Autogenous therapeutic lipid carriers

Abstract

Provided are autogenous therapeutic lipid particles incorporating therapeutic lipids as a key component for protecting and delivering them to sites of interest in the body. The Autogenous Therapeutic Lipid Carriers (ATLCs) generally comprise 5 types of components namely: 1) Therapeutic Lipid (TL), 2) Helper Lipid, 3) Cholesterol, 4) PEGylated Lipid, and optionally 5) Excipient. The therapeutic particles are useful for treating diseases and disorders via mechanisms that include modulation of the immune response.

Description

AUTOGENOUS THERAPEUTIC LIPID CARRIERSCROSS REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of priority to U.S. Provisional Application No. 63 / 673,164. filed on July 18, 2024. the disclosure of which is incorporated herein by reference.FIELD OF PRESENT DISCLOSURE

[0002] The present application is generally drawn to autogenous therapeutic lipid particles incorporating therapeutic lipids as a key component for protecting and delivering them to sites of interest in the body. The therapeutic particles are useful for treating diseases and disorders via mechanisms that include modulation of the immune response.BACKGROUND

[0003] Acute pro-inflammation is a protective and reparative response to insults or perturbations such as pathogens, tissue injury, and the like. Ideally this response is selfregulated and leads to clearance of pathogens, cellular debris, and inflammatory mediators allowing tissues to return to homeostasis. However, an excessive pro-inflammatory' response becomes pathological leading to tissue and organ damage in cardiovascular, metabolic, neurological and degenerative diseases and disorders. Hence, development of therapeutics that temper pathological inflammation are of considerable interest.

[0004] While therapeutic lipids are known to be active against pathological inflammation, they face significant challenges in becoming effective therapeutics. Therapeutic lipids have poor aqueous solubility, low stability, and / or are rapidly cleared from the bloodstream. Therapeutic lipids therefore have low bioavailability or show toxicity when administered at therapeutically effective doses, or frequent and / or over long dosing regimens. Overcoming these challenges is necessary to fulfill the therapeutic promise of these molecules. The present disclosure addresses these needs.SUMMARY OF THE DISCLOSURE

[0005] Methods of making, compositions, and methods for treating neurocognitive, neurodegenerative. and other inflammatory disorders in a subject are provided. Compositions comprise “Autogenous Therapeutic Lipid Carriers (ATLCs)” wherein autogenous refers to the assembly of lipid, lipid-derived, and / or lipid-based molecules without requiring the incorporation of any non-lipid component to result in the generation of lipid particles that confer therapeutic properties and tunable transport or delivery’ capabilities. Autogenous Therapeutic Lipid Carriers generally comprise one or more biocompatible lipids with knownor postulated bioactivity referred to as “Therapeutic Lipids (TLs)” that are incorporated in ATLCs as primary therapeutic agents. Generally, the assembly of ATLCs is achieved without the use of any additional non-lipid material. In some embodiments, ATLCs may encapsulate one or more non-lipid agents and therapeutic agents to increase efficacy or enhance particle safety profile.

[0006] Therapeutic lipids are heterogenous, dynamic, and predominantly hydrophobic organic molecules. Most of the therapeutic lipids incorporated in the particles of the present disclosure occur in nature. These include but are not limited to fatty acids (including omega- 3, omega-6, and omega-9 fatty' acids), fatty7acid-derived therapeutic lipids, fatty7acid-based therapeutic lipids, sterols, sterol-derived therapeutic lipids, and sterol-based therapeutic lipids. In some embodiments, therapeutic lipids may7include synthetically made lipids such as synthetic analogs of natural therapeutic lipids. ATLCs provide a means to protect and deliver the TLs to sites of interest. ATLCs improve solubility, stability, and membrane permeability of the TL to enable optimal biodistribution with low immune responses. In some embodiments the ATLCs can be functionalized or modified by chemical means to enable targeting of specific tissues, cells, or cellular components.

[0007] Methods of making pharmaceutical compositions comprising the ATLCs as well as methods of administration of the lipid particles in therapeutically effective amounts to treat inflammation and disorders in a subject are also provided. Disorders include neurocognitive, neurodegenerative, and other inflammatory diseases and disorders.BRIEF DESCRIPTION OF THE FIGURES

[0008] For a fuller understanding of the nature and objects of the disclosure, reference should be made to the following detailed description taken in conjunction with the accompanying figures.

[0009] FIG. 1. Matrix of combinatorial library of 72 synaptamide ATLCs.

[0010] FIG. 2. PDI values of 20 synaptamide ATLCs before (pre-incubation) and 24 hrs after (post-incubation) particle incubation in serum-like conditions, i.e., 37°C in media comprising PBS + 5% FBS.

[0011] FIG. 3. TPA-ATLC-#3 and #-7 demonstrated improved ability to attenuate LPS-induced IL-6 production in RAW cells, relative to “naked” TPA. TPA-ATLC-#3 showed the best dose-dependent improvement.

[0012] FIG. 4. IC50S for reduction of IL-6 levels by TP A- ATLCs.

[0013] FIG. 5. Effects of NA-, DHA-, Maresin-1-, and Resolvin D5 ATLCs on LPS- induced IL-6 production.

[0014] FIG. 6. DTHA-ATLC-#12 and -#26 demonstrate improved bioactivity (IL-6 reduction) relative to “naked” DTHA. (DTHA and DTHA-ATLC concentrations are, left to right: 2.5uM, 5uM, lOuM.

[0015] FIG. 7. DTHA-ATLC#12 is more than 15-times more potent than “naked” DTHA to reduce IL-6 levels.

[0016] FIG. 8. Protocol for LPS model of neurocognitive impairment.

[0017] FIG. 9. DHA-ATLC- 3 and TPA-ATLC- 3 reverse LPS-induced neurocognitive deficiencies in mice.

[0018] FIG. 10. Maresin-l-ATLC-#7’ and SNA-ATLC-#3 reverse LPS-induced neurocognitive deficiencies in mice.DETAILED DESCRIPTION

[0019] Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0020] Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistiy. molecular biology7, chemical engineering, pharmacology, toxicology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

[0021] Inflammation can be initiated, propagated, or accelerated by various sterile or non-sterile insults or perturbations including but not limited to pathogens, chemicals, trauma, cell debris, and low oxygen conditions. Regulated by the immune system, inflammation related pathways and processes exhibit convergences and divergences based on underling risk or resilience factors, cell ty pes involved, location of activity, and the type, timing, and duration of immunomodulatory perturbations or insults. The immune system comprises innate and adaptive components including but not limited to the complement system, leukocytes, monocytes, phagocytes, macrophages, microglia, astrocytes, neutrophils, and T, B, and NK cells. It is emerging that cells not conventionally classified as immune cells such as endothelial cells, epithelial cells, stromal cells, mesenchymal stem cells, adipocytes, and neurons may also play important roles in immunomodulation. Pathological inflammationresults from heightened, prolonged, chronic, or inadequate inflammatory responses in response to wide ranging stimuli. The goal of therapeutic immunomodulation is to defend an organism against pathological inflammation that elicit abnormal or dysregulated inflammatory responses, thereby maintaining or restoring cellular and tissue integrity or homeostasis.

[0022] Therapeutic lipids evoke common and distinct mechanisms to modulate pathological inflammation with varying potencies (Advances in Nutrition 2016, 7(5). 905- 916; Frontiers in immunology 2018, 9, 38; Nature Reviews Immunology 2002, 2(10), 787- 795). These include but are not limited to 1) Engaging with membrane surface receptors to shift immune response towards an anti-inflammatory or inflammation resolving profile, 2) Serving as chemotactic modulators to stimulate or inhibit the directional movement of immune cells to tissues or areas of injury or repair, 3) Modulating transcription and posttranscription activity by facilitating activities such as transcription factor nuclear translocation, transcription factor interaction promoters and enhancers, and mRNA degradation, 4) Incorporating into membranes to reduce or protect against oxidative insults, 5) Facilitating formation and integrity of membrane bound domains and organelles like lipid rafts, phagosomes and synaptic vesicles, 6) Serving as a reservoir for crucial downstream metabolites necessary for mediating inflammation resolution or therapeutic immunomodulation. Through these pathway s and processes, therapeutic lipids avert, reduce, or resolve pathologic inflammation to rescue or restore homeostasis.

[0023] Therapeutic lipids treat neurodegenerative, neurocognitive disorders, and other disorders by modulating inflammation but may also treat those disorders by regulating other mechanisms including but not limited to myelination and bioenergetic modulation. Incorporating the therapeutic lipid in the particles of the present disclosure overcomes the issues of poor solubility, and oxidative and enzy matic instability. Additionally, incorporation reduces the potential toxicity', and allows for more control to tune where the therapeutic lipids are delivered and their release kinetics.

[0024] As used interchangeably herein, "‘autogenous therapeutic lipid carriers” (ATLCs), or “autogenous therapeutic lipid particles (ATLPs)” refers to lipid particles comprising therapeutic lipids self-assembled with other lipid components. In some embodiments, the ATLCs may encapsulate another non-lipid agent, therapeutic agent, bioactive agent, or drug to increase efficacy or reduce unwanted toxicities. These additional agents will be chosen based on the disorder to be treated, the intended administration and duration of the treatment, synergy with the therapeutic lipid, additive activity with thetherapeutic lipid, and the like. Non-lipid therapeutic or bioactive agents that may be encapsulated by ATLCs include small molecules and biologic agents. They may be chosen to increase anti -infl ammatory activity and may provide synergistic results.

[0025] The morphology and structure of the autogenous therapeutic lipid carriers may vary7, and include liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs). Typically. ATLCs can be spherical or non-spherical in shape including but not limited to worm-like, cubosomes, hexosomes. and spongosomes (Pharmaceutics 2021, 73(11), 1840; ACS Omega 2018, 3, 3235-3247; Eur. J. Lipid Sci. Technol. 2011, 773, 1174).

[0026] In general, the ATLCs of the present disclosure, will comprise one or more TLs, and serve to protect the therapeutic lipids from degradation or clearance. In some embodiments, ATLCs may7comprise more than one TL. The TLs to be combined may be chosen based on their mechanism of action and can be used together to enhance the immunomodulatory effects. Borneol, a terpene, can be used with other TLs to enhance the delivery7of ATLCs to specific sites and facilitate the crossing of the blood brain barrier. The ATLCs can help limit unwanted side effects, sustain and / or control therapeutic lipid dose, or be targeted to desired locations to improve the safety and effectiveness of therapeutic lipids. The ATLCs may7optionally comprise one or more targeting elements that can selectively interact with or bind to cells, tissues, or organs of the body.

[0027] Compositions of the present disclosure comprise ATLCs. The ATLCs generally comprise 5 types of components namely: 1) Therapeutic Lipid (TL), 2) Helper Lipid, 3) Cholesterol, 4) PEGylated Lipid, and optionally 5) Excipient. In some embodiments, ATLCs are composed entirely of therapeutic lipid and other lipid molecules. In some embodiments, the ATLCs include excipients or other components which may or may not be lipid molecules, resulting in an ATLC composed of less than 100% therapeutic lipid and lipid related molecules.

[0028] Typically, ATLCs will contain less than about 25% ionizable cationic lipids that are not helper lipids, less than about 15% ionizable cationic lipids that are not helper lipids, less than about 10% ionizable cationic lipids that are not helper lipids, or less than about 5% ionizable cationic lipids that are not helper lipids (e.g., less than 25%, less than 24%, less than 23%, less than 22%, less than 21%, less than 20%, less than 19%, less than 18%, less than 17%, less than 16%, less than 15%, less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, or less than 5%). In most instances, ATLCs will contain 0% ionizable cationic lipids that are not helper lipids or no appreciable amount of ionizable cationic lipids. Selected ATLCcomponents and their relative ratios determine physicochemical characteristics of the particle including but not limited to particle morphology, shape, stability, size, surface charge. These parameters also determine biophysiological functions of ATLCs such as membrane permeability, biodistribution, and release.

[0029] In some embodiments, therapeutic lipids may include but are not limited to therapeutic synthetic lipid analogs, therapeutic lipid mimetics, and related substances that are functionally or biosy nthetically related to natural therapeutic lipids.

[0030] The “TLs” are selected from therapeutic lipids including but not limited to "Fatty Acyls’’ and “Sterols.” Fatty' acyls comprise non-mutually exclusive categories, namely, “Fatty Acids”, “Fatty Acid-Derived Therapeutic Lipids”, and “Fatty Acid-Based Therapeutic Lipids”. Sterols comprise non-mutually exclusive categories, namely, “Sterols”. “Sterol-Derived Therapeutic Lipids”, and “Sterol-Based Therapeutic Lipids”. Fatty' acid- derived or sterol-derived lipids refer to those that are generated through processes including but not limited to such as elongation, amidation and hydroxylation. Fatty acid-derived or sterol-based lipids refer to those that are generated through processes including but not limited to such as esterification and hydrolysis. For example, a sterol-derived lipid comprises an ester group, an aliphatic group, and a sterol group.

[0031] “Fatty Acyls” comprise non-mutually exclusive categories, namely, “fattyacids”, “fatty acid-derived therapeutic lipids”, and “fatty acid-based therapeutic lipids”. Fattyacids (FAs) are heterogenous, dynamic, and predominantly hydrophobic organic blocking blocks of fatty acyl species. They include saturated, monounsaturated, and polyunsaturated lipids with linear or branched hydrocarbon chains having odd and even numbered carbon atoms ranging 8-46 therefore including short chain: C8-C13 (SC), medium chain: C14-C17 (MC), long chain: C18-C22 (LC), very- long chain: C23-C42 (VLC), and ultra long chain: C43-C46 (ULC) lipids. Fatty acids of the unsaturated kinds include lipids with 1 to 9 double bonds with the location of the first double bond from the methyl end at 2, 3, 4, 5, 6, 7, 8, 9, and 11, or as referred to in the literature as double bond locations <n2, <n3, 0)4, o 5, 0)6, co7, 0)8. 0)9, and 0)11. TLs with a chain length of carbon atoms ranging from about 8 to about 46. from about 8 to about 40, from about 8 to about 36. from about 8 to about 34, about 8 to about 32 (that is, about C8 to about C46, about C8 to about C40, about C8 to about C36, about C8 to about C34, about C8 to about C32, about C8 to about C30, about C8 to about C24, about C8 to about C20) can be incorporated into the lipid compositions of the disclosure and include those discussed below.

[0032] “Fatty' acid-derived therapeutic lipids” are products of fatty acids generated through processes such as elongation, amidation and hydroxylation. “Fatty acid-derived therapeutic lipids” include fatty acyl species spanning fatty acids, fatty acid amides (FAAs), fatty acid amines, oxylipins (also known as oxylipids, hydroxylated fatty acids, or FAOs), keto fatty acids, epoxy fatty7acids, epoxy fatty acids, peroxy fatty acids, and hydroperoxy fatty acids. Notably, oxylipins can have 1, 2, 3, 4, or more hydroxy groups. They are otherwise referred to as mono-, di-, tri- and tetra-oxylipins or hydroxylated fatty acids.

[0033] “Fatty acid-based therapeutic lipids” are products of fatty acids and fatty acid- derived therapeutic lipids generated through processes such as esterification and hydrolysis. “Fatty7acid-based therapeutic lipids” comprise free (non-esterified) or esterified fatty acids and fatty acid-derived therapeutic lipids. Esterified fatty acids and fatty acid-derived therapeutic lipids can be in phospholipid, cholesteryl ester, sterol-ester, ceramide, sphingomyelin, ganglioside and Fatty Acid Esters of Hydroxy Fatty7Acids (FAHFA).

[0034] TLs may be denoted by Therapeutic Lipid ID, which applies the standard nomenclature for FA species preceded by its sub-class, i.e., FA C#:D#nN# where C is represents the carbon length; D is degree of saturation or the number of double bonds; N is the position of the first double bond. The standard description of the TL uses the standard nomenclature to identify the FA building block together with its sub-classification. For example, Nervonic Acid is FA C24: ln9.

[0035] In some embodiments, odd chain fatty acids of various degrees of unsaturation, number and location of double bond(s) include C9:0, C 15:0, C17:0, C17:2n6, C17:3n3, and C21:5n3. In some embodiments, even chain fatty7acids of various degree of unsaturation, number and location of double bond(s) include C8:0, C18: ln9, C18:2n6, C18:3n3. C20:3n9. C22: ln9, C21:5n3, C22: lnl l. C22:4n6. C22:5n3, C22:6n3, C24: ln9, C24:2n6, C24:5n3, C22:4n6, C22:6n3, C32:6n3. In some embodiments, mono-oxylipins include mono- C10: ln8, C18: ln3, C18:ln6, C18:ln7, C18: ln9, C18:2n3, C18:2n6, C18:2n7,C18:3n3, C20:0, C20:4n6, C20:4n7, C20:5n3, C22:6n3, C22:6n6, C22:6n7, C24:0, and C24: ln9 with mono- C10: ln8, C24:0. C24: ln9 as preferred mono-oxylipin species. In some embodiments, di-oxylipins include di- C18: ln6. CI8: ln9, C18:2n3, C18:2n3, C18:2n6, C18:3n4, C18:6n4 with di- C20: ln7, C20:3n6, C20:4n6, C20:5n4, C20:5n5, C22:5n3, C22:5n6, C22:6n3, C24:2n3, and C34:6n3 as preferred di-oxylipin species. In some embodiments, tri-oxylipins include tri- C18:ln7, C18:ln8, C18:2n3, C20:5n4, C20:5n4 with tri-C20:4n4 and C20:4n7 as preferred tri-oxylipin species. In some embodiments, tetra- oxylipins include tetra-C20:5n4 oxylipin species. In some embodiments, epoxy fatty acids areselected from C18:ln6, C18:ln7, C18:ln8, C18:ln9, C18:2n2, C18:2n3, C18:2n6, C18:3n3, C20:4n6. C22:6n3. In some embodiments, hydroperoxy fatty acids are selected from C18:2n6, C18:2n7, C18:3n3, C18:3n4. In some embodiments, keto fatty acids are selected from C18:0, C18:ln6, C18: ln7, C 18: ln7, C18: ln8, C18:ln9, C18:2n3, C18:2n3, C18:2n6, C18:2n7, C18:3n3 with C22:6n3 as a preferred specie. In some embodiments, FAHFAs include C16:0, C16: l and C18: l FA esters of C18:0. Example FAHFAs include hydroxystearic acid and 9-PAHSA in preferred embodiments. In some embodiments the fatty acid amides or fatty acid amines are selected from saturated Cl 2:0 to C22:0; monounsaturated C18:ln9, C24: ln9, or Polyunsaturated C18:2n6, C20:4n6, C20:5n3, C22:4n6, C22:6n3 and others. In some embodiments the fatty acid amides or fatty acid amines are C16:0, C22:6n3, C18: ln9 and C22:6n3. In some embodiments, the fatty acids, fatty acid amides or fatty acid esters are selected from the group consisting of docosahexaenoic acid (DHA), nervonic acid (NA), synaptamide (N-docosahexaenoyl- ethanolamine) (SNA), caprylic acid (CPA), palmitoylethanolamide (PEA), 9- (palmitoyloxy)octadecanoic acid (9-PAHSA). tetracos apentaenoic acid (TP A), 14(Z),17(Z).20(Z).23(Z),26(Z),29(Z)-dotnacontahexaenoic acid (DTHA), 10-Hydroxy-2(E)- decenoic acid (10-HDA), 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (maresin-1), and 7S,17S-dihydroxy-4Z,8E,10Z,13Z,15E,19Z-docosahexaenoic acid (resolvin D5).

[0036] “Sterols” comprises non-mutually exclusive categories, namely, “sterol-based therapeutic lipids” and “sterol -derived therapeutic lipids”. In some embodiments, sterols include cholesterol, ergosterol, lanosterol, brassicasterol, 24-alkyl cholesterol, (e.g., 24-ethyl cholesterol, 24-methyl cholesterol, oxysterols (27-carbon forms of cholesterol, that contain additional oxygen functions as hydroxyl, carbonyl, or epoxide groups), cholesteryl esters (esters of cholesterol and saturated or unsaturated fatty acids), Vitamin D (e.g.. Vitamin D2, Vitamin D3), steroid hormones (e.g., estrogen, glucocorticoids, corticosteroids like medrysone, methylprednisolone) bile acids (e.g. ursodeoxycholic acid; Chenodeoxycholic Acid), cholic acids, deoxy cholic acids, phytosterols (e.g., campesterol, stigmasterol, sitostanol, campestanol) and cholesterol sulfate. The “Cholesterol” component comprises one or more steroids, such as, for example, one or more sterols, such as, for example, cholesterol or its analogues such as beta-sitosterol, ergosterol, lanosterol, brassicasterol, and cholesteryl esters. In general, cholesterol or its analogue helps with particle stability by modulating particle integrity and fluidity. Cholesterol also reduces the amount of membrane bound protein, thereby improving circulation half-life.

[0037] The “Helper lipid” component comprises non-ionic, cationic, anionic, or zwitterionic helper lipids, including any amphipathic helper lipids having hydrophobic and polar head group moieties, such as monoglycerides, diglycerides, glycerophospholipids, sphingomyelin, glycosphingolipids, dialiphatic glycolipids, and others known in the art used alone or in combinations. Generally, helper lipids are efficiency determinants whose ratios in a particle determine ATLC integrity and stability. Helper Lipids may control membrane rigidity to increase incorporation of TLs preventing premature disassembly or leakage of TLs. Example helper lipids are zwitterionic l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), l,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), anionic 1,2-distearoyl-sn- glycero-3-phospho-(T-rac-glycerol) (18PG), l,2-dimyristoyl-sn-glycero-3-phosphate (14PA), didodecyldimethylammonium bromide (DDAB) and l,2-dioleoyl-3- trimethylammoniumpropane (DOTAP). In some embodiments, the helper lipid is zwitterionic or otherwise neutral. In some embodiments, the helper lipid bears a net charge. In some embodiments, the helper lipid is anionic. In some embodiments the helper lipid is cationic. In some embodiments, more than one helper lipid may be incorporated into the ATLCs. It has been demonstrated that a number of helper lipids may be used.

[0038] The “PEGylated lipids” include hydrophilic polymers having a long chain highly hydrated flexible neutral polymer attached to lipid molecules. These hydrophilic polymers typically include polyethylene glycol (PEG) and its analogs. Non-limiting examples of the hydrophilic polymer include, but are not limited to. polyethylene glycol (PEG), PEG derivatized with Tween, PEG derivatized with distearoylphosphatidylethanolamine (PEG- DSPE), ganglioside GM, DMG-PEG2000, DMPE-PEG550, and other highly water-soluble synthetic polymers. PEGylated lipids help maintain uniformity of particles, prevent aggregation and immune clearance, and help control particle size, stability, and influence biodistribution. PEGylated lipids may influence targeting; for example, PEGylated ceramide may facilitate liver targeting.

[0039] Conventionally , excipients include stabilizers, surfactants, emulsifiers, lubricants and antioxidants that protect and maintain particle morphology in on-shelf conditions and biological environments. The “Excipients” component in ATLCs are preferably lipid surfactants, emulsifiers and antioxidants or surfactants with tissue targeting advantages that naturally home to membranes, cells, cell organelles, tissue or organs. Lipid- surfactants include ceramides, phosphatidylcholine, bile salt, and taurocholate; passive (brain) targeting surfactants include chitosan and polysorbate (Tween 80); protective emulsifiers include lecithin, mono- and diglycerides; lipid antioxidants include fat solubleVitamins E and K, all of which can be used alone or in combinations. Other non-limiting examples of surfactants include, ethylene oxide copolymers, propylene oxide copolymers, poloxamine, poloxamers, sorbitan ethylene oxide, polysorbate 20, polysorbate 60, sorbitan esters, span 20, span 40, span 60, span 80, alkylaryl polyether alcohol polymers, tyloxapol, gemini surfactants, alcohols, diethylene glycol monoethyl ether, propanediol, capryl glucoside, decy glucoside, kolliwax. polysorbate 80, cholate, glycocholate, taurocholate, taurodeoxycholate. or mixtures thereof. Some stabilizers, including but are not limited to, Vitamin E may be used as a '‘therapeutic lipid” stabilizer in autogenous therapeutic lipid particles.

[0040] Ionizable cationic lipids or ionizable lipids that are not helper lipids are generally used for encapsulation of nucleic acids and to support packaging of negatively charged nucleic acid payloads, facilitate cell uptake, and more importantly, support endosomal escape following cellular uptake. In most instances, ATLCs contain no ionizable lipid as the incorporation of TLs does not rely on charge mediated complexation. In some instances, ATLCs may include an ionizable lipid to adjust its ability- to reach cytosol in a timely manner. In these instances, the amount of ionizable lipid is carefully titrated to avoid inflammatory response.

[0041] In designing the ATLCs of the present disclosure, the components will be selected to control or achieve optimal physicochemical properties such as particle size and size distribution, uniformity in solution, surface charge and charge distribution, on shelf and physiological stability of autogenous therapeutic lipid particles and therapeutic compositions comprising autogenous therapeutic lipid particles. These factors play a role in the biological effects of the ATLCs, for example, toxicity, efficacy, and biodistribution which factor into the patient-setting, treatment objectives, administration route, dosing regimen, and the condition to be treated. In designing the ATLCs, the 5 different types of components can be selected from those that are generally recognized as safe or Generally Recognized As Safe (GRAS) agents, resulting in an ATLC that has minimal or no toxicity and should meet requirements and minimize regulatory barriers for clinical testing.

[0042] Size is a factor for consideration in the construction of the lipid molecules. Ideal particle size may vary depending on the route of administration, intended particle location, desired site of TL activity, and disease site. For example, when administered intravenously, particles with size smaller than 10 nm may be ideal for delivery to the kidney as larger particles are generally unable to penetrate the kidney glomerular filtration barrier (International Journal of Molecular Sciences 2021, 22, 11182). Particles that are about20 - about 100 nm may be ideal for prolonged circulation, and those larger than 200 nm may be prone to uptake by circulating cells of the mononuclear phagocyte system J. Control Release 2021, 334, 127-137). In scenarios whereby the preferred particle location is the brain, it is generally expected that nanoparticles with an average diameter ranging from about 20 to about 80 nm may have a higher probability to interact with the brain capillary endothelium and cross the blood-brain barrier through transcytosis or other transport mechanism. In these instances, the nanoparticles are often modified to bind and engage with the brain capillary endothelium cells via cell surface receptors.

[0043] Polydispersity Index (PDI) is used to estimate the average uniformity of a particle solution represented by the distribution of size populations within a given sample. The numerical value of PDI may range from 0.0 (for a perfectly uniform sample with respect to the particle size) to 1.0 (for a highly poly disperse sample with multiple particle size populations). Generally, a PDI from about 0.05 to about 0.35, about 0.05 to about 0.4, about 0.05 to about 0.45. In some instances about 0.05 to about 0.5 is acceptable. Values of about 0.25 and below may be preferred. It is generally ideal for particles to have a lower PDI for more consistent performance and better quality control. Additionally, uniformity is critical for consistent particle behavior and therefore an important feature for products manufacturing and regulation.

[0044] Particle surface charge is dictated by the charge of the individual ATLC components. Generally, negatively charged or neutral particles exhibit a lower risk of side effects of inflammation. High concentrations of cationic components render the ATLCs highly positively charged and thus may induce inflammatory or toxic effects. Particles containing high concentrations of ionizable cationic lipids that are not helper lipids such as DLin-MC3-DMA, may lead to high surface charges in acidic compartments and can induce high levels of inflammatory responses. Thus, the desired particle charge will depend on the desired application. For ATLCs, ideal surface charges should be negative or at most weakly positively charges with a zeta potential in the range of about -30 mV to about +5 mV when measured in the standard phosphate buffered saline.

[0045] Stability is dictated by the individual components of the ATLC. By ' Stability is intended the preservation of a particular nanostructure property ranging from aggregation, composition, crystallinity, shape, size, and surface chemistry. In some embodiments, stability7may be retained with the use of cry oprotectants, trehalose, sucrose, and the like.

[0046] As used herein, a healthy phy siological level of the TL is intended to mean the level required to maintain healthy function. A number of diseases mentioned herein areknown to involve a decrease in TL levels in patients. Therefore, the terms ‘maintaining’ or ‘normalizing’ levels is intended to mean modulating the levels of fatty acyls and sterols to healthy levels.

[0047] The autogenous therapeutic lipid particle compositions and methods of the present disclosure may be used to treat neurocognitive, and neurodegenerative disorders and other disorders. By treat it is intended to prevent, slow, alleviate, ameliorate, relieve, delay onset of, inhibit progression of, reduce severity of, and / or reduce incidence of one or more symptoms or features of neurocognitive, and neurodegenerative disorders and other disorders. In this manner, ATLCs may be administered for prevention (prophylactic) and therapeutic purposes. By disorders, it is intended to include genetic, degenerative, acute, chronic, and aging-related diseases, disorders, or conditions that affect the entire body including those that affect central and peripheral nervous systems, peripheral organs, and factors in circulating biofluids. Acute diseases, disorders, or conditions include but are not limited to those induced by pathogens, toxins or chemicals, surgeries or medical procedures, mechanical injuries, trauma, and bleeding.

[0048] Neurodegenerative and neurocognitive disorders include some of the major diseases and conditions of the brain, eye, spinal cord, and peripheral nen es, whereby a progressive demise of cellular organization leads to impaired function including neurocognitive deficits and dysfunction. These conditions can be acute or predictable and chronic or sporadic in nature. Neurocognitive. and neurodegenerative disorders and other disorders are generally initiated, mediated, accelerated, or associated with pathologic or dysfunctional inflammation. The ATLCs and compositions comprising the ATLCs may be used to treat inflammation and inflammation associated disorders.

[0049] Examples of related chronic or sporadic neurocognitive. neurodegenerative, and other disorders (which may or may not be age related) include, but are not limited to, dementia, mixed dementia, cerebral amyloid angiopathy, spinal muscular atrophy, motor neuron disease, subcortical vascular dementia, Alzheimer’s Disease (AD), Alzheimer’s Disease in patients with Down, Senile Dementia, Primary Degenerative Dementia, Parkinson’s Disease (PD). Paralysis Agitans, Shaking Palsy, Amyotrophic Lateral Sclerosis (ALS), Lou Gehrig’s Disease, Motor Neuron Disease (MND), Huntington’s Disease (HD), Huntington’s Chorea, Huntington’s Disorder, Frontotemporal Dementia (FTD), Pick’s Disease, Frontotemporal Lobar Degeneration (FTLD), Lewy Body Dementia (LBD), Dementia with Lewy Bodies (DLB), Vascular Dementia (VaD), Multi-Infarct Dementia. Multiple System Atrophy (MSA), Shy-Drager Syndrome, Sporadic OlivopontocerebellarAtrophy, Corticobasal Degeneration (CBD), Corticobasal Ganglionic Degeneration (CBGD), Progressive Supranuclear Palsy (PSP), Steele-Richardson-Olszewski Syndrome, and Chronic Traumatic Encephalopathy (CTE).

