004] The immune system plays a key role in the pathophysiology of major diseases such as atherosclerosis, diabetes, and cancer. However, most of the currently developed immunotherapeutic strategies focus either on effector molecules such as cytokines, or on T lymphocytes, cells from the adaptive immune system. In autoimmune and autoinflammatory diseases, anti-cytokine therapies can be successful in neutralizing bioactive cytokines, while the most prominently used immunotherapies in cancer patients involve the application of checkpoint inhibitors. The innate immune system was long thought to lack memory, but recent studies have shown that innate immune cells undergo metabolic and epigenetic rewiring to regulate their functional programs in a process called "trained immunity."

[0005] Sphingolipids are an extended family of bioactive lipids that are ubiquitous in eukaryotes and possess immunomodulatory properties. These lipid molecules regulate fundamental cellular processes including growth, adhesion, migration, apoptosis, and senescence. Furthermore, sphingolipids play an important role in shaping the immune response. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] US2019 / 0290593 issue [Patent Document 2] US2020 / 0253884 issue [Patent Document 3] US2020 / 0376146 issue [Patent Document 4] WO2018 / 071549 No. [Patent Document 5] No. US2022-0332762 [Patent Document 6] US2020 / 0376146 issue [Patent Document 7] U.S. Patent No. 5,665,772 [Patent Document 8] U.S. Patent No. 6,440,990 [Patent Document 9] U.S. Patent No. 5,985,890 [Patent Document 10] U.S. Patent No. 6,200,985 [Patent Document 11] WO 94 / 09010 [Patent Document 12] WO 95 / 16691 [Patent Document 13] WO 96 / 41807 [Non-patent literature]

[0007] [Non-Patent Document 1] "Remington: The Science and Practice of Pharmacy", A. Gennaro, 20th ed., Lippincott, Williams & Wilkins, Philadelphia, PA [Non-Patent Document 2] Bayle et al., Chemistry & Biology, 2006, 13:99-107 [Non-Patent Document 3] Part 8 of Remington's Pharmaceutical Sciences, 17th ed., 1985, Mack Publishing Company, Easton, PA [Non-Patent Document 4] Braza, MS et al., Immunity, 2018. 49(5):819-828e6 [Non-Patent Document 5] Hather et al., Cancer Inform., 2014, 134, 13974 [Non-Patent Document 6] van Leent, MMT et al., Sci Adv, 7, pp. 1-12, 2021 Summary of the Invention [Problem to be solved by the invention]

[0008] There is a need for therapeutic agents and compositions thereof that engage the innate immune system, and methods of use thereof. [Means for solving the problem]

[0009] The present disclosure is directed to sphingolipid-loaded nanobiological agents and methods of use thereof, for example, for the treatment of cancer.

[0010] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) Sphingolipids and The present invention provides a nanobiological composition comprising:

[0011] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) a sphingolipid; (d) Cholesterol and wherein the composition is a nanoparticle having a diameter of about 8 nm to about 150 nm. In embodiments, the nanobiological composition further comprises a phospholipid.

[0012] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) Sphingolipids and (c) a phospholipid; (d) Cholesterol and wherein the sphingolipid is present as about 1-100 mol % of the total lipid composition of the nanobiological composition; The composition is a nanoparticle having a diameter of about 8 nm to about 150 nm. Nanobiological compositions are provided.

[0013] In embodiments, the sphingolipid is selected from the group consisting of ceramide, sphingomyelin, dihydroceramide, glucosylceramide, sphingosine, sphingosine-1-phosphate, galactosylceramide, ceramide-1-phosphate, lactosylceramide, and mixtures thereof.

[0014] In an embodiment, the sphingolipid is of formula (I):

[0015] [ka]

[0016] [In the formula, R 1 is a saturated or unsaturated aliphatic chain, R 2 is H or R 4 , or C(O)R4 and R 3 H, sugar, P(O)(OH) 2 , or P(O)(OH)O(CH 2 ) n R 5 where n=1 to 10; R 4 is a saturated or unsaturated aliphatic chain, R 5 H, NH 2 , N(CH 3 ) 3 + , OH, or sugar] or a pharma- ceutically acceptable salt thereof.

[0017] In an embodiment, the sphingolipid is of formula (IA):

[0018] [ka]

[0019] [In the formula, R 1 and R 2 is defined herein].

[0020] In an embodiment, the sphingolipid is of formula (II):

[0021] [ka]

[0022] [In the formula, R 1 and R 2 is defined herein].

[0023] In an embodiment, the sphingolipid is of formula (II-A):

[0024] [ka]

[0025] [In the formula, R 1 and R 2 is defined herein].

[0026] In an embodiment, the sphingolipid of formula (II) is a sphingolipid of formula (II-B):

[0027] [ka]

[0028] [In the formula, R 1 and R 2 is defined herein].

[0029] In embodiments, the nanobiological composition comprises human apolipoprotein AI (apoA-I).

[0030] In embodiments, the nanobiological composition is in the shape of a disc.

[0031] In embodiments, the nanobiological composition is in a spherical shape.

[0032] In embodiments, the nanobiological composition is suitable for intravenous or intraarterial administration.

[0033] In embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a nanobiopharmaceutical composition provided herein.

[0034] In embodiments, the present disclosure provides a method of treating atherosclerosis in a subject in need thereof, comprising administering to the subject an effective amount of a nanobiopharmaceutical composition provided herein.

[0035] In embodiments, the present disclosure provides a method of preventing organ or tissue rejection in a subject in need thereof, comprising administering to the subject an effective amount of a nanobiopharmaceutical composition provided herein. [Brief description of the drawings]

[0036] [Figure 1A] Schematic depiction of the predominant sphingolipid classes and their metabolic interconversions. Yellow boxes indicate sphingolipid classes incorporated into the nanobiological formulation. [Figure 1B] FIG. 1 is a schematic depiction of an in vitro training immune assay performed using sphingolipid-loaded nanobiological formulations. [Figure 1C] FIG. 1 is a schematic depiction of a sphingolipid-loaded nanobiopharmaceutical composition of the present disclosure. [Figure 1D] 1 is a graph showing the results of the assay described in Example 2, where PBMCs were stimulated for 24 hours with the sphingolipid-loaded nanobiological preparation prepared in Example 1 alone. After a 5-day rest period, cells were stimulated with LPS for 24 hours and cytokine production was measured in the supernatants by ELISA (n=3). Data are expressed as fold log2 change compared to untrained (RPMI) PBMCs. p-values ​​were calculated using one-way ANOVA with Dunnett's post-hoc test. [Figure 1E] Graph showing the results of the assay described in Example 2, in which PBMCs were stimulated for 24 hours with sphingolipid-loaded nanobiological preparations prepared in Example 1 in combination with HKCA. After a 5-day rest period, cells were stimulated with LPS for 24 hours and cytokine production was measured in the supernatant by ELISA (n=3). Data are expressed as fold log2 change compared to PBMCs trained with HKCA. p-values ​​were calculated using one-way ANOVA with Dunnett's post-hoc test. [Diagram 2] FIG. 1 shows tumor growth curves in a B16F10 mouse melanoma model following treatment with PBS or the nanobiopharmaceutical composition described in Example 3. [Figure 3A]FIG. 1 shows lactate dehydrogenase (LDH) measurements in PBMCs treated with sphingolipid-nano biologics for 24 hours. [Figure 3B] Figure 1 shows cytokine production measured in supernatants after PBMCs were stimulated with sphingolipid-nanobiological formulations alone for 24 hours and restimulated with LPS for 24 hours after a 5-day rest period (n=3). Data are expressed as fold change compared to untrained (RPMI) PBMCs. *p<0.05, **p<0.01, ***p<0.001. p-values ​​were calculated using one-way ANOVA with Dunnett's post-hoc test. [Figure 3C] Figure 1 shows cytokine production measured in supernatants after PBMCs were stimulated with sphingolipid-nanobiological formulations alone for 24 hours and restimulated with LPS for 24 hours after a 5-day rest period (n=3). Data are expressed as fold change compared to untrained (RPMI) PBMCs. *p<0.05, **p<0.01, ***p<0.001. p-values ​​were calculated using one-way ANOVA with Dunnett's post-hoc test. [Figure 3D] Cytokine production measured in supernatants after PBMCs were stimulated with sphingolipid-nano biologics in combination with heat-killed Candida Albicans (HKCA) for 24 h and restimulated with LPS for 24 h after a 5-day rest period (n=3). Data are expressed as fold change compared to PBMCs trained with HKCA. *p<0.05, **p<0.01, ***p<0.001. p-values ​​were calculated using one-way ANOVA with Dunnett's post-hoc test. [Figure 3E] Cytokine production measured in supernatants after PBMCs were stimulated with sphingolipid-nano biologics in combination with heat-killed Candida albicans (HKCA) for 24 h and restimulated with LPS for 24 h after a 5-day rest period (n=3). Data are expressed as fold change compared to PBMCs trained with HKCA. *p<0.05, **p<0.01, ***p<0.001. p-values ​​were calculated using one-way ANOVA with Dunnett's post-hoc test. [Figure 4] Figure 1 shows blood chemistry analyses performed in the study described in Example 2. ALP = alkaline phosphatase, AST = aspartate aminotransferase, ALT = alanine transaminase, BUN = blood urea nitrogen, n = 4. [Diagram 5] FIG. 13 shows the pharmacokinetics of 89Zr radiolabeled nanobiological formulation #13. [Figure 6] FIG. 13 shows the biodistribution of 89Zr radiolabeled nanobiological formulation #13 at 24 hours by ex vivo gamma counting (n=5). [Figure 7] FIG. 13 shows bone marrow analyzed by flow cytometry 24 hours after intravenous administration of nanobiological formulation #13 loaded with lipophilic fluorophore DiOC18 in B16F10 melanoma mouse model (n=5). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] definition For convenience, certain terms employed in the specification, examples, and claims are collected below: Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0038] When immediately preceding a numerical value, the term "about" refers to a range (e.g., ±10% of the value). For example, unless the disclosure indicates otherwise or contradicts such an interpretation, "about 50" can mean 45 to 55, "about 25,000" can mean 22,500 to 27,500, etc. For example, in a list of numerical values ​​such as "about 49, about 50, about 55, ...", "about 50" refers to a range that extends to less than half the interval between the preceding and succeeding values, e.g., from greater than 49.5 to less than 50.5. Furthermore, the phrase "less than about" a value or "greater than about" a value should be understood in light of the definition of the term "about" provided herein. Similarly, the term "about" when preceding a series of numerical values ​​or ranges of values ​​(e.g., "about 10, 20, 30" or "about 10 to 30") refers to all values ​​in the series, or to the endpoints of the range, respectively.

[0039] As used herein, the phrase "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / disadvantage ratio.

[0040] As used herein, the term "conservative substitution" refers to the exchange of one amino acid for another among the following groups of amino acids: (i) aliphatic amino acids (alanine, valine, leucine, and isoleucine), (ii) amino acids with hydroxyl groups (serine and threonine), (iii) acidic amino acids (glutamic acid and aspartic acid), (iv) amino acids with amide side chains (asparagine and glutamine), (v) basic amino acids (lysine and arginine), (vii) amino acids with aromatic side chains (phenylalanine, tyrosine, and tryptophan).

[0041] "Salts" include those obtained by reacting a compound that functions as a base with an inorganic or organic acid to form a salt, or those obtained by reacting a compound that functions as an acid with an inorganic or organic base to form a salt. "Salts" include derivatives of active agents, where the active agent is modified by making its acid or base addition salt. Preferably, the salt is a pharmaceutically acceptable salt. Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic and organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylenesalicylic acid, ethanediaminetetraacetic ... Examples of such acids include sulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, sulfate, nitrate, phosphate, percolate, borate, acetate, benzoate, hydroxynaphthoate, glycerophosphate, and ketoglutarate.Examples of base addition salts include, but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine, dicyclohexylamine, and the like. Examples of metal salts include lithium, sodium, potassium, magnesium, calcium salts, and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts, and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, etc. Standard methods for preparing pharma- ceutically acceptable salts and their formulations are well known in the art and are disclosed in various references, including, for example, "Remington: The Science and Practice of Pharmacy", A. Gennaro, ed., 20th ed., Lippincott, Williams & Wilkins, Philadelphia, PA.

[0042] The terms "carrier" or "vehicle" as used interchangeably herein include carriers, excipients, adjuvants, and diluents, or combinations of any of the foregoing, which means materials, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, involved in carrying or transporting a pharmaceutical from one organ or part of the body to another organ or part of the body. In addition to adjuvants, excipients, and diluents known to those skilled in the art, carriers include nanoparticles of organic and inorganic nature.

[0043] The term "treating" as used herein with respect to a patient refers to improving at least one symptom of the patient's disease or disorder. Treating can be improving or at least partially ameliorating the disease or disorder.

[0044] As used herein, the term "patient" or "subject" includes all mammals, and more particularly, humans. The methods described herein can be useful for both human therapy and veterinary applications. In an embodiment, the subject is a human.

[0045] As used herein, a "therapeutically effective amount" refers to an amount of a compound or therapeutically active agent that, when administered to a subject for treating a disease or other undesirable condition, is sufficient to have a beneficial effect with respect to the disease or condition. The therapeutically effective amount varies depending on the type of compound or therapeutically active agent selected, the disease or condition and its severity, and the age, weight, etc., of the patient to be treated.

[0046] As used herein, the term "aliphatic" or "aliphatic group" or "aliphatic chain" refers to a straight-chain (i.e. unbranched), branched, or cyclic, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-30 aliphatic carbon atoms. In embodiments, an aliphatic group contains 10-30 aliphatic carbon atoms. In embodiments, an aliphatic group contains 10-20 aliphatic carbon atoms. In embodiments, an aliphatic group contains 15-20 aliphatic carbon atoms. In embodiments, an aliphatic group contains 15-17 aliphatic carbon atoms. In embodiments, an aliphatic group contains 1-10 aliphatic carbon atoms. In embodiments, an aliphatic group contains 1-8 aliphatic carbon atoms. In embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms, and in embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. An aliphatic group can be a saturated or unsaturated, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl group.

[0047] The term "triglyceride" as used herein means an ester derived from glycerol and three fatty acids. The fatty acids may be the same or different. The notation used herein to describe triglycerides is the same as that used below to describe fatty acids. The fatty acids can be attached to the glycerol molecule in any order, e.g., any fatty acid can react with any of the hydroxyl groups of the glycerol molecule to form an ester bond. For example. In a non-limiting example, a triglyceride can include glycerol with any combination of the following fatty acids: C18:1, C14:1, C16:1, polyunsaturated, and saturated. A triglyceride of C18:1 fatty acid simply means that the fatty acid component of the triglyceride is derived from or based on a C18:1 fatty acid. That is, a C18:1 triglyceride is an ester of glycerol with three fatty acids of 18 carbon atoms each, each fatty acid having one double bond. Similarly, a C14:1 triglyceride is an ester of glycerol with three fatty acids of 14 carbon atoms each, each fatty acid having one double bond. Similarly, a C16:1 triglyceride is an ester of glycerol with three fatty acids of 16 carbon atoms each, each fatty acid having one double bond. A triglyceride combining C18:1 fatty acids with C14:1 and / or C16:1 fatty acids means that (a) a C18:1 triglyceride is mixed with C14:1 triglycerides or C16:1 triglycerides or both, or (b) at least one of the fatty acid components of the triglyceride is derived or based on a C18:1 fatty acid, while the remaining two are derived or based on a C14:1 fatty acid and / or a C16:1 fatty acid.

[0048] The term "fatty acid" and like terms refer to a carboxylic acid having a long aliphatic tail that is either saturated or unsaturated. The terms "long aliphatic tail" and "fatty acid chain" are used interchangeably herein. As used herein, fatty acid chain lengths include C4-C30 (e.g., C6-C30), are saturated or unsaturated, cis or trans, Zusammen (Z) or entgegen (E), unsubstituted or substituted, and have a C1-10 side chain.

[0049] Unsaturated fatty acids have one or more double bonds between carbon atoms. Saturated fatty acids do not contain any double bonds. In embodiments, fatty acids may be described herein by a capital letter "C" representing a carbon atom, followed by a number describing the number of carbon atoms in the fatty acid, followed by a colon and another number representing the number of double bonds in the fatty acid. For example, C16:1 indicates a 16 carbon atom fatty acid with one double bond, such as palmitoleic acid. The number after the colon in this designation does not specify the arrangement of the double bonds in the fatty acid, nor whether the hydrogen atoms attached to the carbon atom of the double bond are cis to each other. Other examples of this designation include C18:0 (stearic acid), C18:1 (oleic acid), C18:2 (linoleic acid), C18:3 (a-linolenic acid), and C20:4 (arachidonic acid).

[0050] As used herein, the term "sterols" refers to animal or plant steroids that contain at least one hydroxyl group. In an embodiment, the sterols of the present disclosure have a single hydroxyl group at the C3 position. Generally, sterols contain 27-30 carbon atoms and one double bond at the 5 / 6 position, occasionally at the 7 / 8, 8 / 9 or other positions. Non-limiting examples of sterols contemplated herein include sigmasterol, campesterol, sitosterol, sitostanol, brassicasterol, stigmasterol, D5 avenasterol, D7 avenasterol, ergosterol, citrostadienol, cholesterol, lanosterol, spongosterol, fungisterol, sterasterol, zymosterol, and mixtures thereof. In an embodiment, the sterol is cholesterol.

[0051] As used herein, the term "sterol ester" refers to an ester derived from a sterol and a carboxylic acid as defined above. In an embodiment, the carboxylic acid has the formula R b -C(O)-OH, wherein R b is an aliphatic group. In embodiments, the carboxylic acid is acetic acid, propionic acid, hexanoic acid, butyric acid, valeric acid, caproic acid, caprylic acid, 2-ethylhexanoic acid, capric acid, cyclopentanepropionic acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, petroselinic acid, linoleic acid, conjugated linoleic acid (CLA), linolenic acid, elaeosteric acid, arachidic acid, arachidonic acid, gadoleic acid, behenic acid, and erucic acid.

[0052] The term "phospholipid" refers to an amphipathic compound composed of a glycerol molecule attached to two fatty acid "tails" and a phosphate "head" group. The phosphate group can be further attached to hydrogen, choline, serine, ethanolamine, or inositol, thereby diversifying into phosphatidic acid, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, and phosphatidylinositol phospholipids, respectively.

[0053] As used herein, the term "lysophospholipid" refers to a derivative of a phospholipid (such as those defined above) in which one of the acyl fatty acid tails has been removed by hydrolysis. Thus, a lysophospholipid has a free alcohol at either the sn-1 or sn-2 position. In a non-limiting embodiment, the lysophospholipid is 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (MHPC), 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (PHPC), or 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (SHPC).

[0054] The terms "apolipoprotein AI" or "apoA-I" and "apolipoprotein A1" or "apoA1" refer to the protein that in humans is encoded by the APOA1 gene.

[0055] Detailed Description Throughout this disclosure, various patents, patent applications, and publications are cited. The disclosures of these patents, patent applications, and publications are incorporated by reference in their entirety into this disclosure for all purposes in order to more fully describe the state of the art as known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, the present disclosure shall control.

[0056] Until recently, immunological memory was considered to be an exclusive feature of the adaptive immune system. However, this view was challenged by the discovery that innate immune cells also adaptively equip themselves with a form of immunological memory. After exposure to a specific stimulus, monocytes and macrophages can generate faster and more potent inflammatory responses to subsequent unrelated stimuli.

[0057] Innate immune memory, also called "trained immunity", is a metabolically and epigenetically regulated functional state of bone marrow cells. Trained immunity is important for host defense, but can also be modulated to achieve therapeutic goals. For example, inhibition of trained immunity can be used to promote organ acceptance after transplantation, and promotion of trained immunity can be used to provide anti-cancer effects.

[0058] The epigenetic modifications that underlie trained immunity are tightly linked to metabolic changes, including the induction of aerobic glycolysis, glutaminolysis, and cholesterol metabolism. Intermediates of these metabolic pathways serve as substrates for epigenetic enzymes or as regulators of these enzymes.

[0059] Nanobiologic Compositions Nanobiological agents can contain multiple components, including lipids (eg, phospholipids, sphingolipids, triglycerides, cholesterol) and apolipoprotein A (apoA-1), the major protein component of high density lipoprotein.

[0060] In an embodiment, the nanobiological composition is spherical in shape. A spherical nanobiological composition typically comprises apoA-1 or a peptidomimetic of ApoA-1, one or more phospholipids, one or more sphingolipids, one or more therapeutically active agents (e.g., small molecule drugs or prodrugs thereof), optionally cholesterol, and a hydrophobic core material such as one or more triglycerides or one or more polymers. For example, the inclusion of one or more triglycerides and / or one or more polymers in the nanoparticles disclosed herein can facilitate modulation of the particle size (e.g., from about 10 nm to more than 30 nm, or even to more than 100 nm) and shape (discoid to spherical) of the nanobiological composition. In turn, the size, rigidity, and viscosity of the nanobiological composition can also affect loading and biodistribution.

[0061] Without being bound by theory, the intrinsic propensity for myeloid cell uptake of nanobiologics allows for efficient delivery of the payload to the innate immune system.

[0062] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) Sphingolipids and The present invention provides a nanobiological composition comprising:

[0063] In embodiments, the nanobiological compositions of the present disclosure may further comprise one or more additional components (e.g., 1, 2, 3, or 4 components), each occurrence independently selected from the group consisting of phospholipids, lysophospholipids, hydrophobic matrix core molecules, and sterols (e.g., cholesterol).

[0064] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) a sphingolipid; (c) sterols (e.g. cholesterol) The present invention provides a nanobiological composition comprising:

[0065] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) a phospholipid; (c) Sphingolipids and The present invention provides a nanobiological composition comprising:

[0066] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) Sphingolipids and (c) a phospholipid; (d) Lysophospholipids The present invention provides a nanobiological composition comprising:

[0067] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) a sphingolipid; (c) a phospholipid; (d) sterols (e.g. cholesterol) The present invention provides a nanobiological composition comprising:

[0068] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) a sphingolipid; (c) a phospholipid; (d) Cholesterol and wherein the composition is a nanoparticle having a diameter of about 8 nm to about 150 nm. Nanobiological compositions are provided.

[0069] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) Sphingolipids and (c) a phospholipid; (d) lysophospholipid; (e) Sterols (e.g. cholesterol) The present invention provides a nanobiological composition comprising:

[0070] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) a phospholipid; (c) cholesterol; (d) Sphingolipids and wherein the sphingolipid is present as about 1-100 mol % of the total lipid composition of the nanobiological composition; The composition is a nanoparticle having a diameter of about 8 nm to about 150 nm. Nanobiological compositions are provided.

[0071] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) a sphingolipid; (c) a sterol (e.g., cholesterol); (d) a hydrophobic matrix core (e.g., triglycerides); The present invention provides a nanobiological composition comprising:

[0072] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) a phospholipid; (c) a sphingolipid; (d) a hydrophobic matrix core (e.g., triglycerides); The present invention provides a nanobiological composition comprising:

[0073] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) Sphingolipids and (c) a phospholipid; (d) lysophospholipid; (e) a hydrophobic matrix core (e.g., triglycerides); The present invention provides a nanobiological composition comprising:

[0074] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) a sphingolipid; (c) a phospholipid; (d) cholesterol; (e) a hydrophobic matrix core (e.g., triglycerides); The present invention provides a nanobiological composition comprising:

[0075] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) Sphingolipids and (c) a phospholipid; (d) lysophospholipid; (e) a sterol (e.g., cholesterol); (f) a hydrophobic matrix core (e.g., triglycerides); The present invention provides a nanobiological composition comprising:

[0076] In embodiments of the nanobiological compositions provided herein, the sphingolipid is selected from the group consisting of ceramide, sphingomyelin, dihydroceramide, glucosylceramide, sphingosine, sphingosine-1-phosphate, galactosylceramide, ceramide-1-phosphate, lactosylceramide, and mixtures thereof.

[0077] In embodiments of the nanobiological compositions provided herein, the sphingolipid is selected from the group consisting of dihydroceramide, glucosylceramide, sphingosine, sphingosine-1-phosphate, galactosylceramide, ceramide-1-phosphate, lactosylceramide, and mixtures thereof.

[0078] In embodiments of the nanobiological compositions provided herein, the sphingolipid is selected from the group consisting of dihydroceramide, glucosylceramide, sphingosine, sphingosine-1-phosphate, galactosylceramide, ceramide-1-phosphate, lactosylceramide, and mixtures thereof.

[0079] In embodiments of the nanobiological compositions provided herein, the sphingolipid is selected from the group consisting of glucosylceramide, galactosylceramide, and lactosylceramide.

[0080] In embodiments of the nanobiological compositions provided herein, the sphingolipid is glucosylceramide or galactosylceramide.

[0081] In embodiments of the nanobiological compositions provided herein, the sphingolipid is a ceramide. In embodiments, the sphingolipid is sphingomyelin. In embodiments, the sphingolipid is a dihydroceramide. In embodiments, the sphingolipid is a glucosylceramide. In embodiments, the sphingolipid is a sphingosine. In embodiments, the sphingolipid is a sphingosine-1-phosphate. In embodiments, the sphingolipid is a galactosylceramide. In embodiments, the sphingolipid is a ceramide-1-phosphate. In embodiments, the sphingolipid is a lactosylceramide.

[0082] In embodiments of the nanobiological compositions provided herein, the sphingolipid is selected from the group consisting of ceramides, sphingomyelins, cerebrosides, sulfatides, globosides, gangliosides, and mixtures thereof.

[0083] In embodiments of the nanobiological compositions provided herein, the sphingolipid is one or more sphingolipids selected from ceramide, phytosphingosine, phosphosphingolipid, glycosphingolipid, or sphingosine. In embodiments, the sphingolipid may be selected from the group consisting of sphingosine, sphinganine, ceramide, sphingomyelin, ganglioside, glycosphingolipid, phosphosphingolipid, phytosphingosine, and derivatives thereof.

[0084] In embodiments of the nanobiological compositions provided herein, the sphingolipid is one or more sphingolipids selected from phytoceramide, sulfatide, lactosylsphingolipid, galactosylsphingolipid, glucosylsphingolipid, ganglioside, globoside, 2-hydroxyceramide, dihydroceramide phosphate, dihydroceramide, 1-O-acylceramide, ceramide, methylated sphingosine, phosphorylated sphingosine, sphinganine. In embodiments, the sphingolipid is a naturally occurring sphingosine (e.g., egg sphingosine, brain sphingosine) or a naturally occurring ceramide (e.g., ceramide (egg), ceramide (brain), brain CPE).

[0085] In embodiments of the nanobiological compositions provided herein, the sphingolipid is one or more sphingolipids selected from the following: D-ribo-phytosphingosine-1-phosphate, D-ribo-phytosphingosine (C17 base), phytosphingosine-N,N-dimethyl, N-24:0 (2S-OH) phytosphingosine, phytosphingosine-N,N-dimethyl, N-02:0 phytosphingosine, N-08:0 phytosphingosine, N-18:0 phytosphingosine, N-16:0 phytosphingosine, N-24 ...0 phytosphingosine, N-24:0(2R-OH) phytosphingosine, 24:0CPE(d18:1 / 24:0), 24:1CPE(d18 / 24:1), C12 sphingosyl PE(d17:1 / 12:0), sphingosyl PE(d18:1), sphingosyl PI(d18:1), KRN7000, sulfatide(brain), C24:1 mono-sulfogalactosyl(β)ceramide(d18:1 / 24:1), C17 mono-sulfogalactosyl(β)ceramide(d18:1 / 17:0), C12 mono-sulfogalactosyl(β)ceramide(d18: 1 / 12:0), C12 di-sulfogalactosyl(β)ceramide (d18:1 / 12:0), C24 mono-sulfogalactosyl(β)ceramide (d18:1 / 24:0), 18:0(2R-OH) sulfoGalCer, 18:0(2S-OH) sulfoGalCer, C24:1 mono-sulfogalactosyl(alpha)ceramide (d18:1 / 24:1), C8 lactosyl(β)ceramide (d18:1 / 8:0), lactosyl(β)sphingosine (d18:1), C12 lactosyl(β)ceramide (d18:1 / 12:0), C8 L-threo-lactosyl galactosyl(β)ceramide (d18:1 / 8:0), C16 lactosyl(β)ceramide (d18:1 / 16:0), C24 lactosyl(β)ceramide (d18:1 / 24:0), C18:1 lactosyl(β)ceramide (d18:1 / 18:1), C17 lactosyl(β)ceramide (d18:1 / 17:0), C24:1 lactosyl(β)ceramide (d18:1 / 24:1), C18 lactosyl(β)ceramide (d18:1 / 18:0), C8 galactosyl(α)ceramide (d18:1 / 8:0), C16 galactosyl(α)ceramide (d18:1 / 16:0),C24:1 galactosyl(α)ceramide (d18:1 / 24:1(15Z)), galactosyl(α)sphingosine (d18:1), adamantanylgalactosyl(β)ceramide, C16 galactosyl(β)ceramide (d18:1 / 16:0), galactosyl(β)sphingosine (d18:1), C8 galactosyl(β)ceramide (d18:1 / 8:0), C12 galactosyl(β)ceramide (d18:1 / 12:0), C24:1 galactosyl(β)ceramide (d18:1 / 24:1(15Z)), galactosyl( β) dimethylsphingosine (d18:1), C18:1 galactosyl (β) ceramide (d18:1 / 18:1(9Z)), C16 galactosyl (α) dihydroceramide (d18:0 / 16:0), C16 galactosyl (β) dihydroceramide (d18:0 / 16:0), C18(2R-OH) galactosyl (β) ceramide, C18(2S-OH) galactosyl (β) ceramide, C18 galactosyl (β) ceramide (d18:1 / 18:0), C24:0 galactosyl (β) ceramide (d18:1 / 24:0), cerebroside (brain), glucosylceramide soybean, glucosyl(β)sphingosine (d20:1), glucosyl(α)sphingosine (d18:1), glucosyl(β)sphingosine (d18:1), C16 glucosyl(β)ceramide (d18:1 / 16:0), C8 glucosyl(β)ceramide (d18:1 / 8:0), C12 glucosyl(β)ceramide (d18:1 / 12:0), C18 glucosyl(β)ceramide (d18:1 / 18:0), C18:1 glucosyl(β)ceramide (d18:1 / 18:1(9Z)), C24:1 glucosyl(β)ceramide (d18:1 / 24:1 (15Z)), C17 glucosyl (β) ceramide (d18:1 / 17:0), ganglioside-total, ganglioside GD1a (pig brain), ganglioside GD1b (pig brain), ganglioside GM3 (bovine milk), ganglioside GT1b (pig brain), ganglioside GD3 (bovine milk), NGcGM3 (bovine spleen), ganglioside GM1 (sheep brain), C18:0GM3 (synthetic), C17:0GD1a (d18:1 / 17:0), ganglioside GQ1b (pig brain), C20:0GM1 (synthetic), C18:0GT1b (d18:1 / 18:0),C18:0GD1a (d18:1 / 18:0), C17:0GM1 (synthetic), C18:0GM1-biotin (synthetic), C17:0GB3 (synthetic), C17:0GA2, lyso-iGB3 (synthetic), C17:0iGB3 (synthetic), lysoGB3 (synthetic), lysoGA2, natural sphingomyelin (egg SM, brain SM, milk SM), synthetic sphingomyelin derivatives (e.g., 02:0SM (d18:1 / 2:0), 06:0SM (d18:1 / 6:0), 12:0SM (d18:1 / 12:0), 16:0SM (d18:1 / 16:0), 17:0SM (d18:1 / 1 7:0), 18:0SM (d18:1 / 18:0), 18:1SM (d18:1 / 18:1(9Z)), 24:0SM, 24:1SM, lysoSM (d18:1), lysoSM (dihydro) (d18:0), lysoSM-d7, lysoSM (d17:1), 12:0dihydroSM (d18:0 / 12:0), 16:1SM (d18:1 / 16:1(9Z)), 14:0SM (d18:1 / 14:0), 12:0(2R-OH)ceramide, 2:0(2S-OH)ceramide, 16:0(2R-OH)ceramide, 16:0(2S-OH)ceramide, 17 ... H) ceramide, 17:0(2S-OH)ceramide, 20:0(2R-OH)ceramide, 20:0(2S-OH)ceramide, 22:0(2R-OH)ceramide, 22:0(2S-OH)ceramide, 24:0(2R-OH)ceramide, 24:0(2S-OH)ceramide, 24:1(2R-OH)ceramide, 24:1(2S-OH)ceramide, 18:1(2R-OH)ceramide, 18:1(2S-OH)ceramide, 18:0(2R-OH)ceramide, 18:0(2S-OH)ceramide, C16 dihydroceramide-1-phosphate (d18:0 / 16:0), C24 Dihydroceramide-1-phosphate (d18:0 / 24:0), C18:1 dihydroceramide (d18:0 / 18:1(9Z)), C2 dihydroceramide (d18:0 / 2:0), C8 dihydroceramide (d18:0 / 8:0), C18 dihydroceramide (d18:0 / 18:0), C24 dihydroceramide (d18:0 / 24:0), C24:1 dihydroceramide (d18:0 / 24:1(15Z)), C14 dihydroceramide (d18:0 / 14:0), C6 dihydroceramide (d18:0 / 6:0), 6 dihydroceramide (d18:0 / 16:0),C12 dihydroceramide (d18:0 / 12:0), 1-O-acyl-ceramide, C24 ceramide-1-phosphate (d18:1 / 24:0), C2 ceramide-1-phosphate (d18:1 / 2:0), C12 ceramide-1-phosphate (d18:1 / 12:0), C8 ceramide-1-phosphate (d18:1 / 8:0), C16 ceramide-1-phosphate (d18:1 / 16:0), 16:03-deoxy-C1P, C18:1 ceramide-1-phosphate (d18:1 / 18:1(9Z)), C8 ceramide-1-phosphate (d17:1 / 8:0), C12 ceramide-1,3-cyclic -phosphate (d18:1 / 12:0), C16 ceramide-1,3-cyclic-phosphate (d18:1 / 16:0), C6 ceramide-1,3-cyclic-phosphate (d18:1 / 6:0), C15 ceramide (d18:1 / 15:0), C22 ceramide (d18:1 / 22:0), C2 ceramide (d18:1 / 2:0), C4 ceramide (d18:1 / 4:0), C6 ceramide (d18:1 / 6:0), C8 ceramide (d18:1 / 8:0), C10 ceramide (d18:1 / 10:0), C12 ceramide (d18:1 / 12:0), C14 ceramide (d18:1 / 14:0) , C16 ceramide (d18:1 / 16:0), C17 ceramide (d18:1 / 17:0), C18 ceramide (d18:1 / 18:0), C18:1 ceramide (d18:1 / 18:1(9Z)), C20 ceramide (d18:1 / 20:0), C24 ceramide (d18:1 / 24:0), C24:1 ceramide (d18:1 / 24:1(15Z)), C18 ceramide (d17:1 / 18:0), C20 ceramide (d17:1 / 20:0), C24 ceramide (d17:1 / 24:0), C24:1 ceramide (d17:1 / 24:1(15Z)), C16 ceramide (d14:1 / 16:0), C22 ceramide (d14:1 / 22:0), C24:1 ceramide (d18:2(4E,8Z) / 24:1(15Z)), C16:0 ceramide (d18:2(4E,8Z) / 16:0), C24:0 ceramide (d18:2(4E,8Z) / 24:0), ceramide (egg), ceramide (brain), brain CPE, CER1 (d18:1 / 26:0 / 18:1), CER9 (t18:0 / 26:0 / 18:1), monomethylsphingosine (d18:1), dimethylsphingosine (d18:1), trimethylsphingosine (d18:1),Dimethylsphingosine-1-phosphate (d18:1), sphingosine-1-phosphate (d18:1), sphinganine-1-phosphate (d18:0), sphingosine-1-phosphate (d17:1), sphingosine-1-phosphate (d17:1), sphingosine-1-phosphate (d20:1), sphinganine-1-phosphate (d20:0), N-12:0-1-deoxysphinganine, sphinganine (d18:0), sphinganine (d17:0), sphinganine (d20 :0), 3-ketosphinganine (d18:0), 3-deoxysphingosine, L-threo-sphingosine (d18:1), sphingosine (d18:1), sphingosine (d17:1), sphingosine (d20:1), sphingosine (d22:1), 4E,14Z-sphingadiene, 4E,8Z-sphingadiene, 4E,11Z-sphingadiene, sphingosine (d16:1), sphingosine (d14:1), Mito-So, and brain sphingosine.

[0086] In an embodiment, the sphingolipid is of formula (I):

[0087] [ka]

[0088] [In the formula, R 1 is a saturated or unsaturated aliphatic chain, R 2 is H or R 4 , or C(O)R 4 and R 3 H, sugar, P(O)(OH) 2 , or P(O)(OH)O(CH 2 ) n R 5 where n=1 to 10; R 4 is a saturated or unsaturated aliphatic chain, R 5 H, NH 2 , N(CH 3 ) 3+ , OH, or sugar] or a pharma- ceutically acceptable salt thereof.

[0089] In an embodiment, the sphingolipid is of formula (I):

[0090] [ka]

[0091] [In the formula, R 1 is a saturated or unsaturated aliphatic chain, R 2 is H or R 4 , or C(O)R 4 and R 3 is H, sugar, P(O)(OH) 2 , or P(O)(OH)O(CH 2 ) n R 5 where n=1 to 10; R 4 is a saturated or unsaturated aliphatic chain, R 5 H, NH 2 , N(CH 3 ) 3 + , OH, or sugar] or a pharma- ceutically acceptable salt thereof.

[0092] In an embodiment of the sphingolipid of formula (I), R 1 is an aliphatic chain.

[0093] In an embodiment of the sphingolipid of formula (I), R 1 is C 4~30 It is an aliphatic chain.

[0094] In an embodiment of the sphingolipid of formula (I), R 1 is a saturated aliphatic chain.

[0095] In an embodiment of the sphingolipid of formula (I), R 1 is C 4~30 It is a saturated aliphatic chain.

[0096] In an embodiment of the sphingolipid of formula (I), R 1 is C 4~30 Alkyl or C 4~30 It is alkenyl.

[0097] In an embodiment of the sphingolipid of formula (I), R 1 is C 4~30 It is alkenyl.

[0098] In an embodiment of the sphingolipid of formula (I), R 1 is saturated C 15~17 Aliphatic chain or unsaturated C 15~17 It is an aliphatic chain.

[0099] In an embodiment of the sphingolipid of formula (I), R 1 is C 15~17 Alkyl or C 15~17 It is alkenyl.

[0100] In an embodiment of the sphingolipid of formula (I), R 1 is saturated C 15~17 It is a saturated aliphatic chain.

[0101] In an embodiment of the sphingolipid of formula (I), R 1 is unsaturated C 15~17 It is an aliphatic chain.

[0102] In an embodiment of the sphingolipid of formula (I), R 1 is C 15~17 It is alkenyl.

[0103] In an embodiment of the sphingolipid of formula (I), R 1 is saturated C 15 It is a saturated aliphatic chain.

[0104] In an embodiment of the sphingolipid of formula (I), R 1 is C 15It is an alkyl.

[0105] In an embodiment of the sphingolipid of formula (I), R 1 is unsaturated C 15 It is an aliphatic chain.

[0106] In an embodiment of the sphingolipid of formula (I), R 1 is C 15 It is alkenyl.

[0107] In an embodiment of the sphingolipid of formula (I), R 1 is saturated C 17 It is a saturated aliphatic chain.

[0108] In an embodiment of the sphingolipid of formula (I), R 1 is C 17 It is an alkyl.

[0109] In an embodiment of the sphingolipid of formula (I), R 1 is unsaturated C 17 It is an aliphatic chain.

[0110] In an embodiment of the sphingolipid of formula (I), R 1 is C 17 It is alkenyl.

[0111] In an embodiment, the sphingolipid of formula (I) is of formula (IV-A):

[0112] [ka]

[0113] In an embodiment, the sphingolipid of formula (I) is of formula (IV-B):

[0114] [ka]

[0115] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 2 , H, R 4 , or C(O)R 4 In an embodiment, R 2 is H. In embodiments, R 2 is R 4 In an embodiment, R 2 is C(O)R 4 It is.

[0116] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 3 H, sugar, P(O)(OH) 2 , or P(O)(OH)O(CH 2 ) n R 5 where n=1 to 10.

[0117] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 3 -H, -P(O)(OH) 2 , or sugar.

[0118] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 3 is -H.

[0119] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 3 -P(O)(OH) 2 It is.

[0120] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 3 is P(O)(OH)O(CH 2 ) n R 5wherein n=1-10. In embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10.

[0121] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 3 is a sugar.

[0122] In embodiments, R 3 teeth,

[0123] [ka]

[0124] It is.

[0125] In embodiments, R 3 teeth,

[0126] [ka]

[0127] In an embodiment, R 3 teeth,

[0128] [ka]

[0129] It is.

[0130] In embodiments, R 3 teeth,

[0131] [ka]

[0132] In an embodiment, R 3 teeth,

[0133] [ka]

[0134] In an embodiment, R 3 teeth,

[0135] [ka]

[0136] It is.

[0137] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 5 H, NH 2 , N(CH 3 ) 3 + , OH, or a sugar.

[0138] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 5 H, NH 2 , OH, or a sugar.

[0139] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 5 is H.

[0140] In embodiments, R 5 NH 2 It is.

[0141] In embodiments, R 5 is N(CH 3 ) 3 + It is.

[0142] In embodiments, R 5 is OH.

[0143] In embodiments, R 5 is a sugar.

[0144] In embodiments of the sphingolipid of formula (I), (IV-A), or (IV-B), the sugar is

[0145] [ka]

[0146] It is.

[0147] In embodiments of the sphingolipid of formula (I), (IV-A), or (IV-B), the sugar is

[0148] [ka]

[0149] In an embodiment, the sugar is

[0150] [ka]

[0151] It is.

[0152] In embodiments of the sphingolipid of formula (I), (IV-A), or (IV-B), the sugar is

[0153] [ka]

[0154] It is.

[0155] In embodiments of the sphingolipid of formula (I), (IV-A), or (IV-B), the sugar is

[0156] [ka]

[0157] In an embodiment, the sugar is

[0158] [ka]

[0159] In an embodiment, the sugar is

[0160] [ka]

[0161] It is.

[0162] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is a saturated aliphatic chain or an unsaturated aliphatic chain.

[0163] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 4~30 Saturated aliphatic chain or C 4~30 It is an unsaturated aliphatic chain.

[0164] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 4~30 Saturated aliphatic chain or C 4~30 It is alkenyl.

[0165] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 4~30 Alkyl or C 4~30 It is alkenyl.

[0166] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 11~30 It is an unsaturated aliphatic chain.

[0167] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 11~30 It is alkenyl.

[0168] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 11~30 It is a saturated aliphatic chain.

[0169] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 11~30 It is an alkyl.

[0170] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 11 It is an unsaturated aliphatic chain.

[0171] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 11 It is alkenyl.

[0172] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 15 It is an unsaturated aliphatic chain.

[0173] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 15 It is alkenyl.

[0174] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 17 It is an unsaturated aliphatic chain.

[0175] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 17It is alkenyl.

[0176] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 23 It is an unsaturated aliphatic chain.

[0177] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 23 It is alkenyl.

[0178] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 11 It is a saturated aliphatic chain.

[0179] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 11 It is an alkyl.

[0180] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 15 It is a saturated aliphatic chain.

[0181] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 15 It is an alkyl.

[0182] In embodiments of the sphingolipids of formula (I), (II), (III), (IV-A), or (IV-B), R 4 is C 17 It is a saturated aliphatic chain.

[0183] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 17 It is an alkyl.

[0184] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 23 It is a saturated aliphatic chain.

[0185] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 is C 23 It is an alkyl.

[0186] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 teeth,

[0187] [ka]

[0188] It is.

[0189] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 teeth,

[0190] [ka]

[0191] It is.

[0192] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 teeth

[0193] [ka]

[0194] It is.

[0195] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 teeth

[0196] [ka]

[0197] It is.

[0198] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 teeth

[0199] [ka]

[0200] It is.

[0201] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 teeth

[0202] [ka]

[0203] It is.

[0204] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 teeth

[0205] [ka]

[0206] It is.

[0207] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 4 teeth

[0208] [ka]

[0209] It is.

[0210] In embodiments of the sphingolipids of formula (I), (IV-A), or (IV-B), R 1 and R 4 At least one of the is unsaturated.

[0211] In an embodiment of the sphingolipid of formula (I), R 1 is unsaturated C 14~24 It is an aliphatic chain, R 2 is C(O)R 4 and R 3 is a sugar or H, R 4 is C 14~24 Saturated aliphatic chain or C 14~24 It is an unsaturated aliphatic chain.

[0212] In an embodiment of the sphingolipid of formula (I), R 1 is unsaturated C 14~24 It is an aliphatic chain, R 2 is C(O)R 4 and R 3 is a sugar, R 4 is C 14~24 Saturated aliphatic chain or C 14~24 It is an unsaturated aliphatic chain.

[0213] In an embodiment of the sphingolipid of formula (I), R 1 is unsaturated C 14~16 Aliphatic chains (e.g., C 15 alkenyl), R 2 is C(O)R 4 and R 3 is a sugar, R 4 is C 17~23 Saturated aliphatic chain or C 17~23 Unsaturated aliphatic chains (e.g., C 17 Alkenyl, C 23Alkyl or C 23 alkenyl).

[0214] In an embodiment of the sphingolipid of formula (I), R 1 is unsaturated C 14~24 It is an aliphatic chain, R 2 is C(O)R 4 and R 3 is a sugar, R 4 is C 14~24 It is an unsaturated aliphatic chain.

[0215] In an embodiment of the sphingolipid of formula (I), R 1 is unsaturated C 14~16 Aliphatic chains (e.g., C 15 alkenyl), R 2 is C(O)R 4 and R 3 is a sugar, R 4 is C 17~23 Unsaturated aliphatic chains (e.g., C 17 Alkenyl, C 23 Alkyl or C 23 alkenyl).

[0216] In an embodiment, the sphingolipid of formula (I) is a sphingolipid of formula (II):

[0217] [ka]

[0218] [In the formula, R 1 is unsaturated C 14~24 It is an aliphatic chain, R 2 is C(O)R 4 and R 4 is C 14~24 unsaturated aliphatic chains].

[0219] In embodiments, the sphingolipid of formula (II) is a sphingolipid of formula (II-A) or (II-B):

[0220] [ka]

[0221] [In the formula, R 1 is unsaturated C 14~24 It is an aliphatic chain, R 2 is C(O)R 4 and R 4 is C 14~24 unsaturated aliphatic chains].

[0222] In an embodiment, the sphingolipid of formula (II) is a sphingolipid of formula (II-A).

[0223] [ka]

[0224] In an embodiment, the sphingolipid of formula (II) is a sphingolipid of formula (II-B).

[0225] [ka]

[0226] In an embodiment of the compound of formula (II), (II-A), or (II-B), R 1 is unsaturated C 15~17 In an embodiment, R 1 is C 15~17 alkenyl. In embodiments, R 1 is C 15 It is alkenyl.

[0227] In an embodiment of the compound of formula (II), (II-A), or (II-B), R 4is C 17~23 In an embodiment, R 4 is C 17 Unsaturated aliphatic chain or C 23 In an embodiment, R 4 is C 17~23 alkenyl. In embodiments, R 4 is C 17 Alkenyl or C 23 It is alkenyl.

[0228] In embodiments of the nanobiological compositions provided herein, the sphingolipid is one or more sphingolipids selected from Table 1.

[0229] In embodiments of the nanobiological compositions provided herein, the sphingolipid is one or more sphingolipids selected from Table 1, or a pharma- ceutically acceptable salt thereof.

[0230] [Table 1A]

[0231] [Table 1B]

[0232] [Table 1C]

[0233] In embodiments, the sphingolipid is

[0234] [ka]

[0235] is selected from the group consisting of:

[0236] In embodiments, the sphingolipid is

[0237] [ka]

[0238] [ka]

[0239] is selected from the group consisting of:

[0240] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0241] [ka]

[0242] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0243] [ka]

[0244] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0245] [ka]

[0246] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0247] [ka]

[0248] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0249] [ka]

[0250] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0251] [ka]

[0252] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0253] [ka]

[0254] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0255] [ka]

[0256] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0257] [ka]

[0258] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0259] [ka]

[0260] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0261] [ka]

[0262] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0263] [ka]

[0264] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0265] [ka]

[0266] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0267] [ka]

[0268] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0269] [ka]

[0270] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0271] [ka]

[0272] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0273] [ka]

[0274] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0275] [ka]

[0276] In embodiments of the nanobiological compositions provided herein, the sphingolipid is:

[0277] [ka]

[0278] In embodiments of the nanobiological compositions provided herein, sphingolipids are present at about or at least about 1-100 mol% of the total lipid composition of the nanobiological composition, including about or at least about 0.1 mol%, about or at least about 0.5 mol%, about or at least about 0.75 mol%, about or at least about 1% mol%, about or at least about 2 mol%, about or at least about 3 mol%, about or at least about 4 mol%, about or at least about 5 mol%, about or at least about 6 mol%, about or at least about 7 mol%, about or at least about 8 mol%, about or at least about 9 mol%, about or at least about 10 mol%, about or at least about 11 mol%, about or at least about 12 mol%, about or at least about 13 mol%, about or at least about 14 mol%, about or at least about 15 mol%, about or at least about 16 mol%, about or at least about 17 mol%, about or at least about 18 mol%. , about or at least about 19 mol%, about or at least about 20 mol%, about or at least about 21 mol%, about or at least about 22 mol%, about or at least about 23 mol%, about or at least about 24 mol%, about or at least about 25 mol%, about or at least about 26 mol%, about or at least about 27 mol%, about or at least about 28 mol%, about or at least about 29 mol%, about or at least about 30 mol%, about or at least about 35 mol%, about or at least about 40 mol%, about or at least about 45 mol%, about or at least about 50 mol%, about or at least about 55 mol%, about or at least about 60 mol%, about or at least about 65%, about or at least about 70%, about or at least about 75%, about or at least about 80%, about or at least about 85%, about or at least about 90%, about or at least about 95% to about 100%, including all values ​​and subranges therebetween.

[0279] In embodiments of the nanobiological compositions provided herein, the sphingolipid is present as about 10-25 mol % of the total lipid composition of the nanobiological composition.

[0280] In embodiments of the nanobiological compositions provided herein, the sphingolipid is present as about 20 mol % of the total lipid composition of the nanobiological composition.

[0281] In embodiments, the nanobiological compositions comprise human apolipoprotein AI (apoA-I). For example, the ApoA-I sequence may have the mature peptide sequence shown below, or may include either or both of a signal peptide (e.g., SEQ ID NO: 347) or a propeptide portion (e.g., SEQ ID NO: 348). The peptide may be made by expressing a nucleic acid encoding all three of the signal peptide, the propeptide portion, and the mature peptide. During protein synthesis and maturation, the mature peptide is released and can be purified from the host cell for use in the compositions herein. In certain host cells, such as bacteria, the encoded peptide may not be cleaved into the mature peptide. The N-terminal methionine (M) residue of the Apo-A1 peptide as used herein may be a formyl-methionine (fM) residue. In embodiments, the ApoA-I as used in the compositions herein comprises or consists of the sequence of SEQ ID NO: 349, or a sequence having 1, 2, 4, 5, 6, 7, 8, 9, 10, or up to 20 conservative substitutions thereto.

[0282] [Table 2]

[0283] In embodiments, the nanobiological composition comprises a peptidomimetic of apolipoprotein AI (apoA-I). Suitable apoA-I mimetic polypeptides can have the sequences shown in Table 2B (SEQ ID NOs: 256-263 and 342-346) or SEQ ID NOs: 1-341.

[0284] [Table 3]

[0285] In an embodiment, the apoA-I mimetic is DWLKAFYDKVAEKLKEAF (SEQ ID NO: 256). In an embodiment, the apoA-I mimetic is Ac-DWLKAFYDKVAEKLKEAF-NH 2 (SEQ ID NO: 257). In an embodiment, the apoA-I mimetic is Ac-DWFKAFYDKVAEKFKEAF-NH 2 (Sequence number 260).

[0286] In embodiments, the apoA-I mimic is optionally acetylated at the N-terminus or optionally amidated at the C-terminus. In embodiments, the apoA-I mimic is acetylated at the N-terminus. In embodiments, the apoA-I mimic is amidated at the C-terminus. In embodiments, the apoA-I mimic is acetylated at the N-terminus and amidated at the C-terminus.

[0287] In embodiments, the nanobiological composition of the present disclosure comprises one or more phospholipids. Examples of suitable phospholipids include, but are not limited to, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phospholipid-containing oils such as lecithin oil. Non-limiting examples of phospholipids that may be used in the composition include phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidic acid / ester (PA).

[0288] In embodiments, the phospholipids are independently selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phospholipid-containing oils, phosphatidylglycerol, phosphatidic acid, and combinations thereof.

[0289] In embodiments, the phospholipid is one or more of the following: DDPC CAS-3436-44-0, 1,2-didecanoyl-sn-glycero-3-phosphocholine, DEPA-NA CAS-80724-31-8, 1,2-dierucoyl-sn-glycero-3-phosphate (sodium salt), DEPC CAS-56649-39-9, 1,2-dierucoyl-sn-glycero-3-phosphocholine, DEPE CAS-988-07-2, 1,2-dierucoyl-sn-glycero-3-phosphoethanolamine, DEPG-NA 1,2-dierucoyl-sn-glycero-3-phospho-rac-(1-glycerol) (sodium salt), DLOPC CAS-998-06-1, 1,2-dilinoleoyl-sn-glycero-3-phosphocholine, DLPA-NA 1,2-Dilauroyl-sn-glycero-3-phosphate (sodium salt), DLPC CAS-18194-25-7, 1,2-Dilauroyl-sn-glycero-3-phosphocholine, DLPE 1,2-Dilauroyl-sn-glycero-3-phosphoethanolamine, DLPG-NA 1,2-Dilauroyl-sn-glycero-3-phospho-rac-(1-glycerol) (sodium salt), DLPG-NH4 1,2-Dilauroyl-sn-glycero-3-phospho-rac-(1-glycerol) (ammonium salt), DLPS-NA 1,2-Dilauroyl-sn-glycero-3-phosphoserine (sodium salt), DMPA-NA CAS-80724-3, 1,2-Dimyristoyl-sn-glycero-3-phosphate (sodium salt), DMPC CAS-18194-24-6, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPE CAS-988-07-2, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, DMPG-NA CAS-67232-80-8, 1,2-dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol)(sodium salt), DMPG-NH4 1,2-dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol)(ammonium salt), DMPG-NH4 / NA 1,2-dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol)(sodium / ammonium salt), DMPS-NA 1,2-Dimyristoyl-sn-glycero-3-phosphoserine (sodium salt), DOPA-NA 1,2-Dioleoyl-sn-glycero-3-phosphate (sodium salt), DOPC CAS-4235-95-4, 1,2-Dioleoyl-sn-glycero-3-phosphocholine, DOPE CAS-4004-5-1, 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine, DOPG-NA CAS-62700-69-0, 1,2-Dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (sodium salt), DOPS-NA CAS-70614-14-1, 1,2-Dioleoyl-sn-glycero-3-phosphoserine (sodium salt), DPPA-NA CAS-71065-87-7, 1,2-dipalmitoyl-sn-glycero-3-phosphate (sodium salt), DPPC CAS-63-89-8, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPE CAS-923-61-5, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, DPPG-NA CAS-67232-81-9, 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (sodium salt), DPPG-NH4 CAS-73548-70-6, 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (ammonium salt), DPPS-NA 1,2-dipalmitoyl-sn-glycero-3-phosphoserine (sodium salt), DSPA-NA CAS-108321-18-2, 1,2-distearoyl-sn-glycero-3-phosphate (sodium salt), DSPC CAS-816-94-4, 1,2-distearoyl-sn-glycero-3-phosphocholine, DSPE CAS-1069-79-0, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, DSPG-NA CAS-67232-82-0, 1,2-distearoyl-sn-glycero-3-phospho-rac-(1-glycerol) (sodium salt), DSPG-NH4 CAS-108347-80-4, 1,2-distearoyl-sn-glycero-3-phospho-rac-(1-glycerol)(ammonium salt), DSPS-NA 1,2-distearoyl-sn-glycero-3-phosphoserine (sodium salt), EPC egg PC, HEPC hydrogenated egg PC, HSPC hydrogenated soy PC, MPPC 1-myristoyl-2-palmitoyl-sn-glycero-3-phosphocholine, MSPC 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine, PMPC 1-palmitoyl-2-myristoyl-sn-glycero-3-phosphocholine, POPC CAS-26853-31-6, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, POPE 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine, POPG-NA CAS-81490-05-3, 1-palmitoyl-2-oleoyl-sn-glycero-3[phospho-rac-(1-glycerol)](sodium salt), PSPC 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, SMPC 1-stearoyl-2-myristoyl-sn-glycero-3-phosphocholine, SOPC 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine, SPPC 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine.,

[0290] In embodiments, the phospholipid is selected from the group consisting of dimyristoylphosphatidylcholine (DMPC), soy lecithin, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dilaurylolyphosphatidylcholine (DLPC), dioleoylphosphatidylcholine (DOPC), dilaurylolylphosphatidylglycerol (DLPG), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidyl dioleoyl phosphatidylglycerol (DPPG), distearoyl phosphatidylglycerol (DSPG), dioleoyl phosphatidylglycerol (DOPG), dimyristoyl phosphatidic acid (DMPA), dimyristoyl phosphatidic acid (DMPA), dipalmitoyl phosphatidic acid (DPPA), dipalmitoyl phosphatidic acid (DPPA), dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphatidylserine (DMPS), dipalmitoyl phosphatidylserine (DPPS), and mixtures thereof.

[0291] In embodiments of the nanobiological compositions provided herein, the phospholipid is selected from the group consisting of 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), and mixtures thereof.

[0292] In embodiments of the nanobiological compositions provided herein, the phospholipid is 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC).

[0293] In embodiments of the nanobiopharmaceutical compositions provided herein, the phospholipid is DMPC.

[0294] In embodiments, the nanobiological composition comprises a phospholipid and a lysophospholipid.

[0295] In an embodiment, the lysophospholipid is lysophosphatidylcholine.

[0296] In embodiments, the lysophospholipid is LYSOPC MYRISTIC 1-myristoyl-sn-glycero-3-phosphocholine, LYSOPC PALMITIC CAS-17364-16-8, 1-palmitoyl-sn-glycero-3-phosphocholine, or LYSOPC STEARIC CAS-19420-57-6, 1-stearoyl-sn-glycero-3-phosphocholine.

[0297] In embodiments of the nanobiological compositions provided herein, the lysophospholipid is selected from the group consisting of 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (MHPC), 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (PHPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (SHPC), and mixtures thereof.

[0298] In embodiments of the nanobiological compositions provided herein, the phospholipid is 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and the lysophospholipid is 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (PHPC).

[0299] In embodiments, when the composition comprises two types of phospholipids, the mass ratio of the two types of phospholipids ranges from about 1:10 to about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, up to about 10:1, including all values ​​and ranges therebetween.

[0300] In embodiments, when the composition comprises a phospholipid and a lysophospholipid, the mass ratio of the phospholipid to the lysophospholipid ranges from about 1:10 to about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, up to about 10:1, including all values ​​and ranges therebetween.

[0301] In embodiments, the nanobiological compositions of the present disclosure include a sterol, such as cholesterol. Typically, the nanobiological compositions include a sterol of about 1 mol%, about 1% mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol%, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 mol%, about 43 mol%, about 44 mol%, about 45 mol%, about 46 mol%, about 47 mol%, about 48 mol%, about 49 mol%, about 50 mol%, about 51 mol%, about 52 mol%, about 53 mol%, about 54 mol%, about 55 mol%, about 56 mol%, about 57 mol%, about 58 mol%, about 59 mol%, about 60 mol%, about 61 mol%, about 62 mol%, about 63 mol%, about 64 mol%, about 65 mol%, about 66 mol%, about 67 mol%, about 68 mol%, about The ranges and values ​​include up to about 100 mol% cholesterol (i.e., a 1:1 mol / mol mixture of cholesterol and phospholipid (e.g., DMPC)), including about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 35 mol%, about 40 mol%, about 45 mol%, about 50 mol%, about 55 mol%, about 60 mol%, about 65 mol%, about 70 mol%, about 75 mol%, about 80 mol%, about 85 mol%, about 90 mol%, about 95 mol%, up to about 100 mol%, including all ranges and values ​​therebetween. In embodiments, the nanobiological composition includes about 1 mol% to about 30 mol% cholesterol. In embodiments, the nanobiological composition includes about 15 mol% to about 25 mol% cholesterol relative to the phospholipid. In embodiments, the nanobiological composition includes about 20 mol% cholesterol relative to the phospholipid. In embodiments, the nanobiological composition includes about 10 mol% to about 35 mol% cholesterol relative to the phospholipid. In embodiments, the nanobiological composition comprises about 15 mol% to about 30 mol% cholesterol relative to the phospholipid. In embodiments, the nanobiological composition comprises about 15 mol% to about 25 mol% cholesterol relative to the phospholipid. In embodiments, the nanobiological composition comprises about 28 mol% to about 23 mol% cholesterol relative to the phospholipid. In embodiments, the nanobiological composition comprises about 20 mol% to about 27 mol% cholesterol relative to the phospholipid.

[0302] Without being bound by theory, the addition of cholesterol may stabilize the nanobiological composition and improve entrapment efficiency.

[0303] In embodiments of the nanobiological compositions provided herein, cholesterol is present at about 1-30 mol % relative to the phospholipid.

[0304] In embodiments of the nanobiological compositions provided herein, cholesterol is present at about 5-25 mol % relative to the phospholipid.

[0305] In embodiments of the nanobiological compositions provided herein, the nanobiological composition does not include cholesterol.

[0306] In embodiments of the nanobiological compositions provided herein, the molar ratio of cholesterol:phospholipid in the nanobiological composition is about 0:1, about 0.025:1, about 0.05:1, about 0.075:1, about 0.1:1, about 0.125:1, about 0.15:1, about 0.175:1, about 0.2:1, about 0.225:1, about 0.25:1, about 0.275:1, about 0.3:1, about 0.325:1, about 0.35:1, about 0.375:1, about 0.4:1, about 0.425:1, about 0.45:1, about 0.475:1, or about 0.5:1, including all values ​​in between. In embodiments, the molar ratio of cholesterol:phospholipids ranges from about 0:1 to about 0:1, about 0.025:1, about 0.05:1, about 0.075:1, about 0.1:1, about 0.125:1, about 0.15:1, about 0.175:1, about 0.2:1, about 0.225:1, about 0.25:1, about 0.275:1, about 0.3:1, about 0.325:1, about 0.35:1, about 0.375:1, about 0.4:1, about 0.425:1, about 0.45:1, about 0.475:1, about 0.5:1, up to about 0.5:1, including all ranges therebetween. In embodiments, the molar ratio of cholesterol:phospholipids ranges from about 0.05:1 to about 0.25:1. In an embodiment, the molar ratio of cholesterol is about 0.2:1.

[0307] In embodiments, the mass percentage of cholesterol is from about 0% (w / w), to about 1% (w / w), to about 1.5% (w / w), to about 2% (w / w), to about 2.5% (w / w), to about 3% (w / w), to about 3.5% (w / w), to about 4% (w / w), to about 4.5% (w / w), to about 5% (w / w), to about 5.5% (w / w), to about 6% (w / w), to about 6.5% (w / w), to about 7% (w / w), to about 7.5% (w / w) of the lipid or nanobiological composition. / w), about 8% (w / w), about 8.5% (w / w), about 9% (w / w), about 9.5% (w / w), about 10% (w / w), about 10.5% (w / w), about 11% (w / w), about 11.5% (w / w), about 12% (w / w), about 12.5% ​​(w / w), about 13% (w / w), about 13.5% (w / w), about 14% (w / w), about 14.5% (w / w), up to about 15% (w / w), including up to about 15% (w / w). In embodiments, the mass percentage of cholesterol is from about 0% (w / w), to about 1% (w / w), to about 1.5% (w / w), to about 2% (w / w), to about 2.5% (w / w), to about 3% (w / w), to about 3.5% (w / w), to about 4% (w / w), to about 4.5% (w / w), to about 5% (w / w), to about 5.5% (w / w), to about 6% (w / w), to about 6.5% (w / w), to about 7% (w / w), to about 7.5% (w / w) of the nanoparticle, lipid, or composition. In embodiments, the weight percentage is the weight percentage of cholesterol relative to the phospholipid. In embodiments, the weight percentage is the weight percentage of cholesterol relative to the total lipid. In embodiments, the weight percentage is the weight percentage of cholesterol relative to the nanobiological composition. In embodiments, the weight percentage of cholesterol ranges from about 1-10% cholesterol (w / w%) of the nanobiological composition. The weight percentage of cholesterol ranges from about 2-8% cholesterol (w / w%) of the nanobiological composition.In embodiments, the weight percentage of cholesterol ranges from about 3.5-7.5% cholesterol (w / w%) of the nanobiological composition. In embodiments, the weight percentage of cholesterol ranges from about 5-10% cholesterol (w / w%) of the nanobiological composition. In embodiments, the weight percentage of cholesterol is about 3.6 (w / w%) of the nanobiological composition. In embodiments, the weight percentage of cholesterol is about 7.2 (w / w%) of the nanobiological composition. In embodiments, the weight percentage of cholesterol is about 5.9 (w / w%) of the nanobiological composition.

[0308] In embodiments, the mass percentage of cholesterol in the nanobiological compositions of the present disclosure is from about 0% (w / w) to about 1% (w / w), about 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 5.5% (w / w), about 6% (w / w), about 6.5% (w / w), about 7% (w / w), about 7.5% (w / w), or about 8% (w / w) based on phospholipids. In some embodiments, the cholesterol content ranges from about 15% (w / w), including up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w), up to about 15% (w / w).

[0309] In embodiments, nanoparticle size and circulation time can be modulated, for example, by controlling the lipid to ApoA-I ratio and the lipid to polymer or lipid to triglyceride ratio.

[0310] In embodiments, the nanobiological composition is from about 5:1 to about 5:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 100:1, about 110:1, about 120:1, about 130:1, about 140:1, about 150:1, about 160:1, about 170:1, about 180:1, about 190:1, about 200:1, about 210:1, about 220:1, about 230:1, about 240:1, about 250:1, about 260:1 , about 270:1, about 280:1, about 290:1, about 300:1, about 310:1, about 320:1, about 330:1, about 340:1, about 350:1, about 360:1, about 370:1, about 380:1, about 390:1, about 400:1, about 410:1, about 420:1, about 430:1, about 440:1, about 450:1, about 460:1, about 470:1, about 480:1, about 490:1, about 500:1, about 510:1, about 520:1, about 530:1, about 540:1, about 550:1 , about 560:1, about 570:1, about 580:1, about 590:1, about 600:1, about 610:1, about 620:1, about 630:1, about 640:1, about 650:1, about 660:1, about 670:1, about 680:1, about 690:1, about 700:1, about 710:1, about 720:1, about 730:1, about 740:1, about 750:1, about 760:1, about 770:1, about 780:1, about 790:1, about 800:1, about 810:1, about 820:1, about 830:1, about 840: 1, about 850:1, about 860:1, about 870:1, about 880:1, about 890:1, about 900:1, about 910:1, about 920:1, about 930:1, about 940:1, about 950:1, about 960:1, about 970:1, about 980:1, about 990:1, up to about 1000:1, including up to 1000:1, and all subranges and values ​​therebetween.

[0311] In embodiments, the nanobiological composition comprises a lipid:apoA-I ratio (e.g., on a molar basis) of about 70:1 to 125:1. In embodiments, the HDL-derived nanoparticles comprise a lipid:apoA-I mimic ratio (e.g., on a molar basis) of about 5:1 to 10:1.

[0312] In embodiments, the HDL-derived nanoparticles comprise a mass ratio of lipid:apoA-I or apoA-I mimic of about 2:1 to 3:1.

[0313] In embodiments of the nanobiological compositions provided herein, the phospholipids, sphingolipids, and cholesterol are present in a molar ratio of about 1:0.05-0.25:0.05-0.25.

[0314] In embodiments of the nanobiological compositions provided herein, the phospholipids, sphingolipids, and cholesterol are present in a molar ratio of about 1:0.15-0.25:0.1-0.25.

[0315] In embodiments of the nanobiological compositions provided herein, the phospholipids, sphingolipids, and cholesterol are present in a molar ratio of about 1:0.2:0.1-0.3.

[0316] In embodiments of the nanobiological compositions provided herein, the phospholipids, sphingolipids, and cholesterol are present in a molar ratio of about 1:0.2:0.2.

[0317] In embodiments, the nanobiological composition comprises i) apoA-I or a peptidomimetic of apoA-I, ii) a phospholipid, iii) a lysophospholipid, and iv) cholesterol.

[0318] In embodiments, the nanobiological composition comprises i) apoA-I or a peptidomimetic of apoA-I, ii) a phospholipid, and iii) cholesterol.

[0319] In embodiments, the nanobiological composition comprises i) apoA-I or a peptidomimetic of apoA-I, ii) a phospholipid, iii) a lysophospholipid, iv) a hydrophobic matrix core, and v) cholesterol.

[0320] In embodiments, the structure and properties (e.g., particle size, rigidity, viscosity, loading, etc.) of HDL-derived nanoparticles can be modified by incorporating a hydrophobic matrix. As used herein, hydrophobic matrix refers to the core or filler or structure modifier of the nanobiological preparation. Non-limiting examples of suitable hydrophobic matrix molecules include triglycerides, fatty acid esters, hydrophobic polymers, sterol esters, or combinations thereof.

[0321] Any suitable synthetic or natural fatty acid or fatty acid ester known in the art is contemplated for use in the nanobiological compositions of the present disclosure. Non-limiting examples of fatty acids for use include arachidonic acid, oleic acid, arachidic acid, lauric acid, sad, capric acid, myristic acid, palmic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, three decanoins, glycerol mono-fatty acid esters, dilaurin, 1-Sunsoft 767, laurocapram (1-dodecyl-aza-cycloheptane-2-ketone), acylcarnitines, acylcholines or C 1 ~C 10 Examples include arrcostab (isopropyl myristate IPM, etc.), monoglycerides, diglycerides, or pharma- ceutically acceptable salts thereof.

[0322] Any suitable synthetic or natural triglyceride known in the art is contemplated for use in the nanobiological compositions of the present disclosure. Non-limiting examples of triglycerides for use include tricaprylin, tristearin, triolein, tripalmitin, 1,2-dipalmitolein, 1,3-dipalmitolein, 1-palmito-3-stearo-2-olein, 1-palmito-2-stearo-3-olein, 2-palmito-1-stearo-3-olein, trilinolein, 1,2-dipalmitrinolein, 1-palmito-dilinolein, 1-stearo-dilinolein, 1,2-diacetopalmitin, 1,2-distearo-olein, 1,3-distearo-olein, trimyristin, trilaurin, and combinations thereof. Suitable triglycerides may be added to the present compositions in neat form. Additionally or alternatively, suitable triglyceride-containing oils and / or processed oils may be added to the composition.Non-limiting examples of oils include coconut oil, corn germ oil, olive oil, palm seed oil, cottonseed oil, palm oil, rapeseed oil, sunflower oil, whale oil, soybean oil, peanut oil, linseed oil, tall oil, and combinations thereof.

[0323] In embodiments of the nanobiological compositions provided herein, the nanobiological compositions have a PDI of from about 0.01 to about 0.5, including about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, including all subranges and values ​​therebetween.

[0324] In embodiments of the nanobiological compositions provided herein, the nanobiological compositions have a PDI of about 0.1 to about 0.3.

[0325] In embodiments, the diameter of the nanobiological composition is from about 5 nm, about 5 nm, about 6 nm, about 7 nm, about 8 nm, about 9 nm, about 10 nm, about 11 nm, about 12 nm, about 13 nm, about 14 nm, about 15 nm, about 16 nm, about 17 nm, about 18 nm, about 19 nm, about 20 nm, about 21 nm, about 22 nm, about 23 nm, about 24, about 25 nm, about 26 nm, about 27 nm, about 28 nm, about 29, about 30 nm, about 31 nm, about 32 nm, about 33 nm, about 34, about 35 nm, about 36 nm, about 37 nm, about 38 nm, about 39, about 40 nm, about 41 nm, about 42 nm, about 43 nm, Approximately 44nm, approximately 45nm, approximately 46nm, approximately 47nm, approximately 48nm, approximately 49nm, approximately 50nm, approximately 51nm, approximately 52nm, approximately 53nm, approximately 5 4nm, about 55nm, about 56nm, about 57nm, about 58nm, about 59nm, about 60nm, about 61nm, about 62nm, about 63nm, about 64, about 65nm, about 66nm, about 67nm, about 68nm, about 69nm, about 70nm, about 71nm, about 72nm, about 73nm, about 74nm, about 75 nm, about 76nm, about 77nm, about 78nm, about 79nm, about 80nm, about 81nm, about 82nm, about 83nm, about 84nm, about 85nm, Approximately 86nm, approximately 87nm, approximately 88nm, approximately 89, approximately 90nm, approximately 91nm, approximately 92nm, approximately 93nm, approximately 94, approximately 95nm, approximately 96nm, Approximately 97nm, approximately 98nm, approximately 99nm, approximately 100nm, approximately 101nm, approximately 102nm, approximately 103nm, approximately 104nm, approximately 105nm, approximately 10 6nm, about 107nm, about 108nm, about 109nm, about 110nm, about 111nm, about 112nm, about 113nm, about 114nm, about 1 15nm, about 116nm, about 117nm, about 118nm, about 119nm, about 120nm, about 121nm, about 122nm, about 123nm, about 1 24nm, about 125nm, about 126nm, about 127nm, about 128nm, about 129nm, about 130nm, about 131nm, about 132nm, about 133nm, about 134nm, about 135nm, about 136nm, about 137nm, about 138nm, about 139nm, about 140nm, about 141nm, about 142nm, about 143nm, about 144nm, about 145nm, about 146nm, about 147nm, about 148nm, about 149nm, about 150nm, Approximately 160nm, approximately 170nm, approximately 180nm, approximately 190nm, approximately 200nm, approximately 210nm, approximately 220nm, approximately 230nm, approximately 240nm,The nanobiological compositions may range from about 250 nm, about 260 nm, about 270 nm, about 280 nm, about 290 nm, about 300 nm, about 310 nm, about 320 nm, about 330 nm, about 340 nm, about 350 nm, about 360 nm, about 370 nm, about 380 nm, about 390 nm, up to about 400 nm, including all ranges and values ​​therebetween. In embodiments of the nanobiological compositions provided herein, the nanobiological compositions are about 5 nm to about 30 nm in diameter, 5 nm to about 150 nm in diameter, about 20 nm to about 150 nm in diameter, about 15 nm to about 250 nm in diameter, or about 305 nm to about 100 nm in diameter. In embodiments of the nanobiological compositions provided herein, the nanobiological compositions are about 20 nm to about 100 nm in diameter. In embodiments of the nanobiological compositions provided herein, the nanobiological compositions are from about 25 nm to about 60 nm in diameter. In embodiments, the diameter of the nanobiological composition is measured by dynamic light scattering (DLS).

[0326] In embodiments, the nanobiological composition of the present disclosure is in the form of a disc.

[0327] In embodiments, the nanobiopharmaceutical composition of the present disclosure is spherical.

[0328] In embodiments, the nanobiological compositions of the present disclosure comprise one or more trained immune promoters or trained immune inhibitors disclosed in US2019 / 0290593, US2020 / 0253884, US2020 / 0376146, WO2018 / 071549, and US2022-0332762, which are incorporated by reference in their entireties for all purposes.

[0329] In embodiments, the nanobiological composition of the present disclosure comprises a trained immune promoter. In embodiments, the trained immune promoter is a Dectin-1 receptor agonist. In embodiments, the trained immune promoter is a NOD2 agonist, such as muramyl dipeptide (MDP), muramyl tripeptide (MTP), or a derivative or prodrug thereof (e.g., mifamurtide). In embodiments, the trained immune promoter is a derivative of muramyl dipeptide (MDP). In embodiments, the trained immune promoter is muramyl dipeptide phosphatidylethanolamine.

[0330] In embodiments, the nanobiological composition comprises N-(N-acetylmuramoyl)-L-alanyl-D-alpha-glutaminyl-N-[(7R)-4-hydroxy-4-oxido-10-oxo-7-[(1-oxohexadecyl)oxy]-3,5,9-trioxa-4-phosphapentacos-1-yl]-L-alaninamide.

[0331] In an embodiment, the nanobiological composition of the present disclosure comprises a trained immune inhibitor. In an embodiment, the trained immune inhibitor is one or more trained immune inhibitors disclosed in US2020 / 0376146, which is incorporated herein by reference. In an embodiment, the trained immune inhibitor is an mTOR inhibitor. In an embodiment, the mTOR inhibitor is rapamycin or a prodrug thereof.

[0332] In embodiments, the mTOR inhibitor is CCL-779, RAD001, AP23573, C20-methallylrapamycin (C20-Marap), Cl6-(S)-butysulfonamidorapamycin (C16-BSrap), C16-(S)-3-methylindolerapamycin (C16-iRap) (Bayle et al., Chemistry & Biology, 2006, 13:99-107), AZD8055, BEZ235 (NVP-BEZ235), chrysophanic acid (chrysophanol), deforolimus (MK-8669), everolimus (RAD0001), KU-0063794, PI-103, PP242, temsirolimus, and WYE-354. In embodiments, the trained immune inhibitor is a rapamycin derivative, e.g., as disclosed in U.S. Patent No. 5,665,772, U.S. Patent No. 6,440,990, U.S. Patent No. 5,985,890, or U.S. Patent No. 6,200,985, each of which is hereby incorporated by reference. In embodiments, the compound is 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapambycin, 16-pent-2-ynyloxy-32(S)-dihydro-rapamycin, 16-pent-2-ynyloxy-32(S)dihydro-40-O-(2-hydroxyethyl)-rapamycin, or 40-O-(2-hydroxyethyl)rapamycin. In embodiments, the nanobiological agents include compounds described in WO 94 / 09010, WO 95 / 16691, or WO 96 / 41807, which have been found to be useful, for example, as immunosuppressants.

[0333] In embodiments, the sphingolipids of the present disclosure are formulated with any of the nanobiological compositions disclosed in US2019 / 0290593, US2020 / 0253884, US2020 / 0376146, and WO2018 / 071549, which are incorporated by reference in their entireties for all purposes.

[0334] Pharmaceutical Formulations Containing Nanobiologic Compositions When used as a pharmaceutical, the nanobiological composition of the present disclosure is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical field and contain at least one active compound. In some embodiments, the pharmaceutical composition comprises the nanobiological composition of the present disclosure and a pharmaceutically acceptable carrier. The pharmaceutical composition disclosed herein can contain multiple nanobiological preparations. For example, the first nanobiological preparation can have a spherical structure, and the second nanobiological preparation can have a discoid structure.

[0335] Generally, the nanobiological compositions of the present disclosure are administered in a pharma- ceutical effective amount. The amount of compound actually administered can typically be determined by a physician in view of the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0336] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending agents, dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, gum tragacanth, or gelatin, excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, or corn starch, lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide, sweeteners such as sucrose or saccharin, or flavorings such as peppermint, methyl salicylate, or orange flavoring.

[0337] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As before, the active compound in such compositions is typically a minor component, often about 0.05-10% by weight, with the remainder being the injectable carrier etc.

[0338] The above-mentioned components for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, etc. are described in Part 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pa., which is incorporated herein by reference.

[0339] The term "unit dosage form" refers to a physically discrete unit suitable for unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect, together with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions.

[0340] Treatment Provided herein are methods of treating subjects susceptible to or suffering from immune-related diseases and conditions, including, for example, infectious diseases, immunosuppressive states in sepsis and infections, cell proliferation disorders (such as cancer), autoimmune and autoinflammatory disorders, transplantation, cardiovascular disease, neurodegenerative diseases, allergies, and other immune-related diseases and conditions.

[0341] Examples of autoimmune diseases include celiac disease, type I diabetes, multiple sclerosis, thyroiditis, Graves' disease, systemic lupus erythematosus, scleroderma, psoriasis, arthritis, rheumatoid arthritis, alopecia greata, ankylosing spondylitis, Churg-Strauss syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, Crohn's disease, dermatomyositis, glomerulonephritis, Guillain-Barre syndrome, IBD, lupus nephritis, myasthenia gravis, myocarditis, pemphigus / pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, rheumatic fever, sarcoidosis, Sjogren's syndrome, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis.

[0342] In embodiments, the nanobiological compositions used herein may be used to treat atherosclerotic lesions, such as coronary atherosclerosis, diabetic atherosclerosis, atherosclerosis, acute coronary syndromes, myocardial infarction, angina pectoris, peripheral vascular disease, intermittent claudication.

[0343] In embodiments, the present disclosure provides a method of inducing transplant tolerance in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a nanobiological composition of the present disclosure.In embodiments, the present disclosure provides a method of preventing organ or tissue rejection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a nanobiological composition of the present disclosure.

[0344] In embodiments, the present disclosure provides a method of treating a subject having a viral, fungal, mycoplasmal, bacterial, or protozoal infection comprising administering to the subject a therapeutically effective amount of a nanobiological composition of the present disclosure.

[0345] In embodiments, the present disclosure provides methods of improving organ or tissue transplant survival in a patient in need thereof.

[0346] In embodiments, the transplant tissue is lung tissue, cardiac tissue, renal tissue, liver tissue, retinal tissue, corneal tissue, skin tissue, spleen tissue, intestinal tissue, reproductive tissue, ovarian tissue, bone tissue, tendon tissue, bone marrow, or vascular tissue. In embodiments, the transplant tissue is an intact organ. In embodiments, the subject is a human and the organ or tissue transplant is an allogeneic tissue or organ transplant. In embodiments, the nanobiological composition is administered prior to, in conjunction with, or after the allogeneic tissue or organ transplant. In certain embodiments, the method further comprises administering one or more immunosuppressants to the patient.

[0347] In embodiments, the present disclosure provides a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a nanobiopharmaceutical composition of the present disclosure.

[0348] The cancer may be selected from the group consisting of bladder cancer, bone cancer, brain cancer (e.g., glioblastoma multiforme, glioma, astrocytoma), breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lung cancer, oral cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer (e.g., neuroendocrine prostate cancer), rectal cancer, colorectal cancer, stomach cancer, skin cancer, gastric cancer, testicular cancer, pharyngeal cancer, thyroid cancer, urothelial cancer, and uterine cancer.

[0349] In embodiments, the cancer is selected from the group consisting of bladder cancer, vascular cancer, bone cancer, brain cancer, breast cancer, cervical cancer, breast cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, oral cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, colorectal cancer, skin cancer, stomach cancer, testicular cancer, pharyngeal cancer, thyroid cancer, urothelial cancer, and uterine cancer.

[0350] In embodiments, the cancer is selected from the group consisting of breast cancer, prostate cancer, melanoma, colorectal cancer, lung cancer, pancreatic cancer, and glioblastoma.

[0351] The nanobiological compositions of the present disclosure are contemplated for administration by a variety of routes, including oral, rectal, intraocular, transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, intradermal, directly into the cerebrospinal fluid, intratracheal, and intranasal. Often, administration is intravenous.

[0352] The trained immune promoter or trained immune inhibitor (e.g., those disclosed herein) may be incorporated into the nanobiological preparation or may be physically separate from the nanobiological preparation. The physically separate trained immune promoter or trained immune inhibitor and nanobiological preparation may be administered together, for example, in a suspension, or may be administered separately, by the same route of administration or by different routes of administration. When administered separately, the trained immune promoter or trained immune inhibitor and nanobiological preparation may be administered within 20 minutes, within 1 hour, within 2 hours, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of each other. In embodiments, the trained immune promoter and nanobiological preparation may be administered at least 12 hours, at least 1 day, at least 2 days, at least 3 days, at least 7 days, or at least 2 weeks apart.

[0353] The compositions and methods disclosed herein provide two inputs to enhancing trained immunity. A nanobiological composition containing sphingolipids may contain a trained immunity promoter or may be administered together with a trained immunity promoter close enough together to obtain a combined effect of both on the innate immune system. In embodiments, provided herein is a method of inducing or increasing a trained immune response comprising administering a nanobiological composition of the present disclosure. In embodiments, inducing trained immunity is characterized by enhanced IL-6 production in PBMCs treated with sphingolipid nanobiological formulations upon LPS stimulation, as compared to control PBMCs incubated with culture medium (RPMI), in an in vitro training immunity assay, such as described herein. In embodiments, increasing trained immunity is characterized by enhanced IL-6 production in PBMCs treated with sphingolipid nanobiological formulations and HKCA upon LPS restimulation, as compared to control PBMCs treated with HKCA alone, in an in vitro training immunity assay, such as described herein.

[0354] In embodiments, provided herein is a method of suppressing a trained immune response comprising administering a nanobiological composition of the present disclosure. In embodiments, suppressing or inhibiting trained immunity is characterized by suppressed TNF production in PBMCs treated with sphingolipid nanobiological formulations upon LPS restimulation, as compared to control PBMCs incubated with culture medium (RPMI), in an in vitro training immunity assay, such as described herein. In embodiments, suppressing or inhibiting trained immunity is characterized by suppressed TNF and / or IL-6 production in PBMCs treated with sphingolipid nanobiological formulations and HKCA upon LPS restimulation, as compared to control PBMCs treated with HKCA alone, in an in vitro training immunity assay, such as described herein.

[0355] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: (i) (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) a phospholipid; (c) cholesterol; (d) Sphingolipids and wherein the sphingolipid is present as about 1-50 mol% of the total lipid composition, and the nanobiological composition is about 8 nm to about 150 nm in diameter; (ii) a trained immune promoter or inhibitor; The present invention provides a method for stimulating or inhibiting a trained immune response in a subject, comprising administering

[0356] The nanobiological compositions described herein can be provided in a kit. In some embodiments, the kit comprises (a) a nanobiological composition described herein, and optionally (b) informational material. The informational material can be descriptive, instructional, marketing, or other material relating to the methods described herein and / or the use of the compositions described herein for the methods described herein. In embodiments, the informational material can include information regarding the generation of the nanobiological composition. In some embodiments, the informational material relates to methods of administering the nanobiological composition. In embodiments, the informational material can include instructions for administering the nanobiological composition described herein in a suitable manner, e.g., in a suitable dose, dosage form, or mode of administration (e.g., a dose, dosage form, or mode of administration described herein), for carrying out the methods described herein. In some embodiments, the informational material can include instructions for administering a compound described herein to a suitable subject, e.g., a human, e.g., a human having or at risk for a disorder described herein.

[0357] The kit can include one or more containers for the composition containing the nanobiological composition described herein. In some embodiments, the kit contains separate containers, dividers, or compartments for the composition and informational material. For example, the composition can be contained in a bottle, vial, or syringe, and the informational material can be contained in a plastic sleeve or packet. In some embodiments, the separate elements of the kit are contained within a single undivided container. For example, the composition can be contained in a bottle, vial, or syringe to which the informational material is attached in the form of a label. In some embodiments, the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms (e.g., dosage forms described herein) of the nanobiological composition described herein.

[0358] In embodiments, provided herein are nanobiological compositions prepared according to the methods disclosed herein. EXAMPLES

[0359] Example 1 Formulation of sphingolipid-loaded nanobiologics 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), cholesterol, and sphingolipids were obtained from Avanti Lipids with purity >99%. ApoA-1 was isolated from human HDL concentrate (Biosource Technology) as previously reported (Braza, MS, et al., Immunity, 2018. 49(5):819-828 e6). DMPC (2.50 mg, 3.69 μmol, 1.0 equiv.), cholesterol (0.29 mg, 0.74 μmol, 0.2 equiv.), and sphingolipid (0.74 μmol, 0.2 equiv.) were placed in a 20 mL vial and dissolved in chloroform (2.0 mL). For unloaded nanobioformulations used as controls, sphingolipid was replaced with an additional 0.2 equiv. of DMPC. The solvent was evaporated under vacuum to produce a lipid film, and then apoA-1 (1.0 mg, 33 nM) in PBS (5.0 mL) was added. The suspension was sonicated for 7 min using a Branson digital sonifier SFX150 operated at 60% power while cooling in an ice-water bath. The slightly opaque solution was concentrated by centrifugal filtration using Vivaspin tubes (Sartorius Biotech, 10 kDa molecular weight cutoff, 4000 rpm and 4° C.) until approximately 1.0 mL of volume remained. PBS (2.0 mL) was added and the sample was centrifuged again until 1.0 mL remained. This was repeated once more. The resulting solution was filtered through a 0.22 μm polyethersulfone (PES) syringe filter (Celltreat) to obtain the sphingolipid-loaded nanobiological formulation as a white emulsion.

[0360] Characterization of size and sphingolipid loading of sphingolipid-loaded nanobiopharmaceuticals Particle size was determined by dynamic light scattering (DLS) using a ZetaPALS analyzer from Brookhaven Instrument Corporation. An aliquot (20 μL) of the nanobiologic was diluted with 1.0 mL of PBS and filtered using a 0.22 μm PES syringe filter to remove any dust. Six separate runs of 1 min each were recorded and the average of the number average size distribution was reported. Sphingolipid concentrations in the nanobiologic emulsions were 1 The solubility of the nanobioparticles was determined by H NMR. Aliquots of the formulated sphingolipid-loaded nanobioparticles (approximately 0.25 mL) were lyophilized and resuspended in a mixture of deuterated chloroform and methanol (50:50 vol.%, 0.5 mL total) containing a known concentration of DMPC. 1 H NMR analysis showed that DMPC(CH 2 The intensities of signals characteristic of sphingolipids (-COO) and sphingolipids (double bonds) were used to determine the concentration of sphingolipids.

[0361] The sphingolipid-loaded nanobiological compositions listed in Table 3 below were prepared. Sizes are reported as the mean of the number-average size distribution. Both particle size and dispersity index of the nanoparticles were determined by dynamic light scattering.

[0362] [Table 4A]

[0363] [Table 4B]

[0364] [Table 4C]

[0365] Example 2 In vitro evaluation of the effects of exogenously administered sphingolipids on innate immune memory in human primary monocytes In this study, we investigated the effect of exogenously administered sphingolipids on innate immune memory in primary human monocytes. To facilitate efficient delivery of sphingolipids to monocytes, sphingolipids were formulated within the nanobiological delivery platform described in Example 1 and Figure 1C, which is highly targeted to myeloid cells.

[0366] method Isolation of human PBMCs PBMCs were isolated by differential centrifugation over Ficoll-Paque (Lymphoprep, StemCell Technologies, Inc.). Cells were washed twice with PBS. PBMCs were resuspended in RPMI culture medium supplemented with 2 mM glutamax, 1 mM pyruvate, and penicillin / streptomycin (all from Thermo Fisher Scientific) and counted in a Casy counter (Innovatis).

[0367] Measurement of lactate dehydrogenase to assess cytotoxicity Using the CyQuant LDH cytotoxicity assay (Thermo Fisher Scientific), LDH concentrations were measured in the supernatants of PBMCs after 24 h of incubation with small molecule inhibitors or nanoparticles. LDH concentrations are calculated as a percentage of the maximum possible LDH concentration in fully lysed cells according to the following formula:

[0368]

number

[0369] Training experiments with sphingolipid-nanoparticles Human PBMCs were isolated and plated as described above. After washing, cells were incubated with culture medium alone as a negative control or treated with sphingolipid-loaded nanobiologics for 1 h at 37°C. Cells were then cultured at 10 5The cells were incubated with the respective sphingolipid-loaded nanoparticles (50 μM) with 10 cells / ml of HKCA (Invivogen) for 24 h at 37°C. HKCA is a heat-killed preparation of C. albicans. HKCA activates the β-glucan-specific Dectin-1 receptor expressed on phagocytes. Here, we used HKCA to promote trained immunity, and then the cells were washed and rested in RPMI culture medium containing 10% FBS for 5 days. After the resting period, the cells were stimulated with either RPMI as a negative control, 10 ng / ml LPS (Invivogen), or 1 μg / ml Pam3CSK4 (Invivogen).

[0370] Monocyte isolation Monocytes were isolated using the Pan Monocyte Isolation Kit (Miltenyi Biotech) using negative MACS isolation. Briefly, stimulated PBMCs were washed with PBS and incubated with versene solution (0.48 mM EDTA, Sigma Aldrich) for 30 min at 37°C. Cells were scraped off the plate, counted, spun down, and resuspended in MACS isolation buffer (PBS with 0.5% BSA and 2 mM EDTA). Monocyte isolation was performed according to the manufacturer's instructions.

[0371] Cytokine measurements Cytokine production was measured in supernatants using commercially available ELISA kits for human TNF, IL-6, IFNγ, and IL-1β (R&D systems) according to the manufacturer's instructions.

[0372] result All tested nanobiologic formulations were non-toxic to PBMCs at the concentrations used (Figure 3A).

[0373] PBMCs were stimulated with sphingolipid-nano biologics alone (Figures 1D, 3B, and 3C) or in combination with HKCA (Figures 1E, 3D, and 3E) for 24 hours and restimulated with LPS 5 days later.

[0374] Three sphingolipid-nanobiological formulations (d18:1 / 16:0 ceramide (Table 3, #4), d18:1 / 24:1 galactosyl(β)ceramide (Table 3, #13), and 24:0 sphingomyelin (Table 3, #16)) enhanced IL-6 production upon restimulation, indicating that these nanobiological formulations induced trained immunity (Figure 1D, Figure 3C). Four sphingolipid-nanobiological formulations (d18:1 / 16:0 ceramide (Table 3, #4), d18:1 / 24:1 galactosyl(β)ceramidase (Table 3, #13), d18:1 / 24:0 lactosyl(β)ceramide (Table 3, #14), and d18:1 / 18:1 glucosyl(β)ceramide (Table 3, #19)) augmented HKCA-induced trained immune responses for IL-6 (Figure 1E, Figure 3E).

[0375] Other sphingolipid-nanobiological formulations had the opposite effect: d18:1 / 24:1 lactosyl(β)ceramide (Table 3, #15) suppressed the TNF response upon LPS stimulation 5 days later (Figure 1D, Figure 3C). Nine sphingolipid-nano bioformulations (20:1 sphingosine (Table 3, #2), d18:1 / 24:0 ceramide (Table 3, #3), d18:0 / 16:0 dihydroceramide (Table 3, #5), d18:1 / 12:0 ceramide-1-phosphate (Table 3, #9), d18:1 / 16:0 and d18:1 / 24:0 galactosyl(β)ceramide (Table 3, #11 and #12), d18:1 / 24:1 lactosyl(β)ceramide (Table 3, #15), 24:0 sphingomyelin (Table 3, #16), and d18:1 / 18:0 glucosyl(β)ceramide (Table 3 (Table 4, #18)) inhibited HKCA-induced trained immune responses for TNF. 18:1 / 16:0 ceramide-1-phosphate (Table 3, #7) suppressed HKCA trained for both TNF and IL-6 responses (Figures 1E, 3D, and 3E).

[0376] These data indicate that exogenously administered sphingolipid-loaded nanobiological compositions can affect innate immune memory. Even short exposure to exogenously administered sphingolipid-loaded nanobiological compositions can induce long-term changes in innate immune cell function (e.g., for about one week, about one month, or longer), indicative of a trained immune response. Interestingly, this process depends not only on the type of sphingolipid head group, but also on the saturation state of its fatty acid residues. Species with saturated fatty acid chains (Table 3, #12, #14, #18) had the opposite effect on innate immune memory compared to their cis-monounsaturated counterparts (Table 3, #13, #15, #19). Moreover, inhibition of trained immunity by sphingolipid-nanobiologicals had a stronger effect on TNF production compared to IL-6 secretion. In contrast, induction of trained immunity was most clearly observed in the IL-6 response.

[0377] Example 3 In vivo evaluation of sphingolipid nanobiopharmaceutical compositions in the B16F10 mouse melanoma model In this study, nanobiological formulations containing sphingolipids, C24:1 galactosyl(β)ceramide (d18:1 / 24:1(15Z)) (#13), C16ceramide (d18:1 / 16:0) (d18:1 / 24:0) (#4), C24:0 lactosyl(β)ceramide (d18:1 / 24:0) (#14), and C18:1 glucosyl(β)ceramide (d18:1 / 18:1(9Z)) (#19), were tested in the B16F10 melanoma model. In all cases, tumors were inoculated on day -7 and animals were treated on days 0, 2, and 4 (n=10) with intravenous injections of sphingolipid nanobiological formulations at doses of 0.5, 1.5, and 5.0 mg of sphingolipid per kg of mouse. Black asterisks indicate the significance of tumor size on that particular day, as determined by one-way Anova with Dunnett's multiple comparison analysis. Asterisks in rectangular boxes indicate the significance of tumor growth rate. P values ​​were calculated using the Mann-Whitney U test or unpaired t-test. As determined by Hather et al., Cancer Inform., 2014, 134, 13974. * p<0.05, ** p<0.01, *** p<0.001, ns=not significant. The results are shown in Figure 2. The data are for galactosyl(β)ceramide (d18:1 / 24:1(15Z)) (#13) ** p<0.01, C24:0 lactosyl(β)ceramide (d18:1 / 24:0) (#14) * p<0.05, and C18:1 glucosyl(β)ceramide (d18:1 / 18:1(9Z)). ** Figure 1 shows significant tumor growth reducing properties at three different doses of sphingolipid nanobiological formulation containing p<0.01 (#19).

[0378] Naïve C57BL / 6 mice were given the nanobiologicals intravenously on days 0, 2, and 4 at a dose of 0.5 mg / kg for nanobiological formulations #13 and #14, and 5 mg / kg for #19. Two days after the last injection, animals were sacrificed and blood chemistry analysis was performed. The results are displayed in Figure 4 and show that formulations #13 and #19 were highly biocompatible, while formulation #14 induced mild hepatotoxicity as indicated by elevated AST and ALT levels. ALP = alkaline phosphatase, AST = aspartate aminotransferase, ALT = alanine transaminase, BUN = blood urea nitrogen, n = 4.

[0379] Formulation #13 89 The nanobiologics were radiolabeled with Zr (using the procedure reported in van Leent, MMT et al., Sci Adv, 7, 1-12, 2021) and administered intravenously to B16F10 melanoma-bearing mice. The radiolabeled nanobiologics were subsequently evaluated for pharmacokinetics (Figure 5) and biodistribution (Figure 6) by ex vivo gamma counting at 24 hours (n=5).

[0380] Lipophilic fluorophore DiOC 18 Formulation #13 loaded with was injected intravenously into B16F10 melanoma mouse model and 24 hours later the bone marrow of the animals was analyzed by flow cytometry (n=5) (Figure 7). The results show that nanobiologics loaded with formulation #13 display high uptake into bone marrow cells and hematopoietic organs (n=5). Data are mean ± SD and mean ± SEM for tumor growth experiments.

[0381] Embodiment 1. (a) apolipoprotein AI (apoA-I) or a peptidomimetic of apoA-I; (b) a sphingolipid; (c) Cholesterol and wherein the composition is a nanoparticle having a diameter of about 8 nm to about 150 nm.

[0382] 2. The nanobiological composition of embodiment 1, wherein the sphingolipid is selected from the group consisting of ceramide, sphingomyelin, dihydroceramide, glucosylceramide, sphingosine, sphingosine-1-phosphate, galactosylceramide, ceramide-1-phosphate, lactosylceramide, and mixtures thereof.

[0383] 3. Sphingolipids are

[0384] [ka]

[0385] [ka]

[0386] [ka]

[0387] The nanobiological composition of embodiment 1 or 2, selected from the group consisting of:

[0388] 4. Sphingolipids are

[0389] [ka]

[0390] The nanobiological composition of embodiment 3, selected from the group consisting of:

[0391] 5. Sphingolipids are

[0392] [ka]

[0393] [ka]

[0394] The nanobiological composition of embodiment 3, selected from the group consisting of:

[0395] 6. The nanobiological composition of any one of embodiments 1 to 5, comprising a phospholipid.

[0396] 7. The nanobiological composition of embodiment 6, wherein the phospholipid is selected from the group consisting of 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), and mixtures thereof.

[0397] 8. The nanobiological composition of embodiment 7, wherein the phospholipid is DMPC.

[0398] 9. The nanobiological composition of any one of embodiments 1 to 5, comprising a phospholipid and a lysophospholipid.

[0399] 10. The nanobiological composition of any one of embodiments 1 to 9, wherein the phospholipid is 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC).

[0400] 11. The nanobiological composition of embodiment 9, wherein the lysophospholipid is selected from the group consisting of 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (MHPC), 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (PHPC), 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (SHPC), and mixtures thereof.

[0401] 12. The nanobiological composition of embodiment 9, wherein the phospholipid is 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and the lysophospholipid is 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (PHPC).

[0402] 13. The nanobiological composition of any one of embodiments 1 to 12, comprising human apolipoprotein AI (apoA-I).

[0403] 14. The nanobiological composition of any one of embodiments 6 to 13, wherein the sphingolipid is present at about 1-50 mol % of the total lipid composition.

[0404] 15. The nanobiological composition of embodiment 14, wherein the sphingolipid is present at about 10-25 mol% of the total lipid composition.

[0405] 16. The nanobiological composition of embodiment 15, wherein the sphingolipid is present at about 20 mol% of the total lipid composition.

[0406] 17. The nanobiological composition of any one of embodiments 1 to 16, wherein cholesterol is present at about 1-30 mol % relative to the phospholipid.

[0407] 18. The nanobiological composition of embodiment 17, wherein cholesterol is present at about 5-25 mol % relative to the phospholipid.

[0408] 19. The nanobiological composition of any one of embodiments 1 to 18, wherein the phospholipids, sphingolipids, and cholesterol are present in a molar ratio of about 1:0.05-0.25:0.05-0.25.

[0409] 20. The nanobiological composition of any one of embodiments 1 to 19, having a PDI of about 0.1 to about 0.3.

[0410] 21. The nanobiological composition of any one of embodiments 1 to 20, wherein the nanoparticles have a diameter of about 20 nm to about 100 nm.

[0411] 22. The nanobiological composition of embodiment 21, wherein the nanoparticles have a diameter of about 25 nm to about 60 nm.

[0412] 23. The nanobiological composition of any one of embodiments 1 to 22, wherein the nanoparticles are spherical.

[0413] 24. The nanobiological composition of any one of embodiments 1 to 22, wherein the nanoparticles are disc-shaped.

[0414] 25. The nanobiological composition of any one of embodiments 1 to 24, suitable for intravenous or intraarterial administration.

[0415] 26. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a nanobiopharmaceutical composition of any one of embodiments 1 to 25.

[0416] 27. The method of embodiment 26, wherein the cancer is selected from the group consisting of bladder cancer, vascular cancer, bone cancer, brain cancer, breast cancer, cervical cancer, breast cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, oral cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, colorectal cancer, skin cancer, stomach cancer, testicular cancer, pharyngeal cancer, thyroid cancer, urothelial cancer, and uterine cancer.

[0417] 28. The method of embodiment 27, wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, melanoma, colorectal cancer, lung cancer, pancreatic cancer, and glioblastoma.

[0418] 29. The method of any one of embodiments 26 to 28, wherein the nanobiologic composition is administered intravenously or intraarterially.

[0419] 30. The method of any one of embodiments 26 to 29, wherein the subject is a human.

[0420] 31. (i) a nanobiological composition according to any one of embodiments 1 to 25; and (ii) a trained immune promoter; 23. A method for stimulating a trained immune response in a subject, comprising administering

[0421] 32. The method of embodiment 31, wherein the trained immune promoter is a Dectin-1 receptor agonist, a NOD-2 agonist, or a combination thereof.

[0422] 33. The method of embodiment 31, wherein the nanobiological composition comprises a trained immune promoter.

[0423] 34. The method of embodiment 31, wherein the nanobiological composition and the trained immune promoter are administered in separate compositions.

[0424] 35. The method of embodiment 34, wherein the nanobiological composition and the trained immune promoter are administered within 1, 2, 3, 4, 5, 6, or 7 days of each other.

[0425] 36. The method of embodiment 34 or 35, wherein the routes of administration are the same.

[0426] 37. The method of embodiment 36, wherein the route is intravenous.

[0427] 38. The method according to embodiment 34 or 35, wherein the route of administration is different.

[0428] 39. The method of embodiment 38, wherein the nanobiological composition is administered intravenously.

[0429] 40. The method of embodiment 31, wherein the trained immune promoter is a Dectin-1 receptor agonist.

[0430] 41. The method of embodiment 40, wherein the Dectin-1 receptor agonist is HKCA (heat-killed Candida albicans).

[0431] 42. The method of embodiment 31, wherein the trained immune promoter is a NOD-2 agonist.

[0432] 43. The method of embodiment 42, wherein the NOD2-agonist is muramyl dipeptide (MDP), muramyl tri-peptide (MTP), or a derivative or prodrug thereof.

Claims

1. (a) Apolipoprotein AI (apoA-I) or a peptide mimetic of apoA-I, (b) Sphingolipids and (c) Cholesterol and A nanobiopharmaceutical composition comprising nanoparticles having a diameter of approximately 8 nm to approximately 150 nm.

2. The nanobiopharmaceutical composition according to claim 1, wherein the sphingolipid is selected from the group consisting of ceramide, sphingosine-1-phosphate, sphingomyelin, dihydroceramide, glucosylceramide, sphingosine, galactosylceramide, ceramide-1-phosphate, lactosylceramide, and mixtures thereof.

3. Sphingolipids of formula (I): 【Chemistry 1】 [In the formula, R 1 These are unsaturated aliphatic chains or saturated aliphatic chains, R 2 is C(O)R 4, H, or R4, R 3 This is sugar, P(O)(OH)₂, H, or P(O)(OH)O(CH₂). 2 ) n R 5 And, however, n=1 to 10, R 4 These are unsaturated aliphatic chains or saturated aliphatic chains, R 5 is H, NH 2 , N(CH 3 ) 3 + , OH, or a sugar] The nanobiopharmaceutical composition according to claim 1, or a pharmaceutically acceptable salt thereof.

4. R 1 is unsaturated C 14～24 It is an aliphatic chain, R 2 C(O)R 4 And, R 3 but 【Chemistry 2】 And, R 4 C 11～30 Unsaturated aliphatic chain or C 11～30 It is a saturated aliphatic chain, The nanobiopharmaceutical composition according to claim 3.

5. R 1 is unsaturated C 15～17 The nanobiopharmaceutical composition according to claim 4, wherein the chain is an aliphatic chain.

6. R 1 is unsaturated C 15～17 It is an aliphatic chain, R 2 is C(O)R 4 And, R 3 but 【Transformation 3】 And, R 4 C 11～30 It is an unsaturated aliphatic chain. The nanobiopharmaceutical composition according to claim 5.

7. R 1 C 15 The nanobiopharmaceutical composition according to claim 3, wherein it is an alkenyl and / or R 4 is a C14-24 unsaturated aliphatic chain or a C14-24 saturated aliphatic chain.

8. R 4 C 17 Alkenyl or C 23 The nanobiopharmaceutical composition according to claim 3, wherein the alkenyl is present.

9. R 3 but 【Chemistry 4】 The nanobiopharmaceutical composition according to claim 3.

10. Sphingolipids 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 and 【Chemistry 23】 A nanobiologic composition according to claim 1, selected from the group consisting of the following.

11. Sphingolipids 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 and 【Chemistry 28】 A nanobiologic composition according to claim 10, selected from the group consisting of the following.

12. Sphingolipids 【Chemistry 29】 【Transformation 30】 A nanobiologic composition according to claim 10, selected from the group consisting of the following.

13. A nanobiologic composition according to any one of claims 1 to 12, comprising a phospholipid and human apolipoprotein AI (apoA-I).

14. The nanobiologic composition according to claim 13, wherein the phospholipid is selected from the group consisting of 1,2-dimiristoyl-sn-glycero-3-phosphocholine (DMPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and mixtures thereof.

15. The nanobiopharmaceutical composition according to claim 14, wherein the phospholipid is DMPC.

16. The nanobiologic composition according to any one of claims 1 to 12, further comprising a lysophospholipid.

17. The nanobiologic composition according to claim 13, wherein sphingolipids are present in an amount of about 1 to 50 mol% of the total lipid composition.

18. A nanobiologic composition according to any one of claims 1 to 12, wherein cholesterol is present in an amount of about 1 to 30 mol% relative to phospholipids.

19. The nanobiologic composition according to claim 18, wherein cholesterol is present in an amount of about 5 to 25 mol% relative to the phospholipids.

20. A nanobiologic composition according to any one of claims 1 to 12, wherein phospholipids, sphingolipids, and cholesterol are present in a molar ratio of approximately 1:0.05 to 0.25:0.05 to 0.

25.

21. A nanobiopharmaceutical composition according to any one of claims 1 to 12, wherein the nanoparticles have a diameter of about 20 nm to about 100 nm.

22. A nanobiologic composition according to any one of claims 1 to 12, suitable for intravenous or intra-arterial administration.

23. A nanobiologic composition according to any one of claims 1 to 12 for treating cancer in a subject that requires it.

24. (i) A nanobiologic composition according to any one of claims 1 to 12, (ii) Trained Immunopromoter and A method for stimulating a trained immune response in a subject, comprising the step of administering a substance.

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