RNA-containing secretomes and methods of use thereof

Abstract

Disclosed are methods and compositions relating to unique combinations of two or more RNA sequences, including but not limited to microRNA, mRNA, long non-coding RNA, y-RNA, pi-RNA, and other non-coding RNA, packaged in naturally produced mesenchymal stem / stromal cell extracellular vesicles (EVs), synthetic EVs (also known as liposomes or lipid nanoparticles), or combinations thereof, which can modify immune function in a subject.

Description

[Technical field]

[0001] This PCT application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 324,910, filed March 29, 2022, which is incorporated by reference in its entirety herein.

[0002] Reference to sequence listing The Sequence Listing, submitted on March 29, 2023 as an .XML file entitled "11071-013WO1.XML", created on March 29, 2023, and having a file size of 2,914 bytes, is incorporated herein by reference pursuant to 37 C.FR § 1.52(e)(5). [Background technology]

[0003] Bone marrow mesenchymal stem / stromal cells (MSCs) modify the body's immune response primarily by secreting a combination of soluble factors, extracellular matrix, and extracellular vesicles (EVs). EVs contain proteins and RNA molecules that regulate both pro- and anti-inflammatory signaling pathways in immune cells (neutrophils, monocytes, macrophages, dendritic cells, B cells, T cells, natural killer (NK) cells, etc.). Bacterial and viral pathogens have evolved strategies to manipulate and exploit the innate immune response. For example, bacteria and viruses can induce interleukin-10 (IL-10), an anti-inflammatory cytokine that primarily results in immunosuppression, allowing pathogens to increase their infection efficiency and replication rate. In other instances, patients may have genetically associated immune response deficiencies that may reduce the effectiveness of secreted factors and extracellular vesicles in naturally derived therapeutics. These deficiencies may represent defects in immune-modulating signaling molecules or their receptors. There is a need for new compositions that can counteract microbial immune evasion techniques and defective immune responses. Summary of the Invention

[0004] Disclosed are methods and compositions relating to unique combinations of two or more RNA sequences, including but not limited to microRNA, mRNA, long non-coding RNA, y-RNA, pi-RNA, and other non-coding RNA, packaged in naturally produced mesenchymal stem cell / stromal cell extracellular vesicles (EVs), synthetic EVs (also known as liposomes or lipid nanoparticles), or combinations thereof, which can modify immune function in a subject.

[0005] In one aspect, disclosed herein is a composition comprising one or more secretomes (e.g., liposomes, lipid nanoparticles, or mesenchymal stem cell (MSC)-derived exosomes or extracellular vesicles, or any combination thereof) and two or more ribonucleic acids (RNAs) (e.g., microRNAs (miRNAs), messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), y-RNAs, and / or pi-RNAs).

[0006] Also provided herein is a composition of any of the preceding embodiments, wherein the two or more RNAs are selected from the group consisting of RNY4, LOC441666, SNHG1, RNU11, LOC80154, LOC727751, LOC388152, GOLGA2P2Y, GOLGA2P3Y, SNHG12, RNU12, ASMTL-AS1, LOC284454 U2:RF00004.39, U2:RF00004.22, U2:RF00004.35, U2:RF00004.71, U2:RF00004.66 U2:RF00004.91, U2:RF00004.89, U2:RF00004.67, U1:RF00003.5, U1:RF00003.109, U1:RF00003.110, U1:RF00003.8, U1:RF00003.3, U1:RF00003.6, U1:RF00003.38, U1:RF00003.20, U1:RF00003.24, U1:RF00003.73, U1:RF00003.11, U1 :RF00003.27, U1:RF00003.40, U1:RF00003.107, U1:RF00003.62, U1:RF00003.45, U1:RF00003.116, U1:RF00003.126 , U1:RF00003.81, U1:RF00003.100, U1:RF00003.57, U1:RF00003.95, U1:RF00003.31, U1:RF00003.61, U1:RF00003.2 5, U1:RF00003.90, U1:RF00003.46, U1:RF00003.123, U2:RF00004.42, U2:RF00004.61, U2:RF00004.51, U1:RF00003. 122, U1:RF00003.22, U1:RF00003.9, snoMBII-202:RF00324.2, let-7:RF00027.7, U2:RF00004.75, U1:RF00003.69, U 2:RF00004.88, U12:RF00007.1, U7:RF00066.141, U1:RF00003.85, U7:RF00066.49, U2:RF00004.77, U1:RF00003.113 , U1:RF00003.112, U1:RF00003.70, U1:RF00003.83, U7:RF00066.89, U7:RF00066.124, U7:RF00066.75, U7:RF00066.The present invention relates to a composition comprising at least one RNA selected from the group consisting of U7:RF00066.77, U7:RF00066.118, U7:RF00066.103, U7:RF00066.79, U7:RF00066.200, and U7:RF00066.146.

[0007] In one aspect, a composition of any of the foregoing aspects, wherein two or more RNAs are hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p,hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29 c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-mi R-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-mi R-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c- 3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-4 86-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-m Disclosed herein is a composition comprising at least one miRNA selected from the group consisting of hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR-99b-5p. Preferably, disclosed herein is a composition of any of the preceding aspects, wherein the two or more RNAs comprise at least one miRNA selected from the group consisting of miR-92a-3p, let-7i-5p, miR-16-5p, miR-93-5p, miR-21-5p, miR-214-3p, miR-29c-3p, miR-34a-5p, mir-203a-3p, miR-27b-3p, miR-140-3p, miR-24-3p, miR-222-3p, miR-25-3p, miR-10b-5p, miR-221-3p, miR-17-5p, miR-30a-5p, and miR-30d-5p.

[0008] Also, the composition of any of the preceding embodiments, wherein the two or more RNAs are selected from the group consisting of HBII-202, U26, U29, HBII-420, U30, U18A, U81, GSKIP, IFT88, PCDH11X, PCDH11Y, KIAA0226L, PDE11A, PHACTR1, TEX14, DCUN1D2, SIM1, FILIP1, FAM107B, CHADL, ZNF365, MNAT1, CYSTM1, GAS7, HOXB7, ASTN2, LGR5 Disclosed herein is a composition comprising at least one mRNA selected from the group consisting of: ZFHX3, MCM7, GRIK1, MAP2, LHFPL3, PTER, STAMBP, CCDC135, PAX9, RPL13, ABCA13, DAAM1, OPN1LW, OPN1MW2, CNOT6L, MTRNR2L10, SMC4, RPL4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2, and NANS.

[0009] In one embodiment, the composition of any preceding embodiment, wherein the two or more RNAs are selected from the group consisting of UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, H Disclosed herein is a composition comprising at least one antisense mRNA selected from the group consisting of S3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, and GAGE2D:copy21.

[0010] Also disclosed herein is a composition of any of the preceding embodiments, wherein the two or more RNAs comprise at least one lncRNA selected from the group consisting of LOC100129335-5, ZNF238, CADM2-7, SALL1-6, or VWA5A.

[0011] In one embodiment, disclosed herein is a composition of any preceding embodiment, wherein the two or more RNAs comprise at least one antisense lncRNA selected from the group consisting of ANKRD5-1, ZNF236-1, and ACP1.

[0012] Also disclosed herein is a composition of any of the preceding embodiments, wherein the two or more RNAs comprise at least one y-RNA selected from the group consisting of RF00019.441, RF00019.451, RF00019.621, RF00019.646, and RF00019.413.

[0013] In one aspect, disclosed herein is a composition of any preceding aspect, wherein the two or more RNAs comprise at least one pi-RNA selected from the group consisting of piR-33044, piR-33043, and piR-31703.

[0014] Also disclosed herein is a composition of any of the preceding embodiments, wherein the two or more RNAs comprise at least one antisense RNA selected from the group consisting of EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and HNRNPU-AS1.

[0015] In one aspect, disclosed herein is a composition of any of the preceding aspects, wherein the RNA comprises a modification to reduce degradation (e.g., the addition of a 2'-O-methyl group, a 2'-fluoro group, or a 2'-hydro group, etc.).

[0016] Also disclosed herein is a method of modulating an immune response to inflammatory injury in a subject, including but not limited to increasing or decreasing inflammation, comprising administering to the subject any of the compositions of the above-mentioned embodiments. For example, disclosed herein is a method of modulating an immune response, wherein the modulation increases inflammation, and wherein two or more RNAs of the composition are selected from the group consisting of HBII-202, U26, U29, HBII-420, U30, U18A, U81, GSKIP, IFT88, PCDH11X, PCDH11Y, KIAA0226L, PDE11A, PHACTR1, TEX14, DCUN1D2, SIM1, FILIP1, FAM107B, CHADL, ZNF365, MNAT1, CYSTM1, GAS7, HO The method includes detecting at least one mRNA selected from the group consisting of XB7, ASTN2, LGR5, ZFHX3, MCM7, GRIK1, MAP2, LHFPL3, PTER, STAMBP, CCDC135, PAX9, RPL13, ABCA13, DAAM1, OPN1LW, OPN1MW2, CNOT6L, MTRNR2L10, SMC4, RPL4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2, and NANS. Also provided herein, for example, is a method of modulating an immune response, wherein the modulation reduces inflammation, and wherein two or more RNAs of the composition are selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-104a-3p, hsa-miR-105a-3p, hsa-miR-106a-3p, hsa-miR-107a-3p, hsa-miR-108a-3p, hsa-miR-109a-3p, hsa-miR-110b-3p, hsa-miR-111c-3p, hsa-miR-112a-3p, hsa-miR-113b-3p, hsa-miR-114a-3p, hsa-miR-115a-3p, hsa-miR-116a-3p, hsa-miR-117b-3p, hsa-miR-118a-3p, hsa-miR-119a-3p, hsa-miR-120b-3p, hsa-miR-121b-3p, hsa-miR-122a-3p, hsa-miR-123a-3p, hsa-miR-124a-3p, hsa-miR-125a-3p, hsa-miR-126a-3p, hsa-miR-127a-3p, hsa-miR-128a-3p, hsa-miR-129 p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-12 5a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p,hsa-miR-138-5p, hsa-miR-139-5p, hsa-miR-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-miR-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1, hsa-miR-16- 2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, and hsa-miR-19b-3p hsa-miR-20a-5p, hsa-miR-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-miR-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-miR-221, hsa-miR-221-3p, hsa-miR-222, hsa -miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-m iR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hs a-miR-30d-5p、hsa-mir-30e、hsa-miR-30e-5p、hsa-miR-31-3p、hsa-miR-31-5p、hs a-miR-320a、hsa-miR-342-3p、hsa-miR-345-5p、hsa-miR-34a-5p、hsa-miR-361-5p、hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484 , hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hs Methods are disclosed in which the method comprises administering to the subject a miRNA comprising administering to the subject a miRNA comprising at least one miRNA selected from the group consisting of hsa-mir-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR-99b-5p.