[0050] Acute or predictable neurocognitive, neurodegenerative, and other disorders can be induced by insults, stimuli, or perturbations including but not limited to pathogens, toxins or chemical, surgery’ or medical procedures, mechanical injury, trauma, or bleeding. Examples of these disorders or conditions induced by pathogens such as bacteria, viruses, and parasites include HIV-associated neurocognitive decline (HAND), HIV-associated neurocognitive disorder, COVID-19 associated cognitive impairment or neurocognitive decline, Neurologic Lyme Disease, infection-related cognitive dysfunction, urinary tract infection related neurocognitive impairments, urinary tract infection related complications, and urinary tract infection related delirium. Examples of acute or predictable disorders or conditions induced by toxin or chemical include Drug-Induced Delirium and Medication- Induced Confusional State. Examples of acute or predictable disorders or conditions induced by surgery or medical procedure include Intensive care unit (ICU) related agitation, intensive care unit (ICU) related cognitive decline, intensive care unit (ICU) related cognitive dysfunction, intensive care unit (ICU) related cognitive impairment, intensive care unit (ICU) related neurocognitive disorder, intensive care unit (ICU) related delirium, intensive care unit (ICU) related dementia, intensive care unit (ICU) related emergence agitation, intensive care unit (ICU) related encephalopathy, intensive care unit (ICU) related delayed neurocognitive recovery (DNR), post-anesthesia care unit (PACU) related agitation, post-anesthesia care unit (PACU) related cognitive decline, post-anesthesia care unit (PACU) related cognitive dysfunction, post-anesthesia care unit (PACU) related cognitive impairment, post-anesthesia care unit (PACU) related neurocognitive disorder, post-anesthesia care unit (PACU) related delirium, post-anesthesia care unit (PACU) related dementia, post-anesthesia care unit (PACU) related emergence agitation, post-anesthesia care unit (PACU) related encephalopathy, post-anesthesia care unit (PACU) related delayed neurocognitive recovery' (DNR), postoperative agitation, postoperative cognitive decline, postoperative cognitive dysfunction, postoperative cognitive impairment, postoperative neurocognitive disorder, postoperative delirium, postoperative dementia, postoperative emergence agitation, postoperative encephalopathy, postoperative delayed neurocognitive recovery’ (DNR), perioperative agitation, perioperative cognitive decline, perioperative cognitive dysfunction, perioperative cognitive impairment, perioperative neurocognitive disorder, perioperative delirium, perioperative dementia, perioperative emergence agitation, perioperativeencephalopathy, perioperative delayed neurocognitive recovery (DNR), surgery related agitation, surgery related cognitive decline, surgery related cognitive dysfunction, surgery related cognitive impairment, surgery related neurocognitive disorder, surgery related delirium, surgery related dementia, surgery related emergence agitation, surgery related encephalopathy, surgery related delayed neurocognitive recovery (DNR), Cataract Surgery related agitation, Cataract Surgery related cognitive decline, Cataract Surgery’ related cognitive dysfunction. Cataract Surgery related cognitive impairment, Cataract Surgery related neurocognitive disorder, Cataract Surgery related delirium, Cataract Surgery related dementia, Cataract Surgery' related emergence agitation, Cataract Surgery' related encephalopathy, Cataract Surgery related delayed neurocognitive recovery (DNR), Joint Replacement Surgery related agitation, Joint Replacement Surgery related cognitive decline. Joint Replacement Surgery' related cognitive dysfunction, Joint Replacement Surgery related cognitive impairment, Joint Replacement Surgery' related neurocognitive disorder, Joint Replacement Surgery' related delirium, Joint Replacement Surgery' related dementia, Joint Replacement Surgery’ related emergence agitation, Joint Replacement Surgery related encephalopathy. Joint Replacement Surgery related delayed neurocognitive recovery (DNR), Cardiac surgery related agitation, Cardiac surgery' related cognitive decline. Cardiac surgery related cognitive dysfunction, Cardiac surgery' related cognitive impairment, Cardiac surgery' related neurocognitive disorder, Cardiac surgery related delirium. Cardiac surgery related dementia, Cardiac surgery related emergence agitation, Cardiac surgery’ related encephalopathy, Cardiac surgery’ related delayed neurocognitive recovery' (DNR), Coronary artery' bypass grafting (CABG) related agitation, Coronary' artery bypass grafting (CABG) related cognitive decline, Coronary' artery bypass grafting (CABG) related cognitive dysfunction, Coronary artery bypass grafting (CABG) related cognitive impairment, Coronary artery bypass grafting (CABG) related neurocognitive disorder, Coronary artery bypass grafting (CABG) related delirium, Coronary' artery bypass grafting (CABG) related dementia, Coronary’ artery bypass grafting (CABG) related emergence agitation, Coronary artery’ bypass grafting (CABG) related encephalopathy, Coronary artery’ bypass grafting (CABG) related delayed neurocognitive recovery (DNR). Heart valve replacement or repair related agitation, Heart valve replacement or repair related cognitive decline, Heart valve replacement or repair related cognitive dysfunction, Heart valve replacement or repair related cognitive impairment, Heart valve replacement or repair related neurocognitive disorder. Heart valve replacement or repair related delirium, Heart valve replacement or repair related dementia. Heart valve replacement or repair related emergence agitation, Heart valvereplacement or repair related encephalopathy, Heart valve replacement or repair related delayed neurocognitive recovery (DNR), Spinal Surgery related agitation, Spinal Surgery related cognitive decline. Spinal Surgery related cognitive dysfunction, Spinal Surgery related cognitive impairment, Spinal Surgery related neurocognitive disorder, Spinal Surgery related delirium, Spinal Surgery related dementia, Spinal Surgery related emergence agitation. Spinal Surgery related encephalopathy, Spinal Surgery related delayed neurocognitive recovery (DNR). Orthopedic surgery related agitation, Orthopedic surgery related cognitive decline. Orthopedic surgery related cognitive dysfunction. Orthopedic surgery' related cognitive impairment, Orthopedic surgery' related neurocognitive disorder, Orthopedic surgery' related delirium. Orthopedic surgery' related dementia, Orthopedic surgery related emergence agitation. Orthopedic surgery related encephalopathy. Orthopedic surgery' related delayed neurocognitive recovery (DNR), Gallbladder Removal (Cholecystectomy) related agitation, Gallbladder Removal (Cholecystectomy) related cognitive decline, Gallbladder Removal (Cholecystectomy) related cognitive dysfunction, Gallbladder Removal (Cholecystectomy) related cognitive impairment. Gallbladder Removal (Cholecystectomy) related neurocognitive disorder. Gallbladder Removal (Cholecystectomy) related delirium, Gallbladder Removal (Cholecystectomy) related dementia, Gallbladder Removal (Cholecystectomy) related emergence agitation, Gallbladder Removal (Cholecystectomy) related encephalopathy, Gallbladder Removal (Cholecystectomy) related delayed neurocognitive recovery (DNR), Prostate Surgery related agitation, Prostate Surgery- related cognitive decline. Prostate Surgery related cognitive dysfunction, Prostate Surgery related cognitive impairment, Prostate Surgery' related neurocognitive disorder, Prostate Surgery related delirium, Prostate Surgery related dementia, Prostate Surgery related emergence agitation. Prostate Surgery related encephalopathy, Prostate Surgery- related delayed neurocognitive recovery' (DNR), Colorectal Surgery related agitation, Colorectal Surgery related cognitive decline, Colorectal Surgery related cognitive dysfunction, Colorectal Surgery related cognitive impairment, Colorectal Surgery' related neurocognitive disorder, Colorectal Surgery related delirium, Colorectal Surgery related dementia. Colorectal Surgery related emergence agitation, Colorectal Surgery related encephalopathy. Colorectal Surgery related delayed neurocognitive recovery (DNR), Hernia Repair related agitation. Hernia Repair related cognitive decline, Hernia Repair related cognitive dysfunction, Hernia Repair related cognitive impairment, Hernia Repair related neurocognitive disorder, Hernia Repair related delirium, Hernia Repair related dementia, Hernia Repair related emergence agitation, Hernia Repair related encephalopathy. Hernia Repair related delayedneurocognitive recovery (DNR), Pacemaker or Defibrillator Implantation related agitation. Pacemaker or Defibrillator Implantation related cognitive decline, Pacemaker or Defibrillator Implantation related cognitive dysfunction. Pacemaker or Defibrillator Implantation related cognitive impairment, Pacemaker or Defibrillator Implantation related neurocognitive disorder, Pacemaker or Defibrillator Implantation related delirium, Pacemaker or Defibrillator Implantation related dementia, Pacemaker or Defibrillator Implantation related emergence agitation. Pacemaker or Defibrillator Implantation related encephalopathy, Pacemaker or Defibrillator Implantation related delayed neurocognitive recovery (DNR), Skin Cancer Surgery' related agitation, Skin Cancer Surgery' related cognitive decline, Skin Cancer Surgery' related cognitive dysfunction, Skin Cancer Surgery related cognitive impairment, Skin Cancer Surgery related neurocognitive disorder, Skin Cancer Surgery related delirium, Skin Cancer Surgery related dementia, Skin Cancer Surgery' related emergence agitation, Skin Cancer Surgery' related encephalopathy, Skin Cancer Surgery related delayed neurocognitive recovery (DNR), Tonsillectomy and Adenoidectomy related agitation. Tonsillectomy and Adenoidectomy related cognitive decline. Tonsillectomy and Adenoidectomy related cognitive dysfunction, Tonsillectomy and Adenoidectomy related cognitive impairment, Tonsillectomy and Adenoidectomy related neurocognitive disorder, Tonsillectomy and Adenoidectomy related delirium, Tonsillectomy and Adenoidectomy related dementia, Tonsillectomy and Adenoidectomy related emergence agitation, Tonsillectomy and Adenoidectomy related encephalopathy. Tonsillectomy and Adenoidectomy related delayed neurocognitive recovery (DNR), Appendectomy related agitation, Appendectomy related cognitive decline, Appendectomy related cognitive dysfunction, Appendectomy related cognitive impairment, Appendectomy related neurocognitive disorder, Appendectomy related delirium. Appendectomy related dementia, Appendectomy related emergence agitation. Appendectomy related encephalopathy. Appendectomy related delayed neurocognitive recover}' (DNR), Inguinal hernia repair related agitation, Inguinal hernia repair related cognitive decline, Inguinal hernia repair related cognitive dysfunction, Inguinal hernia repair related cognitive impairment, Inguinal hernia repair related neurocognitive disorder. Inguinal hernia repair related delirium, Inguinal hernia repair related dementia, Inguinal hernia repair related emergence agitation, Inguinal hernia repair related encephalopathy, Inguinal hernia repair related delayed neurocognitive recovery' (DNR), Congenital Heart Defect Repair related agitation, Congenital Heart Defect Repair related cognitive decline, Congenital Heart Defect Repair related cognitive dysfunction, Congenital Heart Defect Repair related cognitive impairment. Congenital Heart DefectRepair related neurocognitive disorder, Congenital Heart Defect Repair related delirium, Congenital Heart Defect Repair related dementia, Congenital Heart Defect Repair related emergence agitation, Congenital Heart Defect Repair related encephalopathy. Congenital Heart Defect Repair related delayed neurocognitive recovery (DNR), Ear Tube Surgery (Myringotomy) related agitation, Ear Tube Surgery (Myringotomy) related cognitive decline, Ear Tube Surgery (Myringotomy) related cognitive dysfunction, Ear Tube Surgery (Myringotomy) related cognitive impairment. Ear Tube Surgery (Myringotomy) related neurocognitive disorder, Ear Tube Surgery (Myringotomy) related delirium, Ear Tube Surgery (Myringotomy) related dementia, Ear Tube Surgery (Myringotomy) related emergence agitation, Ear Tube Surgery' (Myringotomy) related encephalopathy, Ear Tube Surgery (Myringotomy’) related delayed neurocognitive recovery (DNR). Repair of fractures related agitation, Repair of fractures related cognitive decline. Repair of fractures related cognitive dysfunction, Repair of fractures related cognitive impairment, Repair of fractures related neurocognitive disorder, Repair of fractures related delirium, Repair of fractures related dementia, Repair of fractures related emergence agitation. Repair of fractures related encephalopathy. Repair of fractures related delayed neurocognitive recovery (DNR). Gastrostomy Tube Placement related agitation, Gastrostomy Tube Placement related cognitive decline, Gastrostomy Tube Placement related cognitive dysfunction, Gastrostomy Tube Placement related cognitive impairment, Gastrostomy Tube Placement related neurocognitive disorder. Gastrostomy Tube Placement related delirium, Gastrostomy Tube Placement related dementia, Gastrostomy Tube Placement related emergence agitation. Gastrostomy Tube Placement related encephalopathy, Gastrostomy Tube Placement related delayed neurocognitive recovery (DNR), anesthesia related agitation, anesthesia related cognitive decline, anesthesia related cognitive dysfunction, anesthesia related cognitive impairment, anesthesia related neurocognitive disorder, anesthesia related delirium, anesthesia related dementia, anesthesia related emergence agitation, anesthesia related encephalopathy, anesthesia related delayed neurocognitive recovery' (DNR), Dental surgery’ related agitation, Dental surgery related cognitive decline, Dental surgery related cognitive dysfunction, Dental surgery related cognitive impairment, Dental surgery related neurocognitive disorder, Dental surgery related delirium, Dental surgery related dementia, Dental surgery' related emergence agitation, Dental surgery related encephalopathy, and Dental surgery related delayed neurocognitive recovery (DNR), and the like. Examples of acute or predictable disorders or conditions induced by mechanical injury, trauma, or bleeding include Traumatic Brain Injury, Blunt force trauma, Penetrating trauma.Concussion, Elderly Falls, Post Traumatic Stress Disorder (PTSD), Military Associated Hearing Loss, Trauma-induced hearing loss, spinal Cord Injury, Lasik Injury induced eye injury, subarachnoid hemorrhage, ischemic stroke, intracerebral hemorrhage, Intracranial hemorrhage, Subdural hematoma, Deep vein thrombosis (DVT), Pulmonary embolism, Thrombocytopenia, Aneury sm, and Compartment syndrome, and the like.

[0051] Examples of other neurocognitive, neurodegenerative. and other disorders include Acid sphingomyelinase deficiency, Age-related Macular Degeneration, Autoimmune inner ear disease. Autosomal dominant leukodystrophy (ADLD), Binswanger disease, Cancer, Cerebral Amyloid Angiopathy (CAA), Cerebral Palsy, Cerebral Visual Impairment, Chronic Bronchitis, Chronic Demyelinating Polyneuropathy, Chronic Hypoxic Respiratory' Failure, Chronic Obstructive Pulmonary Disease (COPD), Congenital ichthyosis, Crohn's disease. Diabetes, Diabetic Neuropathy, Diabetic Peripheral Neuropathy, Diabetic Retinopathy, Dry Macular Degeneration, Emphysema, Endotheliitis, Fabry7disease, Familial Amyloid Polyneuropathy / Hereditary transthyretin amyloidosis (hATTR), Fibrosis, Fish Eye Disease, Friedreich’s ataxia, Gaucher disease, Glaucoma, Guillain-Bane Syndrome, Herpes Stromal Keratitis, Hypoxic-Ischemic Encephalopathy, Inflammatory bowel disease, Krabbe disease. Multiple sclerosis. Mucopolysaccharidoses (MPS) diseases, Niemann-Pick disease, Non-Alcoholic Fatty7Liver Disorder, Optic Neuritis, Peripheral Neuropathy, Peroxisome Biogenesis Disorders, Pompe disease, Pulmonary Fibrosis, Retinitis pigmentosa, Retinopathy of prematurity. Rheumatoid arthritis, Sanfilippo Syndrome. Sensorineural hearing loss, Sickle Cell Anemia, Stargardt disease, Systemic lupus erythematosus, Tay-Sachs disease, Traumatic Comeal Flap Dislocation, Usher Syndrome, Uveitis, and Wilson’s disease.

[0052] Methods of Making ATLCs

[0053] The system and methods for making ATLCs includes therapeutic, structural, and other functional components, their distinct configurations, and methods of preparation to enhance desired biophysiochemical properties.

[0054] Therapeutic lipids may be chosen based upon the knowledge of their activity and efficiency. In some instances, lipids can be tested for activity in assays, such as inflammation modulation assays available in the art.

[0055] A combinatorial library screen approach can be adopted to generate and triage ATLCs. To make the ATLCs, each particle contains one or more ty pes of the following constituents or components, namely TLs, Helper lipids, Cholesterols, PEGylated lipids, and optionally, Excipients. The following four independent composition parameters are adjusted to form the matrix of a combinatorial library7: (i) Total TL molar percentage, i.e., rangingfrom about 1-99%, about 20-80%, about 30-70%, about 40-60% including about 5%, about 10%. about 20%. about 30%, about 40%, about 50%, about 60%. about 70%, about 80%, about 90%, (ii) Cholesterol to PEGylated lipid molar ratio (ChoLPEG), ranging from about 2: 1 to 800: 1, including about 1 : 1, about 10: 1, about 100: 1, about 150: 1, about 200: 1, about 250: 1, about 300: 1, about 350:1, about 400: 1, about 450: 1, about 500: 1, about 550: 1, about 600: 1, about 650: 1, about 700: 1. about 750: 1, about 800: 1, (hi) Helper lipid type, e.g., cationic DOTAP, zwitterionic DSPC or anionic 18PG, and (iv) molar ratio of Helper lipid to the sum of Cholesterol and PEGylated lipid (Helper Lipid: (Choi + DMG-PEG)), ranging from about 0.1 : 1 to 6: 1, including about 0.5: 1, about 1 : 1, about 2: 1, about 3: 1, about 4:1, about 5: 1, about 6: 1. For example, a combinatorial library screen with the following matrix parameters such as (i) 2 designated total TL molar percentages, (ii) 3 designated Choi: PEG ratios, (iii) 3 helper lipid types, and (iv) 4 Helper Lipid: (Choi + DMG-PEG) ratios will generate 72 unique ATLCs. ATLCs with the same TL generated from varying types and ratios of other ATLC components can have different properties, including different size, PDI measurements, different zeta-potential, incorporation efficiency.

[0056] The applicability of the matrix parameters provided above is based on knowledge generated from experiments conducted. For example, it was shown that the TL of DHA can be incorporated into ATLCs at increasing molar percentages from 20-80% without affecting incorporation efficiency. Choi: PEG and Helper Lipid: (Choi + DMG-PEG) ratios ranging 10: 1-500: 1 and 0. 1: 1-4: 1, respectively were shown to result in DHA incorporated into ATLCs. The incorporation of helper lipids of various polar head group charges namely cationic, zwitterionic, and anionic into ATLCs yielded stable particles. By vary ing the composition of the ATLCs, the resulting particles can be optimized for stability parameters, activity, targeting efficiency, size, and PDI. The resulting ATLCs can be selected based on in vitro and in vivo assays for activity at the desired location. These parameters can be adjusted for any ATL.

[0057] In general, the solubility of the TL in the buffer solution will determine the amount of the TL in the ATCL. The less soluble lipids are obtained in lower amounts in the lipid compositions. By "‘less soluble” is intended that the amount present in the ethanol starting solution is about 0.05 to about 5 mg / ml, about 0.075 mg / ml to about 3 mg / ml, about 0.08 mg / ml to about 1.0 mg / ml, about 0.1 mg / ml. For example, for less soluble TLs, the amount of TL in the lipid composition ranges from about 0.5 mol% to about 5 mol% (including about 0.5. about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 2, about 3, about 4, and about 5). In those lipid compositions the helper lipid ranges from about 5 mol%to about 60 mol% (including about 5, about 8, about 10, about 20, about 30, about 40, about 45, about 50. about 55. about 60), the cholesterol component ranges from about 20 mol% to about 60 mol% (including about 20, about 30, about 40, about 45, about 50, about 55, about 60), and the PEG component ranges from about 2 mol% to about 10 mol% (including about 2, about 3, about 4, about 4.5, about 5, about 5.5, about 6, about 7, about 8, about 9, and about 10).

[0058] When more soluble lipids are used as the TL, larger amounts of the TL are present in the ATLC or lipid composition. By “more soluble” or “readily soluble” is intended that the amount present in the ethanol starting solution is an amount equal to or greater than about 10 mg / ml. When using readily soluble TLs the amount of TL in the lipid composition ranges from about 5 mol% to about 80 mol% (including about 5, about 10, about 15. about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, and about 80). In these lipid compositions the helper lipid ranges from about 5 mol% to about 70 mol% (including about 5, about 6, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 35, about 40, about 45. about 50, about 55, about 60. about 65, about 70, about 75, and about 80), the cholesterol component ranges from about 10 mol% to about 80 mol% (including about 10, about 14, about 15, about 16, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70. about 75, and about 80), and the PEG component ranges from about 0. 1 mol% to about 20 mol% (including about 0.1, about 0.15, about 0.2, about 0.5, about 1.0, about 2.0. about 3.0, about 4.0, about 5, about 6, about 7, about 8, about 9, about 10, about, 15, and about 20).

[0059] Thus, as demonstrated the amounts of the individual components may vary depending on the solubility’ of the TL in the buffer solution. Additionally, the TL and the amount of TL in the ATLC may be selected to optimize the size, PDI, delivery method, and stability of the ATLC.

[0060] Cell, tissue, or organ specific targeting capability' may be incorporated into the ATLCs or lipid compositions by functionalization with targeting peptides, antibodies, ligands that bind to receptors on cell membranes or blood-brain interface or other membranes of interest. Other strategies for targeting ATLCs to organs of interest may be based on size, charge, phospholipid head group or some combination of these features. Such targeting strategies are known in the lipid nanoparticle literature and may be used to provide targeting ability to autogenous therapeutic lipid particle compositions of the present disclosure. For example, incorporating carbonate apatite in DOTAP -based lipid nanoparticles has beenshown to increase the interaction between the particles and cellular membranes (Zohra et al. Biomaterials 2009. 30. 4006-4013). Blood-brain-barrier targeting lipid nanoparticles were demonstrated by angiopep-2 grafted nanoparticles (Eur. J. Pharm. Biopharm. 2018. 132, 168-179). Size based transport of LNPs across the blood-brain barrier was demonstrated in traumatic brain injury models in mice (Khalin et al. Small 2022, 18, 2200302).

[0061] Methods of Selecting ATLCs

[0062] ATLCs can be selected based on size, PDI, stability and retained activity of the therapeutic lipid. Assays are available in the art for measurement of these parameters. For example, particle size is measured using dynamic light scattering methods which obtain the z- average hydrodynamic diameter (Dz). Whenever there is a single peak for the particles measured, the DLS size standard deviation is directly related to the PDI and Dz that: DLS size standard deviation= (DZ2 x PDI)1 2Particle stability can be measured by remeasuring the size and PDI of ATLCs post incubation in in-serum like conditions or in buffer solutions. A method to assess whether ATLCs retain bioactivity of the incorporated TL is by testing particle efficacy at reducing supernatant inflammatoiy cytokine levels in cell culture subjected to immunogenic stimulation such as lipopolysaccharide induction.

[0063] Initially, the ATLCs are selected based on size and / or PDI. ATLCs that do not exceed size and PDI cut-offs of 450 nm and a PDI of 0.3 -0.4, respectively, are then subjected to stability testing in an in-serum-like condition stability-based exclusion. Following selection, assessment of ATLC bioactivity such as immunomodulatory properties can be assessed. For example, 72 ATLCs generated using synaptamide as the TL resulted in 20 ATLCs that are less than 450 nm diameter in size and have PDI values of less than 0.35.Eight out of the 20 synaptamide ATLCs have PDI values of less than 0.4 after incubation in in-serum like conditions for 24 hours. The PDI cut-off was increased from 0.35 to 0.4 for inserum stability testing because serum proteins included in the media are postulated to form a protein corona layer around the particle which increases particle size. Eight remaining synaptamide ATLCs were then subjected to ultrafiltration to concentrate the solution and remove ethanol content before in vivo or in vitro administration. LPS-induced inflammatory cytokine IL-6 levels were suppressed by 2 out of the 8 synaptamide ATLCs by at least 30%. Notably, 1 out of 8 synaptamide ATLCs out-performed unincorporated synptamide in a statistically significant manner. In the same manner, ATLCs can be selected for any TL of interest.

[0064] There are other methods of testing ATLCs generated from a combinatorial library using generally known techniques available to one skilled in the art to screen outundesirable candidates. Some non-limiting exemplary characterization measures include particle size and size distribution, surface charge and charge distribution, particle morphology, shelf stability, in vitro and in vivo enzymatic stability and activity, in vivo circulation time, in vitro and in vivo release kinetics, in vitro and in vivo blood-brain interface permeability, in vitro and in vivo brain-cerebrospinal fluid interface permeability'’, biodistribution in animals, in vitro and in vivo metabolomics and / or lipidomics using tissue and / or biofluids, toxicity, changes in concentration of fatty acids and / or oxylipins due to administration of autogenous therapeutic lipid particle compositions of the present disclosure in vivo or in vitro, in vitro and in vivo changes in inflammation including but not limited to changes in gene or protein expression of cytokines, chemokines, and related receptors, changes in cellular morphology and count in a given tissue, changes in reactive oxygen species levels due to administration of autogenous therapeutic lipid particle compositions of the present disclosure, in vitro and in vivo changes in cell viability and death including but not limited to apoptosis, necrosis, necroptosis, ferroptosis, autophagy, pyroptosis, due to administration of therapeutic compositions comprising of autogenous therapeutic lipid particles of the present disclosure, in vitro and in vivo changes in cytoskeleton structure, composition, and function due to administration of autogenous therapeutic lipid particle composition of the present disclosure, in vitro and in vivo changes in myelin structure, composition, and function due to administration of autogenous therapeutic lipid particle of the present disclosure, in vitro and in vivo changes in structure, composition, and function of cellular organelles including but not limited to lipid droplets, mitochondria, peroxisome, endoplasmic reticulum, Golgi apparatus, nucleus, lysosome, endosome due to administration of autogenous therapeutic lipid particle composition of the present disclosure, in vivo efficacy of pharmaceutical compositions of autogenous therapeutic lipid particle compositions of the present disclosure in preventing or ameliorating inflammation including but not limited to changes in gene or protein expression of cytokines, chemokines, and related receptors, changes in cellular morphology and count in a given tissue, and changes in reactive oxygen species, in vivo efficacy of pharmaceutical compositions of autogenous therapeutic lipid particles of the present disclosure in preventing or reducing cell death including but not limited to apoptosis, necrosis, necroptosis, ferroptosis, autophagy, pyroptosis, in vivo efficacy of pharmaceutical compositions of autogenous therapeutic lipid particle compositions of the present disclosure in restoring normal tissue blood oxygenation and flow, in vivo efficacy of pharmaceutical compositions of autogenous therapeutic lipid particle compositions of the present disclosure in restoring flow of cerebrospinal fluid and / or interstitial fluid, in vivoefficacy of pharmaceutical compositions of autogenous therapeutic lipid particle of the present disclosure in ameliorating behavioral and cognitive deficits, and treatment of neurocognitive, neurodegenerative, and other disorders. The techniques and assays used for these measurements are known in the literature and can be adopted for the autogenous therapeutic lipid particles and therapeutic compositions comprising one or more autogenous therapeutic lipid particles by a person of ordinary skill in the art. Measurements of in vitro and in vivo experiments for determination of effects of autogenous therapeutic lipid particles may be carried out on cells, tissue samples, biofluids including blood, plasma, serum, cerebrospinal fluid, tears, vitreous fluid, lymph, saliva, urine, and other biological samples that are used for biological analyses. Such materials and processes for handling these materials are known in the literature and available to one skilled in the art.

[0065] Pharmaceutical compositions.

[0066] ATLCs disclosed herein may optionally be combined with pharmaceutical acceptable carriers to form a pharmaceutical composition (also referred to herein as “therapeutic compositions"’), to improve TL solubility, stability, bioavailability, release profile, and safety. As would be appreciated by one of skill in the art. the carriers may be chosen based on the route of administration, the location of the target issue, and other pharmacological factors. Any route of administration, such as buccal, epidural, inhalational, intracerebral, intracerebroventricular, intradermal, intradural, intralumbar, intralymphatic, intramuscular, intranasal, intraparenchymal. intraperitoneal, intrathecal, intratympanic. intravenous, ocular, oral, parenteral, rectal, subcutaneous, topical, transdermal, vaginal and the like. Administration into cerebrospinal fluid, or instillation into body compartments can also be used.

[0067] As indicated, the pharmaceutical compositions of this disclosure can be administered to a patient by any means known in the art including oral and parenteral routes. In certain embodiments parenteral routes are desirable since they avoid contact with the digestive enzymes that are found in the alimentary canal. According to such embodiments, compositions of the disclosure may be administered by injection (e.g., intravenous, subcutaneous or intramuscular, intraperitoneal injection), rectally, vaginally. topically (as by powders, creams, ointments, or drops,) intranasally or by inhalation (as by sprays).

[0068] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution. U.S.P.. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In one embodiment, the inventive conjugate is suspended in a carrier fluid comprising 1% (w / v) sodium carboxymethyl cellulose and 0. 1% (v / v) TWEEN™ 80. The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0069] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. When formulated into such solid dosage forms, the ATLP is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, poly(vinyl pyrrolidone), sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also comprise buffering agents.

[0070] It will be appreciated that the timing, dosage, and administration route of the ATLC may be adjusted to provide an effective amount of the ATLC to the patient being treated. The treatment of a disorder, inflammation, or a disease state in some instances may not require the delivery’ of the ATLC to the site of the disorder, inflammation, pathology or disease. That is, the delivery and treatment of inflammation or the modulation of immune factors at one site may be effective to treat or ameliorate the disorder at a distant site. For example, in the case of brain inflammation, modulation of peripheral inflammation may result in alleviation of brain inflammation.

[0071] As used herein, the ‘"effective amount” or “therapeutically effective amount” of an ATLC refers to the amount necessary to elicit the desired biological response, i.e., anamount sufficient to treat inflammation-associated, neurocognitive, and neurodegenerative disorders and other disorders. The effective amount of ATLC may vary depending on such factors as the desired biological endpoint, the TL to be delivered, the target tissue, the route of administration, the loading capacity of the ATLCs, etc. Additional factors which may be considered include the severity of the disease state, age, weight and gender of the patient being treated, diet, time, frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to therapy. As noted above, the therapeutic compositions may be designed to increase, normalize, control or maintain concentration of therapeutic lipids in a subject.

[0072] The ATLCs of the disclosure may be formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form’7as used herein refers to a physically discrete unit of carrier appropriate for the patient to be treated. For any ATLC, the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, e.g., mice. The animal model is also used to achieve a desirable concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. In some embodiments, ATLCs containing different TLs may be formulated into a single pharmaceutical composition for administration. Alternatively, pharmaceutical compositions or formulations containing ATLCs with different TLs may be administered simultaneously or sequentially into a patient.

[0073] ATLCs comprise at least one therapeutic lipid (TL) and in some instances may contain more than a single TL. In the same manner, compositions comprising different TLs may be administered concurrently or sequentially to a patient. Additionally, one or more ATLCs may be formulated into a single pharmaceutical composition. The ATLCs may be used in combination with other therapeutic or bioactive agents. In some embodiments the additional therapeutic or bioactive agents may be encapsulated within the ATLC. Some nonlimiting examples of non-lipid therapeutic or bioactive agents include proteins, peptides, nucleosides, nucleotides, antiviral agents, antineoplastic agents, antibiotics, and antiinflammatory drugs.

[0074] Examples of TL s include, but are not limited to. the TLs presented in the following table (Chart 1).

[0075] Chart 1 Fatty acid / lipid names, abbreviations, and nomenclature

[0076] The following embodiments describe the autogenous therapeutic lipid particles of the disclosure in further detail.1. A lipid composition comprising: a. at least one therapeutic lipid; b. cholesterol or a cholesterol derivative; c. one or more helper lipids; d. a PEGylated lipid; e. and optionally one or more excipients.2. The lipid composition of embodiment 1, wherein the helper lipid is selected from the group consisting of anionic lipids, cationic lipids, zwitterionic lipids, and neutral lipids.3. The lipid composition of embodiment 1, wherein the therapeutic lipid is a fatty acid, fatty acid amide, or fatty acid ester.4. The lipid composition of embodiment 1. wherein the therapeutic lipid is a sterol. 5. The lipid composition of embodiment 4, wherein the sterol is a bile acid.6. The lipid composition of embodiment 3, wherein the fatty acid is a monounsaturated fatty acid.7. The lipid composition of embodiment 3. wherein the fatty acid is a polyunsaturated fatty acid.8. The lipid composition of embodiment 7, wherein the polyunsaturated fatty acid is an o-3 polyunsaturated Patty acid, an o-6 polyunsaturated fatty acid, an o-8 polyunsaturated fatty acid, or an o-9 polyunsaturated fatty acid.9. The lipid composition of embodiment 8, wherein the polyunsaturated fatty acid is an o-3 polyunsaturated Patty acid.10. The lipid composition of embodiment 8, wherein the polyunsaturated fatty7acid is an o-8 polyunsaturated fatty7acid.11. The lipid composition of embodiment 8. wherein the polyunsaturated fatty acid is an o-9 polyunsaturated fatty acid.12. The lipid composition of embodiment 3, wherein the fatty7acid, fatty7acid amide or fatty acid ester is selected from the group consisting of lignoceric acid, caprylic acid, palmitoylethanolamide (PEA), nervonic acid (NA), 10-hydroxy-2(E)-decenoic acid (10-HDA), and 9-(palmitoyloxy)octadecanoic acid (9-PAHSA).13. The lipid composition of embodiment 5, wherein the bile acid is ursodeoxycholic acid (UDA or UA).14. The lipid composition of embodiment 7, wherein the polyunsaturated fatty7acid is selected from the group consisting of docosahexaenoic acid (DHA), synaptamide (N- docosahexaenoylethanolamine) (SNA), tetracosapentaenoic acid (TP A), 14(Z),17(Z),20(Z),23(Z),26(Z),29(Z)-dotnacontahexaenoic acid (DTHA), 7RJ4S- dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (maresin-1), and 7S,17S- dihydroxy-4Z,8E,10Z,13Z,15E,19Z-docosahexaenoic acid (resolvin D5).15. The lipid composition of embodiment 1, wherein the one or more helper lipids are selected from the group consisting of l,2-dioleoyl-3-trimethylammoniumpropane (DOTAP), l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1 ,2-dimyristoyl-sn- glycero-3-phosphate (14PA), didodecyldimethylammonium bromide (DDAB), and 1.2-distearoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (18PG).16. The lipid composition of embodiment 1, wherein the PEGylated lipid is selected from the group consisting of: polyethylene glycol (PEG), 1.2-Dimyristoyl-rac-glycero-3- methoxypoly ethylene gly col-2000 (DMG-PEG2000), l,2-Dimyristoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-550] ammonium) (DMPE- PEG550), ganglioside GM, PEG derivatized with Tween, and PEG derivatized with distearoylphosphatidylethanolamine (PEG-DSPE).17. The lipid composition of embodiment 1. wherein the one or more optional excipients are selected from the group consisting of: trehalose, mannitol, sucrose, lipid surfactants, emulsifiers, antioxidants, and surfactants with tissue-targeting properties.18. The lipid composition of any of embodiments 1 - 17, wherein the therapeutic lipid is present in the amount of from about 0.5 mol% to about 85 mol% of the lipid composition.19. The lipid composition of any of embodiments 1 - 17, wherein the cholesterol or cholesterol derivative is present in the amount of from about 5 mol% to about 70 mol% of the lipid composition.20. The lipid composition of any of embodiments 1 - 17, wherein the helper lipid is present in the amount of from about 0.5 mol% to about 70 mol% of the lipid composition.21. The lipid composition of any of embodiments 1 - 17, wherein the PEGylated lipid is present in the amount of from about 0.01 mol% to about 10 mol% of the lipid composition.22. The lipid composition of any of embodiments 1 - 17, wherein the one or more excipients are present in the amount of from about 2 mol% to about 5 mol% of the lipid composition.23. The lipid composition of embodiment 1, wherein the therapeutic lipid is present in an amount of from about 0.5 mol% to about 60 mol%, cholesterol is present in an amount of from about 5 mol% to about 75 mol%, the helper lipid is present in an amount of from about 5 mol% to about 80 mol%, and the PEGylated lipid is present in an amount of from about 0.01 mol% to about 6.0 mol%.The lipid composition of embodiment 23, wherein the therapeutic lipid is present in an amount of about 15 mol% to about 60 mol%. The lipid composition of embodiment 23 or embodiment 24, wherein the therapeutic lipid is selected from the group consisting of docosahexaenoic acid (DHA), nervonic acid (NA), synaptamide (N-docosahexaenoylethanolamine) (SNA), capry lic acid (CPA), ursodeoxycholic acid (UDA), palmitoylethanolamide (PEA), 9- (palmitoyloxy)- octadecanoic acid (9-PAHSA), tetracosapentaenoic acid (TP A), 14(Z),17(Z),20(Z),23(Z),26(Z),29(Z)-dotnacontahexaenoic acid (DTHA), 10- Hydroxy-2(E)-decenoic acid (10-HDA), 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z- docosahexaenoic acid (maresin-1), and 7S,17S-dihydroxy-4Z,8E,10Z,13Z,15E,19Z- docosahexaenoic acid (resolvin D5). The lipid composition of embodiment 1. wherein the therapeutic lipid is present in an amount of from about 50 mol% to about 70 mol%, cholesterol is present in an amount of from about 5 mol% to about 35 mol%, the helper lipid is present in an amount of from about 5 mol% to about 35 mol%, and the PEGylated lipid is present in an amount of from about 0.01 mol% to about 3.5 mol%. The lipid composition of embodiment 26, wherein the therapeutic lipid is present in an amount of from about 55 mol% to about 65 mol%. The lipid composition of embodiment 26 or embodiment 27, wherein the therapeutic lipid is selected from the group consisting of TP A, SNA, DHA, DTHA, CPA, 9- PAHSA, UDA, PEA, nervonic acid, and 10-HDA. A lipid composition comprising: a. a therapeutic lipid, wherein the therapeutic lipid is readily soluble and is present in an amount of from about 10 mol% to about 75 mol% of the lipid composition; b. cholesterol or a cholesterol derivative, wherein the cholesterol or cholesterol derivative is present in an amount of from about 5 mol% to about 70 mol% of the lipid composition; c. a helper lipid, wherein the helper lipid is present in an amount of from about 5 mol% to about 70% of the lipid composition; d. a PEGylated lipid, wherein the PEGylated lipid is present in an amount of from about 0.01 mol% to about 10 mol% of the lipid composition; ande. optionally one or more excipients.30. The lipid composition of embodiment 29, wherein the therapeutic lipid is selected from the group consisting of TP A. SNA. DHA, DTHA, CPA. 9-PAHSA. UDA, PEA, 10-HDA, and nervonic acid and is present in an amount of from about 10 mol% to about 60 mol% of the lipid composition.31. The lipid composition of embodiment 29, wherein the therapeutic lipid is selected from the group consisting of TP A, SNA. DHA, DTHA, CPA, 9-PAHSA, UDA, PEA, 10-HDA. and nervonic acid and is present in an amount of from about 50 mol% to about 70 mol% of the lipid composition.32. The lipid composition of embodiment 1, wherein the therapeutic lipid is present in an amount of from about 0.1 mol% to about 3 mol%, cholesterol is present in an amount of from about 40 mol% to about 50 mol%. the helper lipid is present in an amount of from about 45 mol% to about 55 mol%, and the PEGylated lipid is present in an amount of from about 4 mol% to about 5 mol%.33. The lipid composition of embodiment 32, wherein the therapeutic lipid is selected from the group consisting of maresin-1 and resolvin D5.34. A lipid composition comprising: a. a therapeutic lipid, wherein the therapeutic lipid is less soluble and is present in an amount of from about 0.1 mol% to about 5 mol% of the lipid composition; b. cholesterol or a cholesterol derivative, wherein the cholesterol or cholesterol derivative is present in an amount of from about 20 mol% to about 70 mol% of the lipid composition; c. a helper lipid, wherein the helper lipid is present in an amount of from about 30 mol% to about 60 mol% of the lipid composition; d. a PEGylated lipid, wherein the PEGylated lipid is present in an amount of from about 0.01 mol% to about 10 mol% of the lipid composition; and e. optionally one or more excipients.35. The lipid composition of embodiment 34, wherein said therapeutic lipid is selected from the group consisting of maresin 1 and resolvin D5 and is present in an amount of from about 0.1 mol% to about 3 mol%.36. A lipid composition comprising: a. a therapeutic lipid wherein said therapeutic lipid has a carbon chain length of about 8 to about 46; b. cholesterol or a cholesterol derivative; c. a helper lipid; d. a PEGylated lipid; and e. optionally one or more excipients.37. The lipid composition of embodiment 36, wherein the therapeutic lipid has a carbon chain length of about 8, about 10, about 16, about 22, about 24, or about 32.38. The lipid composition of embodiment 36, wherein the carbon chain of the therapeutic lipid comprises 1, 3, 5 or 6 double bonds.39. The lipid composition of embodiment 1 comprising: a. DHA present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 36.36 mol% of the lipid composition; c. DOTAP present in the amount of about 40 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 3.64 mol% of the lipid composition.40. The lipid composition of embodiment 1 comprising: a. DHA present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 18.18 mol% of the lipid composition; c. DOTAP present in the amount of about 20 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 1.82 mol% of the lipid.41. The lipid composition of embodiment 1 comprising: a. DHA present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 7.27 mol% of the lipid composition; c. DOTAP present in the amount of about 32 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 0.73 mol% of the lipid.42. The lipid composition of embodiment 1 comprising: a. DHA present in the amount of about 20 mol% of the lipid composition;b. cholesterol present in the amount of about 58. 18 mol% of the lipid composition; c. DSPC present in the amount of about 16 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 5.82 mol% of the lipid.43. The lipid composition of embodiment 1 comprising: a. TPA present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 36.36 mol% of the lipid composition; c. DOTAP present in the amount of about 40 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 3.64 mol% of the lipid composition.44. The lipid composition of embodiment 1 comprising: a. TPA present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 18.18 mol% of the lipid composition; c. DOTAP present in the amount of about 20 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 1.82 mol% of the lipid composition.45. The lipid composition of embodiment 1 comprising: a. TPA present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 7.27 mol% of the lipid composition; c. DOTAP present in the amount of about 32 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 0.73 mol% of the lipid composition.46. The lipid composition of embodiment 1 comprising: a. TPA present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 58. 18 mol% of the lipid composition; c. DSPC present in the amount of about 16 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 5.82 mol% of the lipid composition.47. The lipid composition of embodiment 1 comprising:a. SNA present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 36.36 mol% of the lipid composition; c. DOTAP present in the amount of about 40 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 3.64 mol% of the lipid composition. lipid composition of embodiment 1 comprising: a. SNA present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 29.09 mol% of the lipid composition; c. DOTAP present in the amount of about 8 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 2.91 mol% of the lipid composition. lipid composition of embodiment 1 comprising: a. SNA present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 58. 18 mol% of the lipid composition; c. DSPC present in the amount of about 16 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 5.82 mol% of the lipid composition. lipid composition of embodiment 1 comprising: a. SNA present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 18.18 mol% of the lipid composition; c. DOTAP present in the amount of about 20 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 1.82 mol% of the lipid composition. lipid composition of embodiment 1 comprising: a. SNA present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 7.27 mol% of the lipid composition; c. DOTAP present in the amount of about 32 mol% of the lipid composition; andd. DMG-PEG2000 present in the amount of about 0.73 mol% of the lipid composition.52. The lipid composition of embodiment 1 comprising: a. SNA present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 15.84 mol% of the lipid composition; c. DOTAP present in the amount of about 64 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 0.16 mol% of the lipid composition.53. The lipid composition of embodiment 1 comprising: a. SNA present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 15.97 mol% of the lipid composition; c. DOTAP present in the amount of about 64 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 0.03 mol% of the lipid composition.54. The lipid composition of embodiment 1 comprising: a. SNA present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 58. 18 mol% of the lipid composition; c. 18PG present in the amount of about 16 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 5.82 mol% of the lipid composition.55. The lipid composition of embodiment 1 comprising: a. DTHA present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 36.36 mol% of the lipid composition; c. DOTAP present in the amount of about 40 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 3.64 mol% of the lipid composition.56. The lipid composition of embodiment 1 comprising: a. DTHA present in the amount of about 20 mol% of the lipid composition;b. cholesterol present in the amount of about 15.84 mol% of the lipid composition; c. DOTAP present in the amount of about 64 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 0.16 mol% of the lipid composition.57. The lipid composition of embodiment 1 comprising: a. DTHA present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 58. 18 mol% of the lipid composition; c. DSPC present in the amount of about 16 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 5.82 mol% of the lipid composition.58. The lipid composition of embodiment 1 comprising: a. DTHA present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 29.09 mol% of the lipid composition; c. DOTAP present in the amount of about 8 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 2.91 mol% of the lipid composition.59. The lipid composition of embodiment 1 comprising: a. DTHA present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 18.18 mol% of the lipid composition; c. DOTAP present in the amount of about 20 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 1.82 mol% of the lipid composition.60. The lipid composition of embodiment 1 comprising: a. DTHA present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 7.27 mol% of the lipid composition; c. DOTAP present in the amount of about 32 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 0.73 mol% of the lipid composition.61. The lipid composition of embodiment 1 comprising: a. 10-HDA present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 36.36 mol% of the lipid composition; c. DOTAP present in the amount of about 40 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 3.64 mol% of the lipid composition.62. The lipid composition of embodiment 1 comprising: a. 10-HDA present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 29.09 mol% of the lipid composition; c. DOTAP present in the amount of about 8 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 2.91 mol% of the lipid composition.63. The lipid composition of embodiment 1 comprising: a. 10-HDA present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 18.18 mol% of the lipid composition; c. DOTAP present in the amount of about 20 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 1.82 mol% of the lipid composition.64. The lipid composition of embodiment 1 comprising: a. resol vin D5 present in the amount of about 0.67 mol% of the lipid composition; b. cholesterol present in the amount of about 45. 15 mol% of the lipid composition; c. DOTAP present in the amount of about 49.67 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 4.51 mol% of the lipid composition.65. The lipid composition of embodiment 1 comprising: a. resolvin D5 present in the amount of about 2 mol% of the lipid composition;b. cholesterol present in the amount of about 44.55 mol% of the lipid composition; c. DOTAP present in the amount of about 49.0 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 4.45 mol% of the lipid composition. lipid composition of embodiment 1 comprising: a. resolvin D5 present in the amount of about 0.2 mol% of the lipid composition; b. cholesterol present in the amount of about 45.36 mol% of the lipid composition; c. DOTAP present in the amount of about 49.90 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 4.54 mol% of the lipid composition. lipid composition of embodiment 1 comprising: a. resolvin D5 present in the amount of about 0.6 mol% of the lipid composition; b. cholesterol present in the amount of about 72.29 mol% of the lipid composition; c. DOTAP present in the amount of about 19.88 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 7.23 mol% of the lipid composition. lipid composition of embodiment 1 comprising: a. resolvin D5 present in the amount of about 0.6 mol% of the lipid composition; b. cholesterol present in the amount of about 45. 18 mol% of the lipid composition; c. DOTAP present in the amount of about 49.7 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 4.52 mol% of the lipid composition. lipid composition of embodiment 1 comprising: a. Maresin 1 present in the amount of about 2 mol% of the lipid composition;b. cholesterol present in the amount of about 44.55 mol% of the lipid composition; c. DOTAP present in the amount of about 49.0 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 4.45 mol% of the lipid composition.70. The lipid composition of embodiment 1 comprising: a. Maresin 1 present in the amount of about 0.6 mol% of the lipid composition; b. cholesterol present in the amount of about 72.29 mol% of the lipid composition; c. DOTAP present in the amount of about 19.88 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 7.23 mol% of the lipid composition.71. The lipid composition of embodiment 1 comprising: a. Maresin 1 present in the amount of about 0.6 mol% of the lipid composition; b. cholesterol present in the amount of about 45. 18 mol% of the lipid composition; c. DOTAP present in the amount of about 49.7 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 4.52 mol% of the lipid composition.72. The lipid composition of embodiment 1 comprising: a. Maresin 1 present in the amount of about 0.6 mol% of the lipid composition; b. cholesterol present in the amount of about 18.07 mol% of the lipid composition; c. DOTAP present in the amount of about 79.52 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 1.81 mol% of the lipid composition.73. The lipid composition of embodiment 1 comprising: a. Maresin 1 present in the amount of about 0.2 mol% of the lipid composition;b. cholesterol present in the amount of about 72.58 mol% of the lipid composition; c. DSPC present in the amount of about 19.96 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 7.26 mol% of the lipid composition.74. The lipid composition of embodiment 1 comprising: a. Nervonic acid present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 36.36 mol% of the lipid composition; c. DOTAP present in the amount of about 40 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 3.64 mol% of the lipid composition.75. The lipid composition of embodiment 1 comprising: a. Nervonic acid present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 29.09 mol% of the lipid composition; c. DOTAP present in the amount of about 8 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 2.91 mol% of the lipid composition.76. The lipid composition of embodiment 1 comprising: a. Nen onic acid present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 18.18 mol% of the lipid composition; c. DOTAP present in the amount of about 20 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 1.82 mol% of the lipid composition.77. The lipid composition of embodiment 1 comprising:a. Nervonic acid present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 7.27 mol% of the lipid composition; c. DOTAP present in the amount of about 32 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 0.73 mol% of the lipid composition.78. The lipid composition of embodiment 1 comprising: a. Caprylic acid present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 29.09 mol% of the lipid composition; c. DOTAP present in the amount of about 8 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 2.91 mol% of the lipid composition.79. The lipid composition of embodiment 1 comprising: a. Caprylic acid present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 18.18 mol% of the lipid composition; c. DOTAP present in the amount of about 20 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 1.82 mol% of the lipid composition.80. The lipid composition of embodiment 1 comprising: a. 9-PAHSA present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 36.36 mol% of the lipid composition; c. DOTAP present in the amount of about 40 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 3.64 mol% of the lipid composition.81. The lipid composition of embodiment 1 comprising: a. 9-PAHSA present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 7.27 mol% of the lipid composition;c. DOTAP present in the amount of about 32 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 0.73 mol% of the lipid composition.82. The lipid composition of embodiment 1 comprising: a. Palmitoylethanolamide (PEA) present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 36.36 mol% of the lipid composition; c. DOTAP present in the amount of about 40 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 3.64 mol% of the lipid composition.83. The lipid composition of embodiment 1 comprising: a. Palmitoylethanol amide (PEA) present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 58. 18 mol% of the lipid composition; c. DSPC present in the amount of about 16 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 5.82 mol% of the lipid composition.84. The lipid composition of embodiment 1 comprising: a. Ursodeoxycholic acid (UDA) present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 36.36 mol% of the lipid composition; c. DOTAP present in the amount of about 40 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 3.64 mol% of the lipid composition.85. The lipid composition of embodiment 1 comprising: a. Ursodeoxycholic acid (UDA) present in the amount of about 60 mol% of the lipid composition; b. cholesterol present in the amount of about 18.18 mol% of the lipid composition;c. DOTAP present in the amount of about 20 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 1.82 mol% of the lipid composition.86. The lipid composition of embodiment 1 comprising: a. Ursodeoxycholic acid (UDA) present in the amount of about 20 mol% of the lipid composition; b. cholesterol present in the amount of about 58. 18 mol% of the lipid composition; c. 18PG present in the amount of about 16 mol% of the lipid composition; and d. DMG-PEG2000 present in the amount of about 5.82 mol% of the lipid composition.87. The lipid composition of embodiment 1 comprising: a. DHA present in the amount of about 20 mol%; b. DOPE present in the amount of about 0.78%; c. DOTAP present in the amount of about 39.22 mol%; d. cholesterol present in the amount of about 36.36 mol%; and e. DMG-PEG2000 present in the amount of about 3.64 mol%.88. The lipid composition of embodiment 1 comprising: a. DHA present in the amount of 20 mol%; b. 14PA present in the amount of about 3.64 mol%; c. DOTAP present in the amount of about 36.36 mol%; d. Cholesterol present in the amount of about 36.36 mol%; and e. DMG-PEG2000 present in the amount of about 3.64 mol%.89. The lipid composition of embodiment 1 comprising: a. DHA present in the amount of about 20 mol%; b. 18PG present in the amount of about 3.64 mol%; c. DOTAP present in the amount of about 36.36 mol%; d. Cholesterol present in the amount of about 36.36 mol%; and e. DMG-PEG2000 present in the amount of about 3.64 mol%.90. A lipid composition comprising: a. TP A present in the amount of about 10 mol%; b. SNA present in the amount of about 10 mol%;c. DOTAP present in the amount of about 40 mol%; d. Cholesterol present in the amount of about 36.36 mol%; and e. DMG-PEG2000 present in the amount of about 3.64 mol%.91. A lipid composition comprising: a. DHA present in the amount of about 10 mol%; b. SNA present in the amount of about 10 mol%; c. DOTAP present in the amount of about 40 mol%; d. Cholesterol present in the amount of about 36.36 mol%; and e. DMG-PEG2000 present in the amount of about 3.64 mol%.92. A lipid composition comprising: a. DHA present in the amount of about 18 mol%; b. MaRl present in the amount of about 2 mol%; c. DOTAP present in the amount of about 40 mol%; d. Cholesterol present in the amount of about 36.36 mol%; and e. DMG-PEG2000 present in the amount of about 3.64 mol%.93. A method of treating an inflammatory disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a lipid composition of embodiment 1.94. The method of embodiment 92, wherein the inflammatory disorder is selected from the group consisting of degenerative disorders of the central nervous system, degenerative disorders of the peripheral nervous system, inflammatory7bowel diseases, asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, acute lung injury, bronchopulmonary dysplasia, cystic fibrosis, bronchitis, bronchiolitis, arthritis, osteoarthritis, ankylosing spondylitis, rheumatism, and brain inflammation.95. A method of treating neurocognitive deficits, loss of neurological function, or neurodegeneration, in a subject in need thereof, comprising administering a therapeutically effective amount of a lipid composition of embodiment 1.96. The method of embodiment 94, wherein the lipid composition is the lipid composition of any of embodiments 38-89.97. The method of embodiment 95, wherein the subject has undergone a surgical intervention or is experiencing organ dysfunction.98. The method of embodiment 97, wherein the surgical intervention is being performed to treat orthopedic, cardiovascular, pulmonary, urological, or abdominal abnormalities.99. The method of embodiment 97, wherein the organ dysfunction results from traumatic brain injury, stroke, acute kidney failure, chronic kidney failure, spinal cord injury, asthma or other pulmonary-related disorders, infection, sepsis, or an automobile accident.100. The method of embodiment 95, wherein said neurocognitive deficits are selected from the group consisting of delayed neurocognitive recovery, delirium, agitation, hyperactivity, cognitive decline, acute brain failure and chronic brain failure.101. The method of embodiment 100. wherein said neurocognitive deficits occur acutely or chronically.102. The method of embodiment 100, wherein administration of said lipid composition prevents or reduces the severity of the neurocognitive deficits.103. The method of embodiment 100, wherein administration of said lipid composition prevents or reduces the duration of the neurocognitive deficits.104. The method of embodiment 100. wherein said neurocognitive deficits are associated with changes in one or more pro-inflammatory cytokines IL-ip, TNF-a, IL-8, CXCL1, or IL-6.105. The method of embodiment 95, wherein the lipid composition is administered prior to surgical intervention or organ dysfunction.106. The method of embodiment 95, wherein the lipid composition is administered during surgical intervention or organ dysfunction.107. The method of embodiment 95, wherein the lipid composition is administered after surgical intervention or organ dysfunction.108. The method of embodiment 95, wherein the lipid composition is administered by intravenous, subcutaneous, intramuscular, or intrathecal injection.109. The method of embodiment 95, wherein the lipid composition is administered by nasal, transdermal, or oral delivery.1 10. A lipid composition comprising: a. a therapeutic lipid; b. cholesterol or a cholesterol derivative; c. one or more helper lipids; d. a PEGylated lipid; and e. optionally one or more excipients, wherein the therapeutic lipid comprises about C8 to about C46 carbon atoms.111. The lipid composition of embodiment 109, wherein said therapeutic lipid comprises about C8 to about C32 carbon atoms.112. The lipid composition of embodiment 109, wherein said therapeutic lipid comprises about C8 to about C24 carbon atoms.113. The lipid composition of any one of embodiments 110 - 1 12, wherein said therapeutic lipid comprises C8, CIO, Cl 6, Cl 8, C22, C24, or C32 carbon atoms.114. The lipid composition of any one of embodiments 110 - 112, wherein said therapeutic lipid comprises 1, 3, 5 or 6 double bonds.

[0077] Definitions

[0078] As used herein, unless otherwise indicated, “abouf ’. or “substantially’; when used in connection with a measurable variable (such as, for example, a parameter, an amount, a temporal duration, or the like) or a list of alternatives, is meant to encompass variations of and from the specified value including, but not limited to, those within experimental error (which can be determined by, e.g.. a given data set, an art accepted standard, etc. and / or with, e.g., a given confidence interval (e.g. 90%, 95%, or more confidence interval from the mean), such as, for example, variations of + / -10% or less, + / -5% or less, + / -1% or less, and + / -0. 1% or less of and from the specified value), insofar such variations in a variable and / or variations in the alternatives are appropriate to perform in the instant disclosure. As used herein, the term “about” may mean that the amount or value in question is the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it isunderstood that amounts, sizes, compositions, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error, or the like, or other factors known to those of skill in the art such that equivalent results or effects are obtained. In general, an amount, size, composition, parameter, or other quantity' or characteristic, or alternative is "about" whether or not expressly stated to be such. It is understood that where "about." is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0079] Ranges of values are disclosed herein. The ranges set out a lower limit value and an upper limit value. Unless otherwise stated, the ranges include the lower limit value, the upper limit value, and all values between the lower limit value and the upper limit value, including, but not limited to, all values to the magnitude of the smallest value (either the lower limit value or the upper limit value) of a range. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “0. 1% to 5%’" should be interpreted to include not only the explicitly recited values of 0.1% to 5%. but also, unless otherwise stated, include individual values (e g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.5% to 1.1%; 0.5% to 2.4%; 0.5% to 3.2%, and 0.5% to 4.4%, and other possible sub-ranges) within the indicated range. It is also understood (as presented above) that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about”, it will be understood that the particular value forms a further disclosure. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0080] As used herein “subject” is an animal, typically a mammal, including human, such as a patient.

[0081] As used herein, unless otherwise stated, the term “group” or " oiety" refers to a chemical entity that is monovalent (i.e., has one terminus that can be covalently bonded to other chemical species), divalent, or polyvalent (i.e., has two or more termini that can be covalently bonded to other chemical species). The term “group” or “moiety” also includesradicals (e.g., monovalent and multivalent, such as, for example, divalent radicals, trivalent radicals, and the like). Illustrative examples of groups and moieties include:

[0082] As used herein, wherein in chemical structures of the therapeutic lipids of the disclosure are shown having a terminal carboxyl group “-COOR” the “R” is intended to designate a group covalently bonded to the carboxyl such as an alkyl group. In the alternative, the carboxyl group is further intended to have a negative charge as -COO ' and R is a cation including a metal cation or an ammonium cation.

[0083] As used herein, unless otherwise indicated, the term “aliphatic” or “aliphatic groups” or “aliphatic moiety ” refers to branched or unbranched hydrocarbon groups that, optionally, contain one or more degree(s) of unsaturation. Degrees of unsaturation can arise from, but are not limited to, cyclic aliphatic groups. For example, the aliphatic groups / moieties are a Ci6 to C40 aliphatic group, including all integer numbers of carbons and ranges of numbers of carbons therebetween (e.g., Ci6, C17, Cis, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30. C31, C32, C33, C34, C35, C36, C37, C38, C39, and C40). Aliphatic groups include, but are not limited to, alkyl groups, alkene groups, and alky ne groups. The aliphatic group can be unsubstituted or substituted with one or more substituent(s). Examples of substituents include, but are not limited to, various substituents such as, for example, halogens (-F, -Cl, -Br, and -I), azide group, aliphatic groups (e.g., alky l groups, alkene groups, alkyne groups, and the like), aryl groups, hydroxyl groups, alkoxide groups, carboxylate groups, carboxylic acid groups, ether groups, ester groups, amide groups, thioether groups, thioester groups, and the like, and combinations thereof.

[0084] An “alkyd” residue, as used herein, refers to a saturated aliphatic hydrocarbon chain.

[0085] An “alkenyl” residue, as used herein, refers to an unsaturated aliphatic hydrocarbon chain comprising at least two disclosure atoms and at least one carbon-carbon double bond. In a preferred embodiment of the present disclosure the alkenyl group comprises one, two, three, four, five or six double bonds, wherein each double bond is formed between two carbon atoms.

[0086] An “alkynyl” residue, as used herein, refers to an unsaturated aliphatic hydrocarbon chain comprising at least two carbon atoms and at least one carbon-carbon triple bond.

[0087] The alky l, alkenyl, alkynyl residues may also comprise one or more hydroxy (-OH) groups atached to one or more carbon atoms. The term "hydrox alkyl".“hydroxyalkenyl”, and “hydroxyalkynyl” comprise at least one, preferably at least two, more preferably at least three, more preferably at least four, more preferably at least five hydroxy groups.

[0088] An "ether" residue, as used herein, refers to a saturated or unsaturated aliphatic hydrocarbon chain comprising at least one oxygen atom within the chain such that the oxygen atom is connected to two carbon atoms.

[0089] The term “therapeutically effective amount” as used herein refers to that amount of an embodiment of the composition or pharmaceutical composition being administered that will relieve to some extent one or more of the symptoms of the disease or condition being treated, and / or that amount that will prevent, to some extent, one or more of the symptoms of the condition or disease that the subject being treated has or is at risk of developing. As used interchangeably herein, “subj ect”, “individual”, or “patient” refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. The term “pet” includes a dog, cat, guinea pig, mouse, rat, rabbit, ferret, and the like. The term farm animal includes a horse, sheep, pig, cow, and the like.

[0090] The following examples are offered by way of illustration and not by way of limitation.

[0091] Experimental

[0092] General Procedure for ATLC Formulation / Assembly. Depending on theATL being tested, an excel spreadsheet was used to calculate the amount of each lipid component based on pre-determined “Cholesterol :DMG-P EG” molar ratio. “Helper Lipid:Chol. + DMG-PEG” molar ratio, and ATL lipid molar percentage.The calculated volumes of components were pipeted into prelabeled tubes. Ethanol was the first component added. Then, water phase containing MgAc w as added. The mixture is mixed by rapid pipetting or using a vortex.

[0093] PDI and zeta potential were determined at this stage. Typically, lOmL of the ATLC is mixed with 50mL PBS, the resulting solution was aliquoted into a clean cuvete and introduced into a DLS Instrument for measurement. The aliquot w as then returned to the tube.

[0094] To purify, buffer exchange and concentrate the mixture, depending on the total volume, ATLCs were subjected to dialysis in a water bath for 24h then concentrated using aMillipore Ultra Centrifugal Filter Unit or just subjected to ultracentrifugation alone. For the ultracentrifugation step, filters were added to the centrifuge tubes, ATLCs were placed in the respective tubes, and PBS was aliquoted into the tubes after each centrifugation step. The tubes were centrifuged for 4000 ref for 5 minutes. This was repeated approximately 4 times. ATLCs were then tested again on the DLS instrument, to ensure that there was no precipitation following ultrafiltration. ATLCs were then placed in storage at 4°C until use.Example ATLCs made by this procedure are described in Table 1.

[0095] Table 1. Representative ATLCs and physical measurements

[0096] Incorporating DHA into a composition of ATLCs or ATLPs alters particle size. The average size (nm) of DHA ATLCs increases with increasing DHA molar percentage. The empty particle (i.e. , particle formulated without DHA) is about 120 nm, at 5% 140nm, 10% about 150 nm and 20% about 180 nm. DHA incorporation at 0%, 5%, 10%,and 20% molar percentages demonstrated an increase in particle size from -125 nm to -180 nm. DHA molar percentage in particles positively correlated with particle size.

[0097] Choice of DOTAP as helper lipid vs DDAB resulted in DHA ATLCs of smaller sizes (<100 nm). The average size (nm) of a DHA ATLC with DOTAP as the cationic helper lipid ranges from 50 to about 130 nm. With DDAB as the cationic helper lipid the average size ranges from about 100 to 300 nm. Thus, incorporation of DDAB as helper lipid in 5 unique DHA ATLC compositions resulted in greater average particle size compared to ATLCs with DOTAP incorporated as a cationic helper lipid. Aside from DOTAP and DDAB, other helper lipids, 14PA, 18PG, DSPC, or DOPE, were included in each of 5 compositions. There w as one exception whereby a DHA formulation with DDAB or DOTAP as helper lipid resulted in particles of equal size.

[0098] ATLCs can be formed in buffers with different pH and ionic strengths. 3 unique compositions of DHA ATLCs have been fabricated in 3 individual aqueous solutions: magnesium acetate buffered solution (MgAc), phosphate buffered saline (PBS), and doubledistilled water (ddH2O). DHA ATLCs can be self-assembled using aqueous phase of varying pH and ionic strengths.

[0099] DHA TL can be incorporated into different compositions to yield ATLCs of small size and low PDI. DHA was incorporated into 3 ATLC compositions with varying ratios and types of helper lipid components, resulting in nanoparticles of sub 100 nm size and low PDI (<0.25).

[0100] Increasing TL molar percentage increases ATLC size without affecting PDI. Particle sizes increase as DHA dosage increases. PDI across particles remain low7, indicating particle stability at time of particle self-assembly.

[0101] Increasing TL molar percentage does not affect incorporation efficiency. The incorporation capacity (pg / mL) at increasing DHA molar percent dosages range from 20- 80%. Particles had nearly complete encapsulation at 98%. While the solubility of DHA in PBS is 100 pg / mL. by incorporating DHA into an ATLC composition at 80%, an incorporation capacity of >200pg / mL was achieved without an optimized ultrafiltration protocol.

[0102] Stability of unique DHA ATLC compositions is reduced over time in serumlike conditions in vitro. The average poly dispersity index (PDI) of ATLCs increases at increasing DHA molar percent dosages from 20-80% across 48h timespan in serum-like conditions. Particles were resuspended in PBS with 5% FBS and incubated at 37°C. UniqueDHA ATLCs with 20%, 40%, 60% and 80% DHA molar percentage demonstrated increased particle PDI which suggests particle disintegration, aggregation, or loss of stability over time in serum-like conditions in vitro over a 48h timespan.

[0103] Structurally different diverse TLs can each be stably incorporated into an example ATLC composition The average size (nm) ranged from about 100 to about 350 while the average polydispersity index (PDI) ranged from about 0. 1 to about 0.35 of ATLCs incorporated or assembled with various TLs, namely DHA. nervonic acid, lignoceric acid, synaptamide, and cerebronic acid. The individual incorporation of DHA, nervonic acid, lignoceric acid, synaptamide, and cerebronic acid into a unique ATLC composition resulted in particles of varying sizes and low PDI. Low PDI values of these 5 ATLCs with varying size suggests that each TL was successfully and stably incorporated into ATLCs. ATLCs can incorporate structurally diverse TLs across polyunsaturated, monounsaturated, and saturated fatty acids, as well as fatty acid amides and oxylipins.

[0104] TLs of diverse carbon lengths, degree of saturation, and location of double bond can each be incorporated into a library of diverse ATLC compositions followed by physiochemical library screening of 243 compositionally diverse ATLCs. Average size (nm) and average poly dispersity index (PDI) of ATLCs with the incorporation of 3 individual TLs, namely DHA, nervonic acid, and lignoceric acid are recorded post-particle assembly. Library design was based on previous experience with mRNA-LNP library screening design. Each TL is incorporated into 81 unique ATLC compositions with varying helper lipid (DOTAP. DOPE, or 18PG), at varying TL molar percentage (10%, 20%, or 30%), at varying helper lipid: (Cholesterol+DMG-PEG) molar ratio (0.25, 1, or 4), and at varying Cholesterol :DMG- PEG molar ratio (10, 100, or 500). Size and PDI of formulated particles were characterized by dynamic light scattering (DLS). Screened particles sizes ranged from 66.5-651.8nm. The average size was I94.5nm, and the average PDI was 0.156. 27 / 243 particles had an average size of less than or equal to lOOnm. Similar size patterns were observed for particles across the three screened TLs. This suggests ATLC versatility and generalizability.

[0105] TLs including FAs. FAAs, and FAOs of diverse carbon lengths, degree of saturation, or location of double bond can be each stably incorporated into an example ATLC composition. Twelve individual TLs: docosahexaenoic acid (DHA), nervonic acid (NA), lignoceric acid (LA) , synaptamide (SNA), cerebronic acid (CA), caprylic acid (CPA), palmitoylethanolamide (PEA), docosapentaenoic acid (DPA), 9-(palmitoyloxy)octadecanoic acid (9-PAHSA), lignoceric ceramide (LA-C), ursodeoxycholic acid (UDA, and tetracosapentaenoic acid (TP A), were formulated into ATLCs using 1 unique ATLCcomposition. Incorporation of ten of these TLs namely DHA, NA, LA, SNA, CA, CPA, DPA, 9-PAHSA. UDA, and TPA into the ATLC composition was successfully performed. The resulting ATLCs were of varying sizes and low PDI, suggesting TLs were successfully and stably incorporated into ATLCs. ATLCs can incorporate structurally diverse TLs across polyunsaturated, monounsaturated, and saturated fatty acids, as well as fatty acid amides, oxylipins, fatty acid esters of hydroxy fatty acids (FAHFAs), and sterols such as UDA bile acid.

[0106] ATLCs afford greater stability in serum-like conditions relative to TLs. UDA (Bile acid), DHA and TPA were incorporated into ATLCs and the change of PDI was followed across a 48h timespan in serum-like conditions (IX PBS in 5% FBS, 37°C incubation). Compared with non-particle incorporated TLs (free TLs), ATLCs maintained lower PDI values over a period of 48h when incubation in serum-like conditions, suggesting lack of particle aggregation and particle stability' over a period of 48 hours.

[0107] Synaptamide can be incorporated into at least 72 unique ATLCs. (Figure 1) Informed by the exploration efforts performed using DHA as the reference TL. a combinatorial library screen approach was adopted to generate 72 unique ATLPs. Each particle composition contains synaptamide as the TL, cholesterol, DMG-PEG2000, and one helper lipid selected from a group of 3 carry ing different charge types: cationic head groups (DOTAP), zwitterionic head groups (DSPC), and anionic head groups (18PG). The following four independent composition parameters were adjusted: (i) total molar therapeutic lipid (TL) molar percentage, i.e., 20% or 60%, (ii) Cholesterol to DMG-PEG2000 ratio (ChokDMG- PEG), ranging 10: 1, 100: 1, 500: 1, (iii) Helper lipid ty pe, i.e., DOTAP, DSPC or 18PG ,and (iv) Ratio of Helper lipid to Cholesterol to DMG-PEG2000 ratio (Helper Lipid: (ChokDMG- PEG)), ranging 0.1: 1, 0.25: 1, 1 : 1, 4: 1. 72 synaptamide ATLCs generated have differing size and PDI measurements. Screened particles sizes ranged from 52-1936nm. 33 out of 72 synaptamide ATLCs were smaller than 450 nm in diameter. ATLC compositions that incorporated helper lipids with anionic and zwitterionic head groups resulted in ATLCs that were larger in size than those that incorporated a cationic helper lipid.

[0108] Twenty out of 72 unique synaptamide ATLCs were selected based on size and PDI cutoffs. ATLCs that have sizes of less than 450 nm and PDI values of less than 0.35 were selected for next stage testing of particle stability' in in vitro serum-like conditions.

[0109] Eight out of 20 unique synaptamide ATLCs were selected based on PDI cutoff after 24h incubation in serum-like conditions. (Figure 2) Out of 20 synaptamide ATLCssubjected to stability testing, 8 ATLCs maintained at <0.4 PDI after 24 h incubation in in- serum-like conditions (37°C in media comprising PBS + 5% FBS).

[0110] Tetracosapentaenoic acid (TP A) can be incorporated into unique ATLCs.Informed by the library screen efforts performed using synaptamide as the reference TL, TPA was incorporated into 8 distinct ATLC compositions. Each particle composition contains TPA as the TL, cholesterol, DMG-PEG2000, and one helper lipid selected from a group of 3 carrying different charge types: cationic head groups (DOTAP), zwitterionic head groups (DSPC), and anionic head groups (18PG). 6 out of 8 TPA ATLCs, had PDI values of less than 0.35 after particle assembly in solution containing 25% EtoH. All 6 were smaller than the size cutoff of 450 nm in diameter. 5 out of 6 TPA ATLCs, had PDI values of less than 0.4 after 24h incubation in serum-like conditions. Particle PDI values for 5 of 8 TPA ATLCs of less than 0.4 were maintained up to 72 h incubation in serum-like conditions.

[0111] Evaluation of reduction of LPS-induced IL-6 production in RAW cells by ATLCs. Cryopreserved RAW cells were thawed and then washed with 5 mL PBS; after pouring off the PBS, 5 mL of trypsin was added. Cells were incubated for 5 minutes, then 10 mL of DMEM media were added and the entire mixture was transferred to an empty conical tube. The tube w as centrifuged at 300 ref for 5 minutes. After spindown, the supernatant was poured off and the cells were re-suspended in 10 mL DMEM media. A 10 pL aliquot w as removed for treatment with trypan blue stain before placing in a hemocytometer for cell counting. The amount of cells and media needed to create a 96-well plate was calculated, based on 20,000 cells per 100 pL of media per well. After plating, the plate w as sprayed with ethanol and placed in an incubator for 24 hrs.

[0112] Dosing and ELISA preparation: A 96-well dosing plate was made up for each dosing run as follows. The first two columns of the plate were reserved ELISA standards; 3 wells each w ere reserved for LPS and Vehicle controls, and for Dexamethasone (25-75 mM) as positive control. Working LPS media was prepared by adding 50 mL of LPS stock into 9.95 mL of DMEM and vortexing. Typically. 150 pL of this LPS media was added to each w ell used for dosing. After calculating the amount in pL of each ATLC to be added to the wells, that amount of LPS media w as aspirated out (to maintain final volume of 150 pL). Typically, for the LPS Control, 0. 1 pL of EtOH as added to that well; for Vehicle Control, no LPS is added but 0.1 pL EtOH was added to the w ell.

[0113] The seed plate previously prepared was removed from the incubator, sprayed with 70% EtOH. and placed in a biohood. The media was carefully aspirated out of the cellwells without disrupting the cells. Using a multichannel pipette, the dosage media containing predetermined amount of ATL or ATLC was transferred from the dosing plate wells to the respective wells in the seeded plate. When completed, the lid was placed on the now-dosed seeded cells and the plate was sprayed with EtOH and placed back in the incubator.ELISA was performed using the BioLegend Mouse IL-6 ELISA Max Deluxe Set of reagents and protocol. Minor adjustments to the standard protocol were made. The day before running the ELISA, 100 pL of the Capture Antibody solution was added to the wells of a 96-well plate. Coating buffer solution was prepared by adding 2.4 mL of Coating Buffer A to 9.6 mL of deionized water. Capture Antibody solution was made by mixing 60 pL of capture antibody with 12 mL of Coating Buffer A solution. The plate was covered in saran wrap and placed in 4°C overnight.

[0114] ELISA measurements. Wash buffer w as prepared by mixing 1800 mL deionized water, 200 mL of lOx PBS, and 1 mL of TWEEN. The ELISA plate was washed 4 times with buffer, and blotted to remove residual buffer. 200 pL of blocking buffer in IX Assay Diluent w as added to each well, and the plate w as wrapped with saran wrap and allowed to sit one hour undisturbed.

[0115] The ELISA plate was washed 4 times with buffer. ELISA standards and supernatant from the seeded plate (20 pL supernatant from supernatant with. and 120 pL of blocking buffer in IX Assay) were added to the wells. In Row A, columns 1 and 2, of the dilution plate 240 mL of IL-6 standard w ere added to the wells was added to Row A. Serial dilutions were performed by pipetting 120 mL of Row A to Row B, then Row B to Row C, until Row H. The plate was wrapped with saran wrap and allow ed to sit undisturbed for 2 hrs. The ELISA plate was washed 4 times with buffer. Then 100 pL of the diluted detection antibody solution (prepared by mixing 12 pL of detection antibody solution with 12 mL of IX Assay Diluent A) was added to each well. The plate was sealed and allowed to sit for 1 hour. After washing 4 times, 100 pL of diluted Avidin-HRP solution was added to each well. (The Avidin-HRP solution w as made by mixing 12 pL of Avidin-HRP (1000X) and 12 mL of IX Assay Diluent A.) The plate was re-sealed and allowed to sit undisturbed for 30 minutes, then washed 5 times.

[0116] TMB substrate solution w as made up by mixing 6 mL of Reagent A and 6 mL of Reagent B. 100 pL of freshly mixed TMB substrate solution was added to the wells and the plate was incubated in the dark for 20 minutes. The reaction is stopped by adding 50 pLof stop solution (e.g. 2N H2SO4) to each well. The plate is placed into a micro plate reader, and absorbance read at 450 nM.

[0117] CCK-8 cell viability protocol. The APExBIO reagents and protocol were followed, with slight variations. All of the supernatant was removed from the wells of the dosed seeded plate, and 100 .L of fresh DMEM media was added to each well, followed by 10 pL of CCK-8 solution. The plate was incubated for 1-4 hours, then placed into a micro plate reader and the absorbance measured at 450 nM.

[0118] Effects of TPA ATLCs on LPS-induced IL-6 production in vitro. Five distinct ATLC formulations were prepared incorporating TPA as the therapeutic lipid. IL-6 reducing effect of the five TPA ATLCs at 3 concentrations was tested in the LPS-induced RAW cell model (Table 2).

[0119] Table 2.

[0120] Figure 3 shows the data from this experiment. TPA-ATLC-&3 and #-7 demonstrated improved ability to attenuate LPS-induced IL-6 production in RAW cells, relative to free TPA. TPA-ATLC-#3 showed the best dose-dependent improvement. ICsos for reduction of IL-6 levels by the TPA ATLCs are shown in Fig. 4.

[0121] No effect on cell viability was observed by any of the particles at any of the tested doses as evaluated by the CCK-8 assay (data not shown).

[0122] Effects of NA-, DHA-, Maresin-1-, and Resolvin D5-ATLCs on LPS- induced IL-6 production. Nervonic acid, DHA, maresin-1 , and resolvin D5 ATLCs were prepared as described and evaluated for their ability to attenuate LPS-induced IL-6 production in vitro. Results are shown in Fig. 5. NA-ATLC-&3, DHA-ATLCs-#3, -7, and -8, maresin l-ATLC-#7’, and resolvin D5-ATLC-#3’ and -7’ demonstrated ability to attenuate LPS-induced IL-6 production in RAW cells. ATLCs were not cytotoxic at the doses tested (data not shown).

[0123] Effects of DTHA-ATLCs on LPS-induced IL-6 production. Six different ATLC formulations containing DTHA were tested in the in vitro LPS model. Results are shown in Fig. 6, compared with maresin-1 and TPA. DTHA- ATLC-# 12 and -#26demonstrate improved bioactivity (IL-6 reduction) relative to "naked" DTHA. Fig. 7 shows the ICso of DTHA-ATLC-#12 and also maresin 1-ATLC #7’.

[0124] ATLCs reverse LPS-induced behavioral deficits in LPS-treated mice.Spontaneous alternation is the innate tendency of rodents to alternate free choices in a T- maze over a series of successive runs (Dember and Fowler. 1958). This sequential procedure relies on working memory and is sensitive to various pharmacological manipulations affecting memory processes (Gerlai 1998; Stefani and Gold 2001; Spowart-Mannmg and Van der Staay. 2004). Acute administration of LPS was used to induce a cognitive impairment in mice. Cognitive performance was assessed at 7 days post-LPS treatment.

[0125] Experimental Design.

[0126] Table 3. Animals: 60 male CD-I mice (4-5 weeks old) were used for each experiment. They were randomly distributed to 6 different experimental groups (10 animals per group). An example of a study design is as follows:

[0127] Induction of cognitive deficit: LPS was injected i.p. at a volume of 20ml / kg (0.25mg / kg), 1 week prior to the T-maze trial. This day is set as Day 0.

[0128] Treatment schedule: The vehicle (PBS) was administered daily with the treatment on day 0, just before LPS and the last treatment Ih before the test.

[0129] Test ATLCs were prepared in PBS and given i.p. at a volume of lOml / kg. For the chronic treatment, the ATLCs were administered on a daily basis. The treatment on day 0 was just before the LPS one, and the last treatment was Ih before the T-maze test. For the acute treatment, the ATLC was administered just once on day 0, just before the LPS. The following days, vehicle was administered to ensure the same number of treatments for eachanimal. For the positive control, DHA (docosahexaenoic) prepared in 90mg / ml BSA in saline was injected i.p. at a volume of lOml / kg from day 0 to day 7 (the day of the T-maze).

[0130] T-maze test. The T-maze assay was performed on day 7. The T-maze consists of 2 choice arms and 1 start arm mounted to a square centre. Sliding doors are provided to close specific arms during the force choice alternation task. During the trials, animal handling and the visibility of the operator were minimized as much as possible. The experimental protocol consisted of one single session, which starts with 1 “forced-choice” trial, followed by 14 “free-choice” trials. In the first, “forced-choice” trial, the animal was confined 5 seconds in the start arm and then released while either the left or right goal arm is blocked by closing the sliding door. Afterwards, it negotiated the maze, eventually entering the open goal arm, and returned to the start position. Immediately after the return of the animal to the start position, the left and right goal doors were opened, and the animal was allowed to choose freely between the left and right goal arm (“free-choice” trials). The animal is considered to have entered an arm when it places its four paws in the arm. A session was terminated, and the animal was removed from the maze as soon as 14 free-choice trials had been performed, or 10 min had elapsed, whatever event occurs first. The apparatus was cleaned between each animal using alcohol (70°). The percentage of spontaneous alternations were calculated as number of spontaneous alternations divided through number of free-choice trials (14).

[0131] Statistics. Statistical analysis was assessed using Anova followed by Fischer's Protected Least Significant Difference for pairwise comparison, p level < 0.05 are deemed significant.

[0132] Figure 8 depicts pictorially the study design of the LPS model of neurocognitive impairment.

[0133] As shown in Figure 9, DHA-ATLC-#3 and TPA-ATLC-#3 (Table 1) reversed LPS-induced cognitive deficits in these mice. DHA-ATLC-#3 demonstrated dosedependency in the response.

[0134] ATLCs made incorporating maresin-1, synaptamide, or nervonic acid were also capable of reversing the behavioral deficits in LPS-treated mice, as shown in Figure 10.

[0135] These data suggest that stable ATLCs may be prepared by incorporating a variety of therapeutic lipids. A range of ATLCs incorporating different classes of therapeutic lipid were shown to reduce LPS-induced IL-6 production both in vitro and in vivo. Further, ATLCs incorporating different classes of therapeutic lipid w ere demonstrated to potently reverse the neurocognitive deficits from LPS treatment in an established murine model.

[0136] All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which this disclosure pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0137] Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

We claim:

1. A lipid composition comprising: a. at least one therapeutic lipid; b. cholesterol or a cholesterol derivative; c. one or more helper lipids; d. a PEGylated lipid; and e. optionally one or more excipients.

2. The lipid composition of claim 1, wherein the helper lipid is selected from the group consisting of anionic lipids, cationic lipids, zwitterionic lipids, and neutral lipids.

3. The lipid composition of claim 1, wherein the therapeutic lipid is a fatty acid, fatty acid amide, or fatty acid ester.

4. The lipid composition of claim 1, wherein the therapeutic lipid is a sterol.

5. The lipid composition of claim 4, wherein the sterol is a bile acid.

6. The lipid composition of claim 3, wherein the fatty acid is a monounsaturated fatty acid.

7. The lipid composition of claim 3, wherein the fatty acid is a polyunsaturated fatty acid.

8. The lipid composition of claim 7, wherein the polyunsaturated fatty' acid is an co -3 polyunsaturated fatty acid, an co-6 polyunsaturated fatty acid, an co-8 polyunsaturated fatty acid, or an c -9 polyunsaturated fatty acid.

9. The lipid composition of claim 8, wherein the polyunsaturated fatty' acid is an co -3 polyunsaturated fatty acid.

10. The lipid composition of claim 8 wherein the polyunsaturated fatty acid is an co-8 polyunsaturated fatty7acid.

11. The lipid composition of claim 8 wherein the polyunsaturated fatty7acid is an co-9 polyunsaturated fatty acid.

12. The lipid composition of claim 3, wherein the fatty acid, fatty acid amide or fatty acid ester is selected from the group consisting of lignoceric acid, caprylic acid.palmitoylethanolamide (PEA), nervonic acid (NA), 10-hydroxy-2(E)-decenoic acid (10-HDA), and 9-(palmitoyloxy)octadecanoic acid (9-PAHSA).

13. The lipid composition of claim 5, wherein the bile acid is ursodeoxycholic acid (UDA or UA).

14. The lipid composition of claim 6, wherein the polyunsaturated fatty acid is selected from the group consisting of docosahexaenoic acid (DHA), synaptamide (N- docosahexaenoylethanolamine) (SNA), tetracosapentaenoic acid (TP A), 14(Z),17(Z),20(Z).23(Z),26(Z),29(Z)-dotriacontahexaenoic acid (DTHA), 7R,14S- dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (maresin-1), and 7S,17S- dihydroxy-4Z,8E,10Z,13Z,15E,19Z-docosahexaenoic acid (resolvin D5).

15. The lipid composition of claim 1, wherein the one or more helper lipids are selected from the group consisting of 1.2-dioleoy 1-3 -trimethylammoniumpropane (DOTAP), 1.2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1.2-dimyristoyl-sn-glycero-3- phosphate (14PA), didodecyldimethylammonium bromide (DDAB), and 1,2- distearoyl-sn-glycero-3-phospho-(T-rac-glycerol) (18PG).

16. The lipid composition of claim 1, wherein the PEGylated lipid is selected from the group consisting of: polyethylene glycol (PEG), l,2-Dimyristoyl- / 'ac-glycero-3- methoxypoly ethylene gly col-2000 (DMG-PEG2000), 1.2-Dimyristoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-550] ammonium) (DMPE- PEG550), ganglioside GM, PEG derivatized with Tween, and PEG derivatized with distearoylphosphatidylethanolamine (PEG-DSPE).

17. The lipid composition of claim 1, wherein the one or more optional excipients are selected from the group consisting of: trehalose, mannitol, sucrose, lipid surfactants, emulsifiers, antioxidants, and surfactants with tissue-targeting properties.

18. The lipid composition of any of claims 1-17, wherein the therapeutic lipid is present in the amount of from about 0.5 mol% to about 85 mol% of the lipid composition.

19. The lipid composition of any of claims 1-17, wherein the cholesterol or cholesterol derivative is present in the amount of from about 5 mol% to about 70 mol% of the lipid composition.

20. The lipid composition of any of claims 1-17, wherein the helper lipid is present in the amount of from about 0.5 mol% to about 70 mol% of the lipid composition.

21. The lipid composition of any of claims 1-17, wherein the PEGylated lipid is present in the amount of from about 0.01 mol% to about 10 mol% of the lipid composition.

22. The lipid composition of any of claims 1-17, wherein the one or more excipients are present in the amount of from about 2 mol% to about 5 mol% of the lipid composition.

23. The lipid composition of claim 1, wherein the therapeutic lipid is present in an amount of from about 0.5 mol% to about 60 mol%, cholesterol is present in an amount of from about 5 mol% to about 75 mol%, the helper lipid is present in an amount of from about 5 mol% to about 80 mol%, and the PEGylated lipid is present in an amount of from about 0.01 mol% to about 6.0 mol%.

24. The lipid composition of claim 23, wherein the therapeutic lipid is present in an amount of about 15 mol% to about 60 mol%.

25. The lipid composition of claim 23 or claim 24, wherein the therapeutic lipid is selected from the group consisting of docosahexaenoic acid (DHA), nervonic acid (NA), synaptamide (N-docosahexaenoylethanolamme) (SNA), caprylic acid (CPA), ursodeoxycholic acid (UDA), palmitoylethanolamide (PEA), 9-(palmitoyloxy)- octadecanoic acid (9-PAHSA), tetracosapentaenoic acid (TP A), 14(Z),17(Z),20(Z),23(Z),26(Z),29(Z)-dotriacontahexaenoic acid (DTHA), 10- Hydroxy-2(E)-decenoic acid (10-HDA). 7R.14S-dihydroxy-4Z.8E,10E,12Z,16Z.19Z- docosahexaenoic acid (maresin-1), and 7S,17S-dihydroxy-4Z,8E,10Z,13Z,15E,19Z- docosahexaenoic acid (resolvin D5).

26. The lipid composition of claim 1, wherein the therapeutic lipid is present in an amount of from about 50 mol% to about 70 mol%, cholesterol is present in an amount of from about 5 mol% to about 35 mol%, the helper lipid is present in an amount of from about 5 mol% to about 35 mol%, and the PEGylated lipid is present in an amount of from about 0.01 mol% to about 3.5 mol%.

27. The lipid composition of claim 26, wherein the therapeutic lipid is present in an amount of from about 55 mol% to about 65 mol%.

28. The lipid composition of claim 26 or claim 27, wherein the therapeutic lipid is selected from the group consisting of TP A, SNA, DHA. DTHA, CPA, 9-PAHS A, UDA, PEA, nervonic acid, and 10-HDA.

29. A lipid composition comprising: a. a therapeutic lipid, wherein the therapeutic lipid is readily soluble and is present in an amount of from about 10 mol% to about 75 mol% of the lipid composition; b. cholesterol or a cholesterol derivative, wherein the cholesterol or cholesterol derivative is present in an amount of from about 5 mol% to about 70 mol% of the lipid composition; c. a helper lipid, wherein the helper lipid is present in an amount of from about 5 mol% to about 70% of the lipid composition; d. a PEGylated lipid, wherein the PEGylated lipid is present in an amount of from about 0.01 mol% to about 10 mol% of the lipid composition; and e. optionally one or more excipients.

30. The lipid composition of claim 29. wherein the therapeutic lipid is selected from the group consisting of TP A. SNA, DHA. DTHA. CPA, 9-PAHS A. UDA, PEA, 10- HDA, and nervonic acid and is present in an amount of from about 10 mol% to about 60 mol% of the lipid composition.

31. The lipid composition of claim 29, wherein the therapeutic lipid is selected from the group consisting of TP A, SNA, DHA, DTHA. CPA, 9-PAHS A, UDA, PEA, 10- HDA, and nervonic acid and is present in an amount of from about 50 mol% to about 70 mol% of the lipid composition.

32. The lipid composition of claim 1, wherein the therapeutic lipid is present in an amount of from about 0.1 mol% to about 3 mol%, cholesterol is present in an amount of from about 40 mol% to about 50 mol%. the helper lipid is present in an amount of from about 45 mol% to about 55 mol%, and the PEGylated lipid is present in an amount of from about 4 mol% to about 5 mol%.

33. The lipid composition of claim 32, wherein the therapeutic lipid is selected from the group consisting of maresin-1 and resolvin D5.

34. A lipid composition comprising:a. a therapeutic lipid, wherein the therapeutic lipid is less soluble and is present in an amount of from about 0.1 mol% to about 5 mol% of the lipid composition; b. cholesterol or a cholesterol derivative, wherein the cholesterol or cholesterol derivative is present in an amount of from about 20 mol% to about 70 mol% of the lipid composition; c. a helper lipid, wherein the helper lipid is present in an amount of from about 30 mol% to about 60 mol% of the lipid composition; d. a PEGylated lipid, wherein the PEGylated lipid is present in an amount of from about 0.01 mol% to about 10 mol% of the lipid composition; and e. optionally one or more excipients.

35. The lipid composition of claim 34. wherein said therapeutic lipid is selected from the group consisting of maresin 1 and resolvin D5 and is present in an amount of from about 0. 1 mol% to about 3 mol%.

36. A lipid composition comprising: a. at least one therapeutic lipid, wherein said therapeutic lipid has a carbon chain length of about 8 to about 46; b. cholesterol or a cholesterol derivative; c. a helper lipid; d. a PEGylated lipid; and e. optionally one or more excipients.

37. The lipid composition of claim 36. wherein the therapeutic lipid has a carbon chain length of about 8, about 10, about 16, about 18, about 22, about 24, or about 32.

38. The lipid composition of claim 37, wherein the carbon chain of the therapeutic lipid comprises 1, 3, 5, or 6 double bonds.

39. A method of treating an inflammatory disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a lipid composition of claim 1.

40. The method of claim 39, wherein the inflammatory disorder is selected from the group consisting of degenerative disorders of the central nervous system, degenerative disorders of the peripheral nervous system, inflammatory bowel diseases, asthma,acute respiratory distress syndrome, chronic obstructive pulmonary disease, acute lung injury, bronchopulmonary dysplasia, cystic fibrosis, bronchitis, bronchiolitis, arthritis, osteoarthritis, ankylosing spondylitis, rheumatism, and brain inflammation.

41. A method of treating neurocognitive deficits, loss of neurological function, or neurodegeneration, in a subject in need thereof, comprising administering a therapeutically effective amount of a lipid composition of claim 1.

42. The method of claim 41, wherein the lipid composition is the lipid composition of any of claims 1-17.

43. The method of claim 41. wherein the subject has undergone a surgical intervention or is experiencing organ dysfunction.

44. The method of claim 43, wherein the surgical intervention is being performed to treat orthopedic, cardiovascular, pulmonary, urological, or abdominal abnormalities.

45. The method of claim 43, wherein the organ dysfunction results from traumatic brain injury, stroke, acute kidney failure, chronic kidney failure, spinal cord injury, asthma or other pulmonary-related disorders, infection, sepsis, or an automobile accident.

46. The method of claim 41, wherein said neurocognitive deficits are selected from the group consisting of delayed neurocognitive recovery, delirium, agitation, hyperactivity, cognitive decline, acute brain failure and chronic brain failure.

47. The method of claim 46, wherein said neurocognitive deficits occur acutely or chronically.

48. The method of claim 46, wherein administration of said lipid composition prevents or reduces the severity of the neurocognitive deficits.

49. The method of claim 46, wherein administration of said lipid composition prevents or reduces the duration of the neurocognitive deficits.

50. The method of claim 46, wherein said neurocognitive deficits are associated with changes in one or more pro-inflammatory cytokines IL-1 , TNF-a. IL-8. CXCL1, or IL-6.

51. The method of claim 41, wherein the lipid composition is administered prior to surgical intervention or organ dysfunction.

52. The method of claim 41, wherein the lipid composition is administered during surgical intervention or organ dysfunction.

53. The method of claim 41. wherein the lipid composition is administered after surgical intervention or organ dysfunction.

54. The method of claim 41, wherein the lipid composition is administered by intravenous, subcutaneous, intramuscular, or intrathecal injection.

55. The method of claim 41, wherein the lipid composition is administered by nasal, transdermal, or oral delivery.

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