[0017] In one aspect, disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing an autoimmune disease, an autoinflammatory disease, inflammatory damage resulting from physical injury, inflammatory damage resulting from microbial infection, or inflammatory damage resulting from cancer in a subject, comprising administering to the subject a composition of any of the preceding aspects. [Brief description of the drawings]

[0018] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments and together with the description illustrate the disclosed compositions and methods.

[0019] [Figure 1] FIG. 1 shows the effect of synthetic miRNAs shown by RNA sequencing and quantitative PCR to be present in MSC extracellular vesicle preparations EXOFLO® and EXOFLO® on IL-1β concentrations (n=3 wells of cells per condition). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Before the present compounds, compositions, articles, devices, and / or methods are disclosed and described, it is understood that, unless otherwise specified, they are not limited to specific synthetic methods or recombinant biotechnology methods, or to particular reagents, which can, of course, vary. Furthermore, it is understood that the terminology used herein is used only for the purpose of describing particular embodiments, and is not intended to be limiting.

[0021] A.Definition As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

[0022] Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, using the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each range are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood that there are a number of values ​​disclosed herein, and that each value is also disclosed herein as "about" that particular value, in addition to the value itself. For example, when the value "10" is disclosed, "about 10" is also disclosed. It is also understood that when a value is disclosed, "less than or equal to" that value, "more than or equal to" that value, and possible ranges between values ​​are also disclosed, as would be properly understood by one of ordinary skill in the art. For example, when the value "10" is disclosed, "less than or equal to 10" and "more than or equal to 10" are also disclosed. It is also understood that throughout this application, data is provided in several different formats, and the data represents the end and starting points, as well as ranges of any combination of the data points. For example, if a specific data point "10" and a specific data point 15 are disclosed, it is understood that more than 10 and more than 15, 10 or more and 15 or more, less than 10 and less than 15, 10 or less and 15 or less, 10 and 15 or less, and between 10 and 15 are considered to be disclosed. It is also understood that each unit between two specific units is also disclosed. For example, if 10 and 15 are disclosed, 11, 12, 13, and 14 are also disclosed.

[0023] In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings.

[0024] "Optional" or "optionally" means that the event or circumstance described below may or may not occur, and that the description includes instances when the event or circumstance described above occurs and instances when it does not occur.

[0025] "Increase" can refer to any change that results in a greater amount of a symptom, disease, composition, condition, or activity. An increase can be any individual, median, or average increase in a condition, symptom, activity, or composition in a statistically significant amount. Thus, an increase can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% increase, so long as the increase is statistically significant.

[0026] "Decrease" can refer to any change that results in a lesser amount of a symptom, disease, composition, condition, or activity. A substance is understood to decrease a genetic output when the genetic output of a gene product involving the substance is less compared to the genetic output of a gene product not involving the substance. A decrease can also be, for example, a change in the symptoms of a disorder such that the symptoms are less than those previously observed. A decrease can be any individual, median, or mean decrease in a condition, symptom, activity, composition in a statistically significant amount. Thus, a decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease, as long as the decrease is statistically significant.

[0027] "Inhibit", "inhibiting" and "inhibition" refer to a decrease in an activity, response, condition, disease or other biological parameter. This can include, but is not limited to, the complete elimination of the activity, response, condition, or disease. It can also include, for example, a 10% reduction in the activity, response, condition, or disease compared to native or control levels. Thus, the reduction can be a decrease of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount in between, compared to native or control levels.

[0028] "Reduce" or other forms of the phrase, such as "reducing", "reduction", refer to the reduction of an event or characteristic (e.g., tumor growth). This is typically relative to some standard or expected value, in other words, relative, although it is understood that a standard or relative value need not necessarily be referenced. For example, "reducing tumor growth" refers to a decrease in the rate of tumor growth compared to a standard or control.

[0029] Other forms of the phrase, such as "prevent" or "prevention," intend to stop a particular event or characteristic, stabilize or delay the occurrence or progression of a particular event or characteristic, or minimize the chance of a particular event or characteristic occurring. "Prevent" is typically more absolute than, for example, "reduce," and does not require a comparison to a control. As used herein, something may be reduced but not prevented, but something that is reduced may be prevented. Similarly, something may be prevented but not reduced, but something that is prevented may be reduced. When reduce or prevention is used, it is understood that the use of the other term is expressly disclosed unless specifically indicated otherwise.

[0030] The term "subject" refers to any individual who is the target of administration or treatment. The subject may be a vertebrate (e.g., a mammal). In one embodiment, the subject may be a human, a non-human primate, a cow, a horse, a pig, a dog, or a cat. The subject may also be a guinea pig, a rat, a hamster, a rabbit, a mouse, or a mule. Thus, the subject may be a human or a veterinary patient. The term "patient" refers to a subject under the care of a clinician (e.g., a physician).

[0031] The term "therapeutically effective" refers to the amount of the composition used being sufficient to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration requires only a reduction or alteration, not elimination.

[0032] The term "treatment" refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, i.e., treatment specifically directed at ameliorating a disease, pathological condition, or disorder, and also includes causal treatment, i.e., treatment directed at eliminating the cause of the associated disease, pathological condition, or disorder. In addition, this term includes symptomatic treatment, i.e., treatment designed to alleviate symptoms rather than cure the disease, pathological condition, or disorder; preventive treatment, i.e., treatment aimed at minimizing or partially or completely inhibiting the onset of the associated disease, pathological condition, or disorder; and supportive treatment, i.e., treatment used to supplement another specific treatment directed at ameliorating the associated disease, pathological condition, or disorder.

[0033] "Biocompatible" generally refers to a material and any metabolic or decomposition products thereof that are generally non-toxic to the recipient and do not cause significant adverse effects in the subject.

[0034] "Comprising" is intended to mean that the composition, method, etc. includes the recited elements but does not exclude others. "Consisting essentially of," when used to define compositions and methods, means including the recited elements but excluding other elements that have some essential importance to the combination. Thus, a composition consisting essentially of the elements defined herein does not exclude trace contaminants from the isolation and purification methods, as well as pharma- ceutically acceptable carriers such as phosphate buffered saline, preservatives, etc. "Consisting of" is intended to mean excluding other components and substantial method steps beyond trace elements for administering the compositions provided and / or claimed in this disclosure. Embodiments defined by each such transition term are within the scope of this disclosure.

[0035] A "control" is a substitute control or sample used in an experiment for comparison purposes. Controls can be "positive" or "negative."

[0036] An "effective amount" of a drug refers to an amount of the drug sufficient to produce a desired effect. The amount of an "effective" drug varies from subject to subject, depending on many factors, such as the age and general condition of the subject, the specific agent(s), and the like. Thus, it is not always possible to define a quantified "effective amount". However, the appropriate "effective amount" in any subject case can be determined by those skilled in the art using repeated experiments. Also, as used herein, and unless otherwise specifically stated, an "effective amount" of a drug can also refer to an amount that includes both a therapeutically effective amount and a prophylactically effective amount. The "effective amount" of a drug required to achieve a therapeutic effect can vary depending on factors such as the age, sex, and weight of the subject. The administration regimen can be adjusted to produce an optimal therapeutic response. For example, several divided doses can be administered daily, or the dose can be proportionally reduced depending on the exigencies of the therapeutic situation.

[0037] A "pharmaceutical acceptable" ingredient may refer to an ingredient that is biologically or otherwise undesirable, i.e., the ingredient may be incorporated into a pharmaceutical formulation provided by the present disclosure and administered to a subject as described herein without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other ingredients of the formulation in which it is included. When used in reference to human administration, the term generally means that the ingredient has met the required standards of toxicological and manufacturing testing, or that the ingredient is included in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration.

[0038] A "pharmaceutically acceptable carrier" (sometimes referred to as a "carrier") means a carrier or excipient that is generally safe and non-toxic and useful in preparing pharmaceutical or therapeutic compositions, including carriers that are acceptable for veterinary and / or human pharmaceutical or therapeutic use. The term "carrier" or "pharmaceutically acceptable carrier" can include, but is not limited to, phosphate buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and / or various types of wetting agents. As used herein, the term "carrier" includes, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material known in the art for use in pharmaceutical formulations, and as further described herein.

[0039] As in "pharmacologically active" derivative or analog, "pharmacologically active" (or simply "active") can refer to derivatives or analogs (e.g., salts, esters, amides, conjugates, metabolites, isomers, fragments, etc.) that have the same type and approximately the same degree of pharmacological activity as the parent compound.

[0040] "Therapeutic agent" refers to any composition that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of disorders or other undesirable physiological conditions, and prophylactic effects, e.g., prevention of disorders or other undesirable physiological conditions (e.g., non-immunogenic cancers). These terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of the beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like. When the term "therapeutic agent" is used, or when a particular agent is specifically identified, it should be understood that the term includes the agent itself, as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, and the like.

[0041] A "therapeutically effective amount" or "therapeutically effective dose" of a composition (e.g., a composition containing a drug) refers to an amount effective to achieve a desired therapeutic outcome. In some embodiments, the desired therapeutic outcome is the control of type I diabetes. In some embodiments, the desired therapeutic outcome is the control of obesity. The therapeutically effective amount of a given therapeutic agent typically varies with respect to factors such as the type and severity of the disorder or disease being treated, as well as the age, sex, and weight of the subject. The term may also refer to the amount of therapeutic agent, or the delivery rate of the therapeutic agent (e.g., amount over time), effective to promote a desired therapeutic effect, such as pain relief. The exact desired therapeutic effect will vary according to the condition being treated, the tolerance of the subject, the drug and / or drug formulation being administered (e.g., potency of the therapeutic agent, concentration of the drug in the formulation, etc.), as well as various other factors understood by those skilled in the art. In some cases, the desired biological or medical response is achieved after administration of multiple doses of the composition to the subject over a period of days, weeks, or years.

[0042] Throughout this application, various publications are cited. The disclosures of these publications in their entireties are hereby incorporated by reference in order to more fully describe the state of the art to which this application pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.

[0043] B. Composition Disclosed are the components used to prepare the disclosed compositions, as well as the compositions themselves used within the methods disclosed herein.These and other materials are disclosed herein, and when combinations, subsets, interactions, groups, etc. of these materials are disclosed, it is understood that although the various individual and collective combinations and permutations of these compounds may not be expressly disclosed herein, each is nevertheless specifically contemplated and described.For example, when a particular composition comprising one or more secretomes and two or more ribonucleic acids (RNAs) is disclosed and discussed, some modifications that can be made to some molecules comprising the composition comprising one or more secretomes and two or more ribonucleic acids (RNAs) are discussed, and unless specifically indicated to the contrary, it is any and all combinations and permutations of the composition comprising one or more secretomes and two or more ribonucleic acids (RNAs) and possible modifications that are specifically contemplated. Thus, when classes of molecules A, B, and C, and classes of molecules D, E, and F are disclosed, and examples of combinations of molecules AD are disclosed, each is intended to be individually and collectively disclosed combinations AE, AF, BD, BE, BF, CD, CE, and CF, even if each is not individually listed. Similarly, any subset or combination of these is also disclosed. Thus, for example, subgroups of AE, BF, and CE are considered to be disclosed. This concept applies to all aspects of this application, including, but not limited to, steps in the methods of making and using the disclosed compositions. Thus, when there are various additional steps that can be performed, it is understood that each of these additional steps can be performed by any of the specific embodiments or combinations of the disclosed method embodiments.

[0044] Bone marrow mesenchymal stem / stromal cells (MSCs) primarily modify the body's immune response by secreting a combination of soluble factors, extracellular matrix, and extracellular vesicles (EVs). EVs contain proteins and RNA molecules that regulate both pro- and anti-inflammatory signaling pathways in immune cells (neutrophils, monocytes, macrophages, dendritic cells, B cells, T cells, natural killer (NK) cells, etc.). Bacterial and viral pathogens have evolved strategies to manipulate the natural immune response to their advantage. For example, bacteria and viruses can induce interleukin 10 (IL-10), an anti-inflammatory cytokine that primarily results in immunosuppression, allowing pathogens to increase their infection efficiency and replication rate. In this example, we propose that supplementing naturally derived non-engineered EV therapeutics at the appropriate time along with engineered synthetic miRNA, RNAi, or proteins targeting molecules such as IL-10 that enable persistent infection may result in a more favorable resolution to immune hyper- or immune-depressed disease states.

[0045] In other instances, patients may have genetically-related immune response deficiencies that may reduce the effectiveness of secreted factors and extracellular vesicles in naturally derived therapeutics. These deficiencies may represent deficiencies in immune-regulating signaling molecules or their receptors. Using IL-10 again as an example, individuals with a tendency to autoimmunity upon microbial challenge will develop an autoimmune response when IL-10 is suppressed (Gazzinelli et al). To counter this, we propose that additional supplementation with appropriately engineered IL-10 regulatory RNA or protein will promote enhanced efficacy of the immune response over that achieved by naturally derived therapeutics alone. This therapeutic strategy may simultaneously allow for appropriate compensation of genetically dysregulated immune function within autoimmune-prone patients.

[0046] The use and / or delivery of therapeutic EVs / secreted factors to patients proposed in the above scenarios, together with other engineered molecules, allows for precisely tailored immunotherapy that cannot otherwise be achieved by delivery of individual elements alone. Thus, by adding synthetic biomolecules to naturally derived EV / secreted factor-based therapies, a customized, tailored effect can be achieved that increases efficacy across a broader patient population.

[0047] In one aspect, disclosed herein is a composition comprising one or more secretomes (e.g., liposomes, lipid nanoparticles, or mesenchymal stem cell (MSC)-derived exosomes or extracellular vesicles, or any combination thereof) and two or more ribonucleic acids (RNAs) (e.g., microRNAs (miRNAs), messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), y-RNAs, and / or pi-RNAs).

[0048] As noted throughout, the compositions disclosed herein can utilize liposomes, lipid nanoparticles, and exosomes and / or extracellular vesicles derived from mesenchymal stem cells (MSCs), or any combination thereof.While existing autologous and allogeneic MSCs contained in bone marrow concentrate or adipose-derived stromal vascular fraction (SVF) or various postnatal products from umbilical cord, placenta or amniotic membrane are currently used to treat wounds, orthopedic pathology, and spinal pathology; existing treatments do not contain significant amounts of MSC secretome (including but not limited to growth factors, cytokines, chemokines, exosomes, extracellular vesicles, and / or extracts).

[0049] MSCs are multipotent cells that have the ability to differentiate into multiple cell types, including myocytes, chondrocytes, adipocytes, and osteoblasts. Typically, these cells can be found in the placenta, umbilical cord blood, adipose tissue, bone marrow, or amniotic fluid, including perivascular tissues. As used herein, "MSCs" refers to non-terminally differentiated cells, including, but not limited to, pluripotent stem cells, pluripotent stromal cells, stromal vascular cells, pericytes, perivascular cells, stromal cells, multipotent cells, multipotent cells, adipose-derived fibroblast-like cells, adipose-derived stromal vascular fraction, adipose-derived MSCs, bone marrow-derived fibroblast-like cells, bone marrow-derived stromal vascular fraction, bone marrow-derived MSCs, tissue-derived fibroblast-like cells, adult stem cells, adult stromal cells, keratinocytes, and / or melanocytes.

[0050] In addition to their differentiation potential, MSCs have long been recognized to have immune-modulating capabilities resulting in the expression of many different cytokines and growth factors. As used herein, "MSC preparation" or "MSC secretome composition" refers to a composition that includes MSC growth factors, MSC exosomes, extracellular vesicles, or cell-free extracts of MSCs, or MSC lysates obtained from human MSCs, fibroblast-like cells, non-human animal MSCs (including but not limited to MSCs from horses, cows, pigs, sheep, non-human primates, dogs, cats, rabbits, rats, and mice). In embodiments, the MSCs may be derived from the patient to whom the composition is applied (autologous) or from another individual (allogeneic). The MSCs may be culture-expanded to collect conditioned medium or to increase the amount of cells for lysate, or may be used fresh before incorporation into the compositions of the present disclosure.

[0051] MSC secretome compositions (including, but not limited to, compositions comprising MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles) may comprise about 0.00001 to about 20% by weight, e.g., about 0.01 to about 10% by weight, of a mesenchymal stem cell (MSC) extract, MSC exosome, or MSC growth factor preparation. The MSC preparation may comprise either MSC conditioned medium or MSC lysate from cell culture-expanded MSCs. In some embodiments, the composition may further comprise about 0.01 to about 10% by weight of cell-free medium conditioned by expansion of MSCs or MSC-lineage cells, the cells being cultured under normal high oxygen culture conditions or under artificial wound healing conditions.

[0052] As disclosed herein, the MSCs used to produce the disclosed MSC additives (including the growth factor secretome compositions of either the frozen or powder additives) can be selectively stimulated to produce MSC growth factors, secretomes, cytokines, chemokines, mesenchymal stem cell proteins, peptides, glycosaminoglycans, extracellular matrix (ECM), proteoglycans, secretomes, and exosomes. As used herein, MSC growth factors include, but are not limited to, prostaglandin E2 (PGE2), transforming growth factor β1 (TGF-β1), hepatocyte growth factor (HGF), stromal cell-derived factor 1 (SDF-1), nitrate oxide, indoleamine 2,3-dioxygenase, interleukin-4 (IL-4), IL-6, interleukin-10 (IL-10), IL-1 receptor antagonist, and soluble TNF-α receptor, insulin-like growth factor, fibroblast growth factor (FGF) 1-23 (FGF) 2-23 ... In particular, these include FGF1 and FGF2), bone morphogenetic proteins (BMPs) 1-15, epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), macrophage stimulating protein (MSP), platelet-derived growth factor (PLGF), vascular endothelial growth factor (VEGF), macrophage colony-stimulating factor (M-CSF), insulin, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and hormones including estrogen and thyroid hormone.

[0053] In one embodiment, the MSC preparation (e.g., MSC secretome composition, etc.) comprises MSC growth factors, MSC exosomes, and / or MSC cell extracts or MSC lysates obtained from MSCs cultured under standard high oxygen culture conditions (e.g., 21% oxygen) or MSCs cultured under artificial wound healing conditions (e.g., in the presence of inflammatory cytokines, angiogenic factors, 0.1% to about 5% oxygen, and low glucose, etc.).

[0054] As disclosed herein, artificial wound healing conditions simulate the growth conditions in real wounds, where there is a reduction in nutrient supply and reduced waste removal, usually caused by the disruption of local blood circulation. This creates a harsh environment for cells until new blood vessels are created and blood circulation is restored. Thus, the artificial wound healing conditions used to culture MSCs can include one or more of the following growth conditions: reduced glucose availability, reduced oxygen tension, reduced pH, and increased temperature.

[0055] In some embodiments, glucose availability may be reduced compared to a normal control. Modified culture media that reduce glucose but do not damage cells may provide a 0-50% reduction in glucose, more preferably a reduction in glucose of about 5%-40%. For example, MSC artificial wound healing culture conditions can include about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50% glucose reduction, such as about 5% to about 15%, about 10% to about 20%, about 15% to about 25%, about 20% to about 30%, or about 25% to about 35% glucose reduction.

[0056] In one embodiment, the oxygen tension can be reduced to an oxygen level that leads to hypoxic conditions. Normal atmospheric oxygen is about 21%, and any reduction is considered hypoxic. Thus, in one embodiment, under artificial wound healing conditions, MSCs can be cultured between 0.0% to 20.9% oxygen, about 0.1% to about 0.5%, about 0.1% to about 2.0%, about 0.1% to about 5.0%, about 0.5% to 5.0%, about 1.0% to about 10%, about 5.0% to about 10.0%, about 10.0% to about 15.0% oxygen. Preferably, during MSC wound healing culture conditions, the oxygen tension is between about 0.5% and 20.5% oxygen, e.g., 0, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.7, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 2.1, 2.2, 2.4, 2.5, 2.7, 2.8, 2.9, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 ...9, 2.1, 2.5, 2.6, 2.7, 2.8, 2.9, 2.9, 2.1, 2.2, 2.3, 2.4, 2.5, 2.5, 2.6, 2.7, 2.8, 2 .1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5. 5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8. 9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, or 20.5%.

[0057] The pH can also be lowered under artificial wound healing conditions. Physiological pH is maintained very closely and is usually very close to neutral pH = 7.2 ± 0.2 (7.0 to 7.4). However, in a wound, the acidic environment can have a pH = 6.2 ± 0.2 (i.e., a pH of 6.0 to about 6.4). Thus, under artificial wound healing culture conditions, the pH can be about 6.0 to about 7.4, for example, 6.0 to about 6.4, about 6.2 to about 6.4, about 6.2 to about 6.6, about 6.4 to about 6.6, about 6.4 to about 6.8, or about 6.6 to about 7.0, for example, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, or 7.4.

[0058] Under artificial wound healing culture conditions, the temperature of the culture environment may be increased to simulate the elevated temperature at the site of the wound. Physiological homeostatic temperature is maintained at 37°C (98.6°F). Small increases or decreases can cause significant changes in cell metabolism. A "hot" environment can be created by increasing the temperature above 37°C to any temperature up to about 40°C (104°F). Thus, in certain embodiments, artificial wound healing culture conditions for MSCs may include about 35°C to about 39°C, about 35°C to about 36°C, about 36°C to about 37°C, about 37°C to about 38°C, about 38°C to about 39°C, and about 39°C to about 40°C. In one embodiment, the temperature of the artificial wound healing culture is 35.0, 35.1, 35.2, 35.3, 36.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 39.1, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 39.0, 39.1, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 39.1, 39.1, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 39.0, The temperature may be 7.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, or 40.0°C.

[0059] The combined environment of reduced nutrients and metabolites (artificial wound healing) can induce cultured cells to produce wound healing and anti-inflammatory ECM proteins, growth factors, and extracellular vesicles that are present to induce tissue healing, which can be in the form of new ECM proteins such as collagen and glycosaminoglycans (GAGs) as well as growth factors and cytokines. Thus, it is understood and contemplated herein that MSCs can be stimulated to selectively secrete desired anti-inflammatory proteins, peptides, cytokines, chemokines, glycosaminoglycans, extracellular matrices (ECMs), proteoglycans, exosomes, and secretomes by adjusting cell growth conditions, cell confluency, media supplements, nutrient supplements, oxygen levels, length of culture in those conditions, cell passage number, or combinations thereof, etc.

[0060] In one aspect, it is understood and contemplated herein that growth conditions such as temperature, oxygen tension, pH, glucose saturation, confluency, and growth surface can affect gene expression and protein production of cells growing in culture, thereby resulting in different growth factors and cytokines being produced. For example, growth surface stiffness (Young's Modulous) affects gene expression and protein production of cells growing thereon. Adipocytes and chondrocytes are usually maintained on softer, more elastic growth surfaces (about 10 kPa to 12 kPa), while bone cells grow better on stiffer surfaces (about 106 to 126 kPa). By modulating surface stiffness, it is possible to affect the secretome of cells and their transduction signals (growth factors, exosomes, cytokines, and chemokines).

[0061] In one embodiment, the secretome composition (including but not limited to compositions comprising liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles) can further comprise a protective coating (e.g., cryoprotectant oligosaccharides and protein solutions, etc.) to reduce degradation of the growth factors. It is understood and contemplated herein that the protective coating can be designed as a polymer. "Polymer" refers to a relatively high molecular weight organic compound (natural or synthetic), whose structure can be represented by monomers, which are small repeating units. Non-limiting examples of polymers include polyethylene, rubber, and cellulose. Synthetic polymers are typically formed by addition or condensation polymerization of monomers. The term "copolymer" refers to a polymer formed from two or more different repeating units (monomer residues). By way of example and without limitation, a copolymer can be an alternating copolymer, a random copolymer, a block copolymer, or a graft copolymer. In certain embodiments, it is also contemplated that the various block segments of a block copolymer can themselves comprise a copolymer. The term "polymer" encompasses all forms of polymers, including, but not limited to, natural polymers, synthetic polymers, homopolymers, heteropolymers or copolymers, addition polymers, etc. In one aspect, the gel matrix may comprise copolymers, block copolymers, diblock copolymers, and / or triblock copolymers.

[0062] In one embodiment, the protective coating can include a biocompatible polymer. In one embodiment, the biocompatible polymer can be crosslinked. As used herein, biocompatible polymers include, but are not limited to, polysaccharides; hydrophilic polypeptides; poly(amino acids), such as poly-L-glutamic acid (PGS), gamma-polyglutamic acid, poly-L-aspartic acid, poly-L-serine, or poly-L-lysine; polyalkylene glycols and polyalkylene oxides, such as polyethylene glycol (PEG), polypropylene glycol (PPG), and poly(ethylene oxide) (PEO); poly(oxyethylated polyols); poly(olefinic alcohols); polyvinylpyrrolidone; poly(hydroxyalkyl methacrylamides); poly(hydroxyalkyl methacrylates); poly(saccharides); poly(hydroxy acids); poly(vinyl alcohols), poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), and other poly(3-hydroxypropyl)-p-tolylamine; poly( ... Examples of suitable poly(oxybutyric acid or poly-4-hydroxybutyric acid); polycaprolactones; poly(orthoesters); polyanhydrides; poly(phosphazenes); poly(lactic acid-co-caprolactone); polycarbonates such as tyrosine polycarbonate; polyamides (including synthetic and natural polyamides), polypeptides, and poly(amino acids); polyesteramides; polyesters; poly(dioxanones); poly(alkylene alkylates); hydrophobic polyethers; polyurethanes; polyether esters; polyacetals; polycyanoacrylates; polyacrylates; polymethyl methacrylates; polysiloxanes; poly(oxyethylene) / poly(oxypropylene) copolymers; polyketals; polyphosphoric acids; polyhydroxyvalerates; polyalkylene oxalates; polyalkylene succinates; poly(maleic acid), and copolymers thereof.Biocompatible polymers include polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohol (PVA), methacrylate PVA (m-PVA), polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidones, polyglycolides, polysiloxanes, polyurethanes and their copolymers, alkylcelluloses, hydroxyalkylcelluloses, cellulose ethers, cellulose esters, nitrocellulose, polymers of acrylic and methacrylic acid esters, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylates, cellulose ether ... Also included may be ethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl alcohol), poly(vinyl acetate), polyvinyl chloride polystyrene, and polyvinylpyrrolidone, derivatives thereof, linear and branched copolymers thereof, and block copolymers thereof, and blends thereof.Exemplary biodegradable polymers include polyesters, poly(orthoesters), poly(ethyleneamines), poly(caprolactones), poly(hydroxybutyrates), poly(hydroxyvalerates), polyanhydrides, poly(acrylic acids), polyglycolides, poly(urethanes), polycarbonates, polyphosphates, polyphosphiazenes, derivatives thereof, linear and branched copolymers thereof, and block copolymers, and blends thereof.

[0063] In some embodiments, the protective coating comprises carbohydrate polymers such as monosaccharides, and polysaccharides, including but not limited to disaccharides or non-reducing polysaccharides or disaccharides, and carbohydrate constructs of any combination thereof. Examples of carbohydrates that can be used in the protective coating include glucose, aldoses (D-allose, D-altrose, D-mannose, etc.), glucopyranose, pentahydroxyhexanal, α-D-glucopyranosyl-D-glucose, α-D-glucopyranosyl-dihydrate, polymers of β-D-glycopyranosyl units, β-D-fructofuranosyl, α-D-glucopyranoside (anhydrous / dihydrate), β-D-galactopyranosyl-D-glucose, α-D-glucopyranosyl-α-D-glucopyranoside (anhydrous), and the like. Examples of sugars include the sugars D-galactosyl-β-(l-4)-anhydro-L-galactosyl, cellulose, polymers of β-D-glycopyranosyl units, and starch, as well as the polyhydric alcohols, polyalcohols, alditol, erythritol, glycitol, glycerol, xylitol, and sorbitol.

[0064] In some embodiments, the protective coating comprises a biocompatible and / or biodegradable polyester or polyanhydride, such as poly(lactic acid), poly(glycolic acid), and poly(lactic-co-glycolic acid). The particles may contain one or more of the following: homopolymers comprising glycolic acid units, referred to herein as "PGA," and caprolactone units, such as poly-L-lactic acid, poly-D-lactic acid, poly-D,L-lactic acid, poly-L-lactide, poly-D-lactide, and poly-D,L-lactide, collectively referred to herein as "PLA," and poly(e-caprolactone), collectively referred to herein as "PCL; copolymers comprising lactic acid and glycolic acid units, characterized by the ratio of lactic acid to glycolic acid, such as poly(lactic acid-co-glycolic acid) and poly(lactide-co-glycolide), collectively referred to herein as "PLGA; and polyacrylates, and derivatives thereof. Exemplary polymers also include copolymers of polyethylene glycol (PEG) with the aforementioned polyesters, such as various forms of PLGA-PEG or PLA-PEG copolymers (collectively referred to herein as "PEGylated polymers"). In certain embodiments, the PEG region can be covalently attached to the polymer by a cleavable linker to yield a "PEGylated polymer." In one aspect, the polymer comprises at least 60, 65, 70, 75, 80, 85, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent of acetal pendant groups.

[0065] Triblock copolymers disclosed herein include, for example, core polymers such as polyethylene glycol (PEG), polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone (PVP), polyethylene oxide (PEO), poly(vinylpyrrolidone-co-vinyl acetate), polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-glycolic) acid, poly(lactic-co-glycolic) acid (PLGA), and cellulose derivatives such as hydroxymethylcellulose, hydroxypropylcellulose, and the like.

[0066] Examples of diblock copolymers that can be used in the protective coatings disclosed herein include polymers such as, for example, polyethylene glycol (PEG), polyvinyl acetate, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyethylene oxide (PEO), poly(vinylpyrrolidone-co-vinyl)acetate), polymethacrylate, polyoxyethylene)alkyl ether, polyoxyethylene)castor oil, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-glycolic) acid, poly(lactic-co-glycolic) acid (PLGA).

[0067] In one embodiment, the protective coating is i.e., encapsulated, and the encapsulation composition can further comprise lecithin or hydrolyzed lecithin as a carrier or encapsulating material. As used herein, lecithin and / or hydrolyzed lecithin coatings include coatings containing phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, and phosphatidic acid. The source of lecithin can be a plant or animal source.

[0068] In one embodiment, any of the polymers, monosaccharides, disaccharides, or polysaccharides used to form the protective coating formed by placing the MSC additive in the encapsulation solution can be at a suitable concentration to form the protective coating. For example, the polymer, monosaccharide, disaccharide, or polysaccharide can be at any concentration between 0.01 mM and 10.0 M, such as about 0.01 M to about 0.1 M, about 0.1 mM to about 1.0 M, about 1.0 M to about 10.0 M. Exemplary concentrations include 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.4, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, and 130. , 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 600, 700, 800, 900 mM, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, and 10 M.

[0069] The disclosed compositions derive their inflammation-modulating capabilities from the inclusion of two or more ribonucleic acid molecules, such as microRNAs (miRNAs), messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), y-RNAs, and / or pi-RNAs. Examples of RNAs that can be used in the disclosed compositions include, but are not limited to, hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-1 0b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-m iR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145- 5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa- mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-19 7-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-203a , hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222,hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-24-1, hsa-miR-24-2, hsa-miR-24-3p, hsa-miR-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-miR-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR -30b-5p、hsa-miR-30c-5p、hsa-mir-30d、hsa-miR-30d-5p、hsa-mir-30e、 hsa-miR-30e-5p、hsa-miR-31-3p、hsa-miR-31-5p、hsa-miR-320a、hsa-mi R-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, and hsa-miR-4 24-5p, hsa-miR-484, hsa-miR-486-1, hsa-miR-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, and hsa-m IR-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-miR-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, hsa-miR-99b-5p, HBII- 202、U26、U29、HBII-420、U30、U18A、U81、GSKIP、IFT88、PCDH11X、PCDH11Y、 KIAA0226L、PDE11A、PHACTR1、TEX14、DCUN1D2、SIM1、FILIP1、FAM107B、CHA DL、ZNF365、MNAT1、CYSTM1、GAS7、HOXB7、ASTN2、LGR5、ZFHX3、MCM7、GRIK1、 MAP2、LHFPL3、PTER、STAMBP、CCDC135、PAX9、RPL13、ABCA13、DAAM1、OPN1LW、OPN1MW2, CNOT6L, MTRNR2L10, SMC4, RPL4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2, NANS, LO C100129335-5, ZNF238, CADM2-7, SALL1-6, VWA5A, RF00019.441, RF00019.451, RF00019.621, RF 00019.646, RF00019.413, piR-33044, piR-33043, piR-31703, RNY4, LOC441666, SNHG1, RNU11, L OC80154, LOC727751, LOC388152, GOLGA2P2Y, GOLGA2P3Y, SNHG12, RNU12, ASMTL-AS1, LOC284454 U2:RF00004.39, U2:RF00004.22, U2:RF00004.35, U2:RF00004.71, U2:RF00004.66 U2:RF00004.91, U2:RF00004.89, U2:RF00004.67, U1:RF00003.5, U1:RF00003.109, U1:RF 00003.110, U1:RF00003.8, U1:RF00003.3, U1:RF00003.6, U1:RF00003.38, U1:RF00003.2 0. U1:RF00003.24, U1:RF00003.73, U1:RF00003.11, U1:RF00003.27, U1:RF00003.40, U1: RF00003.107, U1:RF00003.62, U1:RF00003.45, U1:RF00003.116, U1:RF00003.126, U1:RF 00003.81, U1:RF00003.100, U1:RF00003.57, U1:RF00003.95, U1:RF00003.31, U1:RF0000 3.61, U1:RF00003.25, U1:RF00003.90, U1:RF00003.46, U1:RF00003.123, U2:RF00004.42 , U2:RF00004.61, U2:RF00004.51, U1:RF00003.122, U1:RF00003.22, U1:RF00003.9, snoM BII-202:RF00324.2, let-7:RF00027.7, U2:RF00004.75, U1:RF00003.69, U2:RF00004.88,and / or U7:RF00066.146. In some embodiments, at least one of the two or more RNAs may comprise an antisense RNA. Examples of antisense RNA that can be used in the disclosed compositions include, but are not limited to, UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLCN51, ST6GALNAC51, A BCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, GAGE2D:copy21, ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and / or HNRNPU-AS1. Thus, in one embodiment, a composition comprising one or more secretomes and two or more RNAs, wherein the two or more RNAs are selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p,hsa-miR-106a-5p、hsa-miR-106b-5p、hsa-mir-10b、hsa-miR-10b-5p、hsa -mir-1246、hsa-miR-1246、hsa-miR-125a-5p、hsa-miR-125b-5p、hsa-miR -130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-miR-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-miR-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1, hsa-miR -16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, and hsa-miR-199a- 3p、hsa-miR-199a-5p、hsa-miR-199b-5p、hsa-miR-19a-3p、hsa-miR-19b- 3p、hsa-miR-20a-5p、hsa-miR-203a、hsa-miR-203a-3p、hsa-miR-214-3p、h sa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-miR-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-24-1, hsa-miR-24-2, hsa-miR-24-3p, hsa-miR-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-miR-27b, hsa-miR -27b-3p、hsa-miR-29a-3p、hsa-miR-29c-3p、hsa-miR-30a-5p、hsa-miR-3 0a-5p、hsa-miR-30b-5p、hsa-miR-30c-5p、hsa-mir-30d、hsa-miR-30d-5p、hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-3, 76a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir- 486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-87 Disclosed herein is a composition comprising at least one miRNA selected from the group consisting of hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR-99b-5p. Preferably, disclosed herein is a composition, wherein the two or more RNAs comprise at least one miRNA selected from the group consisting of miR-92a-3p, let-7i-5p, miR-16-5p, miR-93-5p, miR-21-5p, miR-214-3p, miR-29c-3p, miR-34a-5p, mir-203a-3p, miR-27b-3p, miR-140-3p, miR-24-3p, miR-222-3p, miR-25-3p, miR-10b-5p, miR-221-3p, miR-17-5p, miR-30a-5p, and miR-30d-5p.

[0070] Also provided is a composition comprising one or more secretomes and two or more RNAs, wherein the two or more RNAs are selected from the group consisting of HBII-202, U26, U29, HBII-420, U30, U18A, U81, GSKIP, IFT88, PCDH11X, PCDH11Y, KIAA0226L, PDE11A, PHACTR1, TEX14, DCUN1D2, SIM1, FILIP1, FAM107B, CHADL, ZNF365, MNAT1, CYSTM1, GAS7, HOXB7, AS Disclosed herein is a composition comprising at least one mRNA selected from the group consisting of TN2, LGR5, ZFHX3, MCM7, GRIK1, MAP2, LHFPL3, PTER, STAMBP, CCDC135, PAX9, RPL13, ABCA13, DAAM1, OPN1LW, OPN1MW2, CNOT6L, MTRNR2L10, SMC4, RPL4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2, and NANS.

[0071] In one embodiment, a composition comprising one or more secretomes and two or more RNAs, wherein the two or more RNAs are selected from the group consisting of UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, Disclosed herein is a composition comprising at least one antisense mRNA selected from the group consisting of NAA351, HS3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, and GAGE2D:copy21.

[0072] Also disclosed herein is a composition comprising one or more secretomes and two or more RNAs, wherein the two or more RNAs comprise at least one lncRNA selected from the group consisting of LOC100129335-5, ZNF238, CADM2-7, SALL1-6, or VWA5A.

[0073] In one embodiment, disclosed herein is any of the aforementioned compositions comprising one or more secretomes and two or more RNAs, wherein the two or more RNAs comprise at least one antisense lncRNA selected from the group consisting of ANKRD5-1, ZNF236-1, and ACP1.

[0074] Also disclosed herein is a composition comprising one or more secretomes and two or more RNAs, wherein the two or more RNAs comprise at least one y-RNA selected from the group consisting of RF00019.441, RF00019.451, RF00019.621, RF00019.646, and RF00019.413.

[0075] In one aspect, disclosed herein is a composition comprising one or more secretomes and two or more RNAs, wherein the two or more RNAs comprise at least one pi-RNA selected from the group consisting of piR-33044, piR-33043, and piR-31703.

[0076] The disclosed compositions can be delivered to target cells in a variety of ways. For example, the compositions can be delivered by electroporation, by lipofection, or by calcium phosphate precipitation. The delivery mechanism selected will depend, in part, on the type of cell being targeted and whether delivery is to be performed, for example, in vivo or in vitro.

[0077] As noted throughout, in addition to MSC-derived exosomes or extracellular vesicles, the disclosed RNA can be delivered in lipid nanoparticles or liposomes, such as cationic liposomes (e.g., DOTMA, DOPE, DC cholesterol) or anionic liposomes. Liposomes can further include proteins to facilitate targeting to specific cells, if desired. Administration of compositions containing compounds and cationic liposomes can be administered to blood introduced to target organs or aspirated into airways to target cells in the airways. For liposomes, see, for example, Brigham et al. Am. J. Resp. Cell. Mol. Biol. 1:95 100 (1989); Felgner et al. Proc. Natl. Acad. Sci USA 84:7413 7417 (1987); U.S. Patent No. 4,897,355. Additionally, compounds can be targeted to specific cell types, such as macrophages, or can be administered as a component of a microcapsule where the diffusion or delivery of the compound from the microcapsule is engineered for a particular rate or dosage.

[0078] In the above-described methods that include administration and absorption of exogenous DNA into the cells of a subject (i.e., gene transduction or transfection), the delivery of the composition to cells can be via various mechanisms.As an example, delivery can be liposome-mediated delivery, using commercial liposomes such as LIPOFECTIN, LIPOFECTAMINE (GIBCO-BRL, Inc., Gaithersburg, MD), SUPERFECT (Qiagen, Inc. Hilden, Germany), and TRANSFECTAM (Promega Biotec, Inc., Madison, WI), and liposomes developed according to the working standards of the art.In addition, the disclosed nucleic acid or vector can be delivered in vivo by means of electroporation, a technology available from Genetronics, Inc. (San Diego, CA), and SONOPORATION machine (ImaRx Pharmaceutical Corp., Tucson, AZ).

[0079] The materials may be in solution, in suspension (e.g., incorporated into microparticles, liposomes, or cells), and they may be targeted to specific cell types via antibodies, receptors, or receptor ligands. The following references are examples of the use of this technology to target specific proteins to tumor tissue (Senter, et al., Bioconjugate Chem., 2:447 451, (1991); Bagshawe, KD, Br. J. Cancer, 60:275 281, (1989); Bagshawe, et al., Br. J. Cancer, 58:700 703, (1988); Senter, et al., Bioconjugate Chem., 4:3 9, (1993); Battelli, et al., Cancer Immunol. Immunother., 35:421 425, (1992); Pietersz and McKenzie, Immunolog. Reviews, 129:57 80, (1992); and Roffler, et al., Biochem. Pharmacol, 42:2062). 2065, (1991)). These techniques can be used for a variety of other specific cell types. Vehicles such as "stealth" and other antibody-linked liposomes (including lipid-mediated drug targeting to colon cancer), receptor-mediated targeting of DNA via cell-specific ligands, lymphocyte-tropic tumor targeting, and highly specific therapeutic retroviral targeting of mouse glioma cells in vivo. The following references are examples of the use of this technique to target specific proteins to tumor tissue (Hughes et al., Cancer Research, 49:6214 6220, (1989); and Litzinger and Huang, Biochimica et Biophysica Acta, 1104:179 187, (1992)). In general, receptors are involved in pathways of endocytosis, either constitutive or ligand-induced. These receptors cluster into clathrin-coated pits, enter the cell via clathrin-coated vesicles, pass through acidified endosomes where the receptors are sorted and then recycled to the cell surface, stored intracellularly, or degraded in lysosomes.Internalization pathways perform various functions such as nutrient uptake, removal of activated proteins, clearance of macromolecules, opportunistic entry of viruses and toxins, dissociation and degradation of ligands, and regulation of receptor levels. Many receptors follow multiple intracellular pathways depending on cell type, receptor concentration, type of ligand, ligand valency, and ligand concentration. The molecular and cellular mechanisms of receptor-mediated endocytosis have been reviewed (Brown and Greene, DNA and Cell Biology 10:6, 399-409 (1991)).

[0080] The nucleic acid delivered to cells that is integrated into the host cell genome typically includes integration sequences.These sequences are often virus-associated sequences, especially when a virus-based system is used.These viral integration systems can also be integrated into the nucleic acid delivered using a non-nucleic acid-based delivery system such as liposome, so that the nucleic acid included in the delivery system can be integrated into the host genome.

[0081] Other common techniques for integration into the host genome include, for example, systems designed to promote homologous recombination with the host genome.These systems typically rely on sequences adjacent to the expressed nucleic acid that have sufficient homology with the target sequence in the host cell genome so that recombination between the vector nucleic acid and the target nucleic acid occurs and the delivered nucleic acid is integrated into the host genome.These systems and methods required to promote homologous recombination are known to those skilled in the art.

[0082] In one embodiment, the secretome compositions disclosed herein (including, but not limited to, compositions comprising liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles) may further comprise any known ingredients typically found in the wound healing field, such as oils, waxes or other standard fatty substances, or conventional gelling and / or thickening agents; emulsifiers; moisturizers; emollients; sunscreens; hydrophilic or lipophilic active agents such as ceramides; agents for combating free radicals; bactericides; sequestering agents; preservatives; basifying or acidifying agents; fragrances; surfactants; bulking agents; aloe or green tea extracts, natural products or extracts of natural products; vitamins; or coloring materials. Other ingredients that can be combined with the powder can include antioxidants, which can be selected from a variety of antioxidants. Suitable antioxidants include vitamins such as vitamin C (L-ascorbate, ascorbate-2 phosphate magnesium salt, ascorbyl palmitate, tetrahexyldecyl ascorbate), vitamin E (tocotrienol), vitamin A (retinol, retinal, retinoic acid, provitamin A carotenoids such as β-carotene), N-acetylglucosamine, or other derivatives of glucosamine. Other ingredients may include Ω-3, Ω-6, and Ω-9 polyunsaturated fatty acids, linoleic acid (LA) such as gamma-linoleic acid (GLA), alpha-linoleic acid (ALA), dihomo-y-linolenic acid (DGLA), arachidonic acid (ARA), and at least one other essential fatty acid. The fatty acids may be derived from a variety of sources, including evening primrose oil, blackcurrant oil, borage oil, or GLA modified safflower seed. Other components may include at least one component that supports ECM production and hyaluronic acid production, such as platelet-rich fibrin matrix, N-acetylglucosamine or other derivatives of glucosamine, ultra-low molecular weight (ULMW) hyaluronic acid, chondroitin sulfate, or keratin sulfate.

[0083] The RNA-loaded secretome can be made by any natural or synthetic process known in the art. For example, naturally occurring RNA synthesis and vesicle loading processes in cells are used to generate the RNA-loaded EVs. Alternatively, the RNA can be synthesized by de novo organic synthesis methods and loaded into artificial lipid nanoparticles. In another example, the RNA species in naturally derived EVs are combined with artificial lipid nanoparticles loaded with synthetic RNA species in various combination ratios from 1:1 to 1:10000, and the various combinations are delivered as individual vesicles. In another example, the RNA species in naturally derived EVs are combined with artificial lipid nanoparticles loaded with synthetic RNA species in various combination ratios from 1:1 to 1:10000, and the various combinations are fused 1:1 to generate combination chimeric natural / synthetic EV particles containing combinations of natural and synthetic RNA sequences. In some configurations, the synthetic RNA can be loaded into synthetic lipid nanoparticles along with cofactor proteins that enhance RNA sequence function. It is understood and contemplated herein that natural and synthetically generated secretomes can be used in the same composition. Thus, in one embodiment, different combinations of naturally and synthetically produced EVs are administered to a recipient at different times to enhance the effect on genes expressed either in different cell types or at different times during the progression of immune modulation resolution.

[0084] 1.Homology / Identity It is understood that one way of defining any known variant and derivative or possible variant of genes and proteins disclosed herein is by defining variant and derivative in terms of homology to a specific known sequence.Specifically disclosed are variants of these and other genes or proteins disclosed herein that have at least 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 percent homology to the sequence specified.Those skilled in the art will easily understand how to determine the homology of two proteins or nucleic acids, such as genes.For example, homology can be calculated after aligning two sequences so that homology is at its highest level.

[0085] Different methods of calculating homology can be performed by published algorithms. Optimal alignment of sequences for comparison can be performed by the local homology algorithm of Smith and Waterman (Adv. Appl. Math. 2:482 (1981)), by the homology sequence algorithm of Needleman and Wunsch (J. MoL Biol. 48:443 (1970)), by the search method for similarity of Pearson and Lipman (Proc. Natl. Acad. Sci. USA 85:2444 (1988)), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by inspection.

[0086] The same type of homology can be obtained for nucleic acids by algorithms disclosed, for example, in Zuker, M. Science 244:48-52, 1989, Jaeger et al. Proc. Natl. Acad. Sci. USA 86:7706-7710, 1989, Jaeger et al. Methods Enzymol 183:281-306, 1989, which are incorporated by reference herein at least for material related to nucleic acid alignment.

[0087] 2. Hybridization / Selective Hybridization The term hybridization typically refers to sequence-driven interaction between at least two nucleic acid molecules, such as primers or probes, and genes. Sequence-driven interaction refers to the interaction that occurs between two nucleotides or nucleotide analogs or nucleotide derivatives in a nucleotide-specific manner. For example, G interacting with C or A interacting with T is a sequence-driven interaction. Typically, sequence-driven interaction occurs on the Watson-Crick or Hoogsteen face of nucleotides. Hybridization of two nucleic acids is influenced by many conditions and parameters known to those skilled in the art. For example, the salt concentration, pH, and temperature of the reaction all affect whether two nucleic acid molecules hybridize.

[0088] Parameters for selective hybridization between two nucleic acid molecules are well known to those of skill in the art. For example, in some embodiments, selective hybridization conditions can be defined as stringent hybridization conditions. For example, the stringency of hybridization is controlled by both temperature and salt concentration of either or both of the hybridization and washing steps. For example, hybridization conditions to achieve selective hybridization may include hybridization in a high ionic strength solution (6xSSC or 6xSSPE) at a temperature about 12-25°C below the Tm (the melting temperature at which half of the molecules dissociate from their hybridization partner), followed by washing at a combination of temperature and salt concentration selected such that the washing temperature is about 5°C-20°C below the Tm. Temperature and salt conditions are easily determined empirically in preliminary experiments in which samples of reference DNA immobilized on filters are hybridized to labeled nucleic acids of interest and then washed under conditions of different stringency. Hybridization temperature is typically higher for DNA-RNA and RNA-RNA hybridization. Conditions can be used as described above or known in the art to achieve stringency. A preferred stringent hybridization condition for DNA:DNA hybridization can be about 68°C (in aqueous solution) in 6xSSC or 6xSSPE, followed by washing at 68°C. Hybridization and washing stringency can be decreased accordingly, if desired, as the desired degree of complementarity is decreased, and further depending on the GC or AT richness of any region where variability is sought. Similarly, hybridization and washing stringency can be increased accordingly, if desired, as the desired homology is increased, and further depending on the GC or AT richness of any region where high homology is desired, all as known in the art.

[0089] Another way to define selective hybridization is by looking at the amount (percentage) of one nucleic acid bound to the other nucleic acid. For example, in some embodiments, selective hybridization conditions are when at least about 60, 65, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 percent of the limiting nucleic acid is bound to the non-limiting nucleic acid. Typically, the non-limiting primer is in excess, for example, 10 or 100 or 1000 times. This type of assay is used to determine whether both the limiting primer and the non-limiting primer are in excess, for example, their k d or under conditions where only one of the nucleic acid molecules is 10-fold, 100-fold, or 1000-fold lower than their k d The reaction can be carried out under conditions exceeding 100° C.

[0090] Another way to define selective hybridization is by looking at the percentage of primers that are enzymatically manipulated under conditions where hybridization is required to promote the desired enzymatic manipulation. For example, in some embodiments, selective hybridization conditions are those where at least about 60, 65, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 percent of the primers are enzymatically manipulated under conditions that promote enzymatic manipulation. For example, where the enzymatic manipulation is DNA extension, selective hybridization conditions are those where at least about 60, 65, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 percent of the primer molecules are extended. Preferred conditions also include those suggested by the manufacturer or those suggested in the art as appropriate for the enzyme performing the manipulation.

[0091] It is understood that, like homology, various methods are disclosed herein for determining the level of hybridization between two nucleic acid molecules.These methods and conditions can provide different percentages of hybridization between two nucleic acid molecules, but it is understood that meeting the parameters of any of the methods is sufficient unless otherwise indicated.For example, if 80% hybridization is required, as long as hybridization occurs within the parameters required in any one of these methods, it will be considered as disclosed herein.

[0092] It is understood that one of skill in the art will understand that if a composition or method, either collectively or alone, meets any one of these criteria for determining hybridization, it is a composition or method disclosed herein.

[0093] 3. Nucleic acid Nucleic acid-based various molecules are disclosed herein. Disclosed nucleic acids are composed of, for example, nucleotides, nucleotide analogs, or nucleotide substitutes. Non-limiting examples of these and other molecules are discussed herein. For example, when a vector is expressed in a cell, it is understood that the mRNA expressed is typically made of A, C, G, U. Similarly, for example, when an antisense molecule is introduced into a cell or cellular environment, for example, by exogenous introduction, it is advantageous for the antisense molecule to be composed of nucleotide analogs that prevent the antisense molecule from being degraded in the cellular environment.

[0094] a) Nucleotides and related molecules A nucleotide is a molecule that contains a base moiety, a sugar moiety, and a phosphate moiety. Nucleotides can be linked together through their phosphate and sugar moieties to create an internucleoside linkage. The base moiety of a nucleotide can be adenine-9-yl (A), cytosine-1-yl (C), guanine-9-yl (G), uracil-1-yl (U), and thymine-1-yl (T). The sugar moiety of a nucleotide is ribose or deoxyribose. The phosphate moiety of a nucleotide is pentavalent phosphate. Non-limiting examples of nucleotides are 3'-AMP (3'-adenosine monophosphate) or 5'-GMP (5'-guanosine monophosphate). There are many varieties of these types of molecules available in the art and available herein.

[0095] Nucleotide analogues are nucleotides that contain any type of modification to either the base, sugar, or phosphate moiety.Modifications to nucleotides are well known in the art and include, for example, 5-methylcytosine (5-me-C), 5-hydroxymethylcytosine, xanthine, hypoxanthine, and 2-aminoadenine, as well as modifications in the sugar or phosphate moiety.There are many types of these types of molecules that are available in the art and can be used herein.

[0096] Nucleotide substitutes are molecules that have similar functional properties as nucleotides, but do not include a phosphate moiety, such as peptide nucleic acid (PNA). Nucleotide substitutes are molecules that recognize nucleic acids in a Watson-Crick or Hoogsteen manner, but are linked together via moieties other than the phosphate moiety. Nucleotide substitutes can adopt a double helix type structure when interacting with the appropriate target nucleic acid. There are many varieties of these types of molecules available in the art and available herein.

[0097] For example, other types of molecules can be linked (conjugates) to nucleotides or nucleotide analogs to enhance cellular uptake. Conjugates can be chemically linked to nucleotides or nucleotide analogs. Such conjugates include, but are not limited to, lipid moieties, such as cholesterol moieties. (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553 6556). There are many types of these types of molecules available in the art and available herein.

[0098] A Watson-Crick interaction is at least one interaction on the Watson-Crick face of a nucleotide, nucleotide analog, or nucleotide substitute. The Watson-Crick face of a nucleotide, nucleotide analog, or nucleotide substitute includes the C2, N1, and C6 positions of a purine-based nucleotide, nucleotide analog, or nucleotide substitute, and the C2, N3, and C4 positions of a pyrimidine-based nucleotide, nucleotide analog, or nucleotide substitute.

[0099] A Hoogsteen interaction is an interaction that occurs on the Hoogsteen face of a nucleotide or nucleotide analogue that is exposed in the major groove of duplex DNA. The Hoogsteen face includes the reactive groups (NH2 or O) at the N7 and C6 positions of purine nucleotides.

[0100] In some embodiments, the RNA can be modified to reduce degradation. For example, the RNA can include the addition of 2'-O-methyl, 2'-fluoro, or 2'-hydroxy groups.

[0101] b) Array The sequences of the human analogs of the RNA molecules disclosed herein, as well as other analogs, and the alleles of these genes, as well as splice variants and other types of variants, are available in various protein and gene databases, including Genbank.Those skilled in the art will understand how to resolve sequence differences and differences, and how to adjust the compositions and methods related to a particular sequence to other related sequences.Primers and / or probes can be designed for any given sequence, given the information disclosed herein and known in the art.

[0102] c) Functional nucleic acid Functional nucleic acid is a nucleic acid molecule that has a specific function, such as binding a target molecule or catalyzing a specific reaction. Functional nucleic acid molecules can be divided into the following categories, which are not meant to be limiting. For example, functional nucleic acids include antisense molecules, aptamers, ribozymes, triplex-forming molecules, and external guide sequences. Functional nucleic acid molecules can act as effectors, inhibitors, modulators, and stimulators of specific activities possessed by target molecules, or functional nucleic acid molecules can possess de novo activities independent of any other molecules. Functional nucleic acid molecules can interact with any macromolecule, such as DNA, RNA, polypeptides, or carbohydrate chains. Thus, the functional nucleic acids include hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-107a-5p, hsa-miR-109a-5p, hsa-miR-110b-5p, hsa-miR-111c-5p, hsa-miR-112a-5p, hsa-miR-113a-5p, hsa-miR-114a-5p, hsa-miR-115a-5p, hsa-miR-116a-5p, hsa-miR-117a-5p, hsa-miR-118a-5p, hsa-miR-119a-5p, hsa-miR-120b-5p, hsa-miR-121b-5p, hsa-miR-122a-5p, hsa-miR-123a-5p, hsa-miR-124a-5p, hsa-miR-125a-5p, hsa-miR-126a-5p, hsa-miR-127a-5p, hsa-miR-128a-5p, hsa-miR-129a-5p, hsa-miR-130a-5p, hsa-miR-131a-5p, hsa-miR-132a-5p, hsa-miR-133a-5p, hsa-miR-134a-5p, a-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa -miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5 p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a , hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir- 16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-1 93a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p,hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-miR-21, hsa-miR-21-3p, hsa-miR-21- 5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-24-1, hsa-miR-24-2, hsa-miR-24-3p, hsa-miR-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-miR-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, and hsa-miR-29c 3p、hsa-miR-30a-5p、hsa-miR-30a-5p、hsa-miR-30b-5p、hsa-miR-30c-5p 、hsa-mir-30d、hsa-miR-30d-5p、hsa-mir-30e、hsa-miR-30e-5p、hsa-miR- 31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, and hsa-miR-376c-3p hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-miR-486-1, hsa-miR-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-miR-92a-1, hsa-miR-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-miR-93, hsa-miR-93-5p, and hsa-miR-9 40、hsa-miR-99a-5p、hsa-miR-99b-5p、HBII-202、U26、U29、HBII-420、U30 、U18A、U81、GSKIP、IFT88、PCDH11X、PCDH11Y、KIAA0226L、PDE11A、PHACTR1、TEX14、DCUN1D2、SIM1、FILIP1、FAM107B、CHADL、ZNF365、MNAT1、CYSTM1、GAS7、HOXB7、ASTN2、LGR5、ZFHX3、MCM7、GRIK1、MAP2、LHFPL3、PTER、STAM BP、CCDC135、PAX9、RPL13、ABCA13、DAAM1、OPN1LW、OPN1MW2、CNOT6L、MTRNR2L10、SMC4、RPL4、PSAP、ASIC4、AHCYL1、RD3L、SIGLEC1、SYCE2、NANS、L OC100129335-5、ZNF238、CADM2-7、SALL1-6、VWA5A、RF00019.441、RF00019.451、RF00019.621、RF00019.646、RF00019.413、piR-33044、piR-330 43、piR-31703、RNY4、LOC441666、SNHG1、RNU11、LOC80154、LOC727751、LOC388152、GOLGA2P2Y、GOLGA2P3Y、SNHG12、RNU12、ASMTL-AS1、LOC284454 U2:RF00004.39、U2:RF00004.22、U2:RF00004.35、U2:RF00004.71、U2:RF00004.66 U2:RF00004.91、U2:RF00004.89、U2:RF00004.67、U1:RF00003.5、U1:RF00003.109、U1:RF00003.110、U1:RF00003.8、U1:RF00003. 3、U1:RF00003.6、U1:RF00003.38、U1:RF00003.20、U1:RF00003.24、U1:RF00003.73、U1:RF00003.11、U1:RF00003.27、U1:RF00003 .40、U1:RF00003.107、U1:RF00003.62、U1:RF00003.45、U1:RF00003.116、U1:RF00003.126、U1:RF00003.81、U1:RF00003.100、U1:RF00003.100 RF00003.57、U1:RF00003.95、U1:RF00003.31、U1:RF00003.61、U1:RF00003.25、U1:RF00003.90、U1:RF00003.46、U1:RF00003.123、U2:RF00004.42, U2:RF00004.61, U2:RF00004.51, U1:RF00003.122, U1:RF00003.22, U1:RF00003.9, snoMBII-202:RF00324.2, let-7: RF00027.7, U2:RF00004.75, U1:RF00003.69, U2:RF00004.88, U12:RF00007.1, U7:RF00066.141, U1:RF00003.85, U7:RF00066.49, U2: RF00004.77, U1:RF00003.113, U1:RF00003.112, U1:RF00003.70, U1:RF00003.83, U7:RF00066.89, U7:RF00066.124, U7:RF00066.75, U7:RF00066.77, U7:RF00066.118, U7:RF00066.103, U7:RF00066.79, U7:RF00066.200, U7:RF00066.146, UBAP11, SMC51, TMX11, LTA4H 1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11 , ZNF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21 , WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, GAGE2D:copy21, ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and / or HNRNPU-AS1. In many cases, functional nucleic acids are designed to interact with other nucleic acids based on sequence homology between the target molecule and the functional nucleic acid molecule. In other situations, specific recognition between a functional nucleic acid molecule and a target molecule is achieved by:Functionality is not based on sequence homology between a nucleic acid molecule and a target molecule, but rather on the formation of a tertiary structure that allows specific recognition to occur.

[0103] Antisense molecules (e.g., UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL 11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, GAGE2D:copy21, ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and HNRNPU-AS1) are designed to interact with the target nucleic acid molecule through either canonical or non-canonical base pairing. The interaction of the antisense molecule with the target molecule is designed to promote the destruction of the target molecule, for example, through RNAse H-mediated RNA-DNA hybrid degradation. Alternatively, the antisense molecule is designed to inhibit a processing function that would normally occur in the target molecule, such as transcription or replication. Antisense molecules can be designed based on the sequence of the target molecule. There are many ways to optimize antisense efficiency by finding the most accessible regions of the target molecule. For example, in vitro selection experiments and DNA modification studies with DMS and DEPC are included. Antisense molecules can be designed based on the sequence of the target molecule. -6 , 10 -8 , 10 -10 , 10 -12 The following dissociation constant (k d) to bind to the target molecule. A representative sample of methods and techniques useful in the design and use of antisense molecules is set forth in the following non-limiting list of U.S. Patents: 5,135,917; 5,294,533; 5,627,158; 5,641,754; 5,691,317; 5,780,607; 5,786,138; 5,849,903; 5,856,103; 5,919,772; 5,955, 590, 5,990,088, 5,994,320, 5,998,602, 6,005,095, 6,007,995, 6,013,522, 6,017,898, 6,018,042, 6,025,198, 6,033,910, 6,040,296, 6,046,004, 6,046,319, and 6,057,437.

[0104] 4. Pharmaceutical Carriers / Drug Delivery As mentioned above, the composition can also be administered in vivo in a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means that the material is not biologically or otherwise undesirable, that is, the material can be administered to a subject together with the nucleic acid or vector without causing any undesirable biological effects or interacting in a harmful manner with any of the other components of the pharmaceutical composition in which it is contained. It is well known to those skilled in the art that the carrier will naturally be selected to minimize the degradation of the active ingredient and to minimize side effects in the subject.

[0105] The composition can be administered orally, parenterally (e.g., intravenously), by intramuscular injection, intraperitoneal injection, transdermally, extracorporeally, locally intranasally, or locally, including by inhalation. As used herein, "local intranasal administration" means delivery of the composition to the nose and nasal cavity through one or both of the noses, and may include delivery by spray or droplet mechanism, or delivery by aerosolization of the nucleic acid or vector. Administration of the composition by inhalation can be done through the nose or mouth via delivery by spray or droplet mechanism. It can also be administered directly to any site of the respiratory system (such as the lungs) by tracheal intubation. The exact amount of the composition required will vary from subject to subject, depending on the species, age, weight, and general condition of the subject, the severity of the allergic disease being treated, the particular nucleic acid or vector used, its mode of administration, and the like. Thus, it is not possible to specify an exact amount for every composition. However, the appropriate amount can be determined by one of ordinary skill in the art with only routine experimentation, given the teachings herein.

[0106] Parenteral administration of compositions, when used, is generally characterized by injection.Injections can be prepared in conventional forms, either as liquid solutions or suspensions (solid forms suitable for solution prior to injection or suspension in liquid as emulsions).More recently revised approaches for parenteral administration include the use of delayed release or sustained release systems, so that a constant dosage is maintained.See, for example, U.S. Patent No. 3,610,795, which is incorporated herein by reference.

[0107] The materials can be in solution, in suspension (e.g., incorporated into microparticles, liposomes, cells), and they can be targeted to specific cell types via antibodies, receptors, or receptor ligands. The following references are examples of the use of this technology to target specific proteins to tumor tissue (Senter, et al., Bioconjugate Chem., 2:447-451, (1991); Bagshawe, KD, Br. J. Cancer, 60:275-281, (1989); Bagshawe, et al., Br. J. Cancer, 58:700-703, (1988); Senter, et al., Bioconjugate Chem., 4:3-9, (1993); Battelli, et al., Cancer Immunol. Immunother., 35:421-425, (1992); Pietersz and McKenzie, Immunolog. Reviews, 129:57-80, (1992); and Roffler, et al. al., Biochem.Pharmacol,42:2062-2065,(1991)). Vehicles such as "stealth" and other antibody-linked liposomes (including lipid-mediated drug targeting to colon cancer), receptor-mediated targeting of DNA via cell-specific ligands, lymphocyte-tropic tumor targeting, and highly specific therapeutic retroviral targeting of mouse glioma cells in vivo. The following references are examples of the use of this technology to target specific proteins to tumor tissue (Hughes et al., Cancer Research,49:6214-6220,(1989); and Litzinger and Huang, Biochimica et Biophysica Acta,1104:179-187,(1992)). In general, receptors are involved in pathways of endocytosis, either constitutive or ligand-induced. These receptors cluster into clathrin-coated pits, enter the cell via clathrin-coated vesicles, pass through acidified endosomes where the receptors are sorted and then recycled to the cell surface, stored intracellularly, or degraded in lysosomes.Internalization pathways perform various functions such as nutrient uptake, removal of activated proteins, clearance of macromolecules, opportunistic entry of viruses and toxins, dissociation and degradation of ligands, and regulation of receptor levels. Many receptors follow multiple intracellular pathways depending on cell type, receptor concentration, type of ligand, ligand valency, and ligand concentration. The molecular and cellular mechanisms of receptor-mediated endocytosis have been reviewed (Brown and Greene, DNA and Cell Biology 10:6, 399-409(1991)).

[0108] a) Pharmaceutically acceptable carrier The compositions comprising the antibodies can be used therapeutically in combination with a pharma- ceutically acceptable carrier.

[0109] Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. AR Gennaro, Mack Publishing Company, Easton, PA 1995. Typically, an appropriate amount of pharma- ceutically acceptable salt is used in the formulation to make the formulation isotonic. Examples of pharma- ceutically acceptable carriers include, but are not limited to, saline, Ringer's solution, and dextrose solution. The pH of the solution is preferably about 5 to about 8, and more preferably about 7 to about 7.5. Further carriers include sustained release preparations, such as semipermeable matrices of solid hydrophobic polymers containing an antibody, the matrices being in the form of shaped articles, such as films, liposomes, or microparticles. It will be apparent to one skilled in the art that certain carriers may be more preferable depending, for example, on the route of administration and the concentration of the composition to be administered.

[0110] Pharmaceutical carriers are known to those skilled in the art. These are most typically standard carriers for administering drugs to humans, including solutions such as sterile water, physiological saline, buffered solutions at physiological pH, etc. The composition can be administered intramuscularly or subcutaneously. Other compounds will be administered according to standard procedures used by those skilled in the art.

[0111] Pharmaceutical compositions may include, in addition to the molecule of choice, carriers, thickeners, diluents, buffers, preservatives, surfactants, etc. Pharmaceutical compositions may also include one or more active ingredients, such as antibacterial agents, anti-inflammatory agents, anesthetic agents, etc.

[0112] The pharmaceutical compositions can be administered in a number of ways, depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be topical (including ophthalmic, vaginal, rectal, nasal), oral, inhalation, or parenteral, such as, for example, drip infusion, subcutaneous injection, intraperitoneal injection, intramuscular injection, etc. The disclosed antibodies can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.

[0113] Formulations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose). Preservatives and other additives may also be present, such as antibacterial agents, antioxidants, chelating agents, and inert gases and the like.

[0114] Pharmaceutical compositions and formulations for topical administration may include transdermal, ointment, lotion, cream, gel, drop, suppository, spray, liquid, and powder. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners, and the like may be necessary or desirable.

[0115] Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets.Thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders may be desirable.

[0116] Some of the compositions may potentially be administered as pharma- ceutically acceptable acid or base addition salts formed by reaction with inorganic acids such as hydrochloric, hydrobromic, perchloric, nitric, thiocyanic, sulfuric, and phosphoric acid, and organic acids such as formic, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, and fumaric acid, or inorganic bases such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, trialkyl, arylamines, substituted ethanolamines, and the like.

[0117] b) Therapeutic use Effective doses and schedules for administering the compositions can be determined empirically, and making such determinations is within the skill of one of ordinary skill in the art. The dose range for administration of the compositions is large enough to produce the desired effect in which the symptoms of the disorder are affected. The dose should not be so large as to cause side effects, such as undesirable cross-reactions or anaphylactic reactions. In general, the dose will vary depending on the age, condition, sex, and extent of the disease of the patient, the route of administration, or whether other drugs are included in the regimen, and can be determined by one of ordinary skill in the art. The dose can be adjusted by the individual physician if there are contraindications. The dose may vary and can be administered once or in multiple divided doses daily for one or several days. Guidance is available in the literature as to appropriate doses for particular classes of pharmaceuticals. For example, guidance in selecting an appropriate dosage of an antibody can be found in the literature on the therapeutic use of antibodies, including, for example, Handbook of Monoclonal Antibodies, Ferrone et al., eds., Noges Publications, Park Ridge, NJ, (1985) ch. 22 and pp. 303-357; Smith et al., Antibodies in Human Diagnosis and Therapy, Haber et al., eds., Raven Press, New York (1977) pp. 365-389. A typical daily dose of an antibody used alone can range from about 1 μg / kg up to 100 mg / kg or more of body weight per day, depending on the factors mentioned above.

[0118] Methods for Regulating Inflammation The disclosed RNAs can target genes involved in immune regulation. For example, miR-92a-3p targets HAS2, NOX4, and / or ADAMTS-4; let-7i-5p targets HAS2, TLR4, NOX2, MMP1, and / or COX2; miR-16-5p targets HAS2, NOS1, and / or COX2; miR-93-5p targets HAS2, NOX2, and / or ADAMTS-4; miR miR-21-5p targets IL-1B, IL6, STAT3, PTEN, TNF, IRAK1, and / or CCL20; miR-214-3p targets CASP1; miR-29c-3p and miR-34a-5p target BDKRB2; mir-203a-3p targets MMP-13, NOX2, and / or ADAMTS-4; miR-27b-3p targets MMP-1 miR-140-3p targets MMP-13, ADAMTS-4, and / or BCL2; miR-24-3p targets MMP-13, ADAMTS-4, and / or IL1B, miR-222-3p targets MMP-13 and / or MMP1; miR-25-3p targets MMP-13, NOX4, and / or IL1B. miR-10b-5p targets NOX2 / ADAMTS-4; miR-221-3p targets MMP1 and / or IL1B; miR-17-5p targets the Jak-stat pathway, PTEN, TNF, CXCL8; miR-30a-5p targets the inhibition of ESCC; and miR-30d-5p is a tumor suppressor in lung tumors.

[0119] Accordingly, also disclosed herein is a method of modulating an immune response to an inflammatory insult in a subject (including, but not limited to, increasing or decreasing inflammation), comprising administering to the subject any of the compositions disclosed herein, including, but not limited to, one or more secretome (including, but not limited to, compositions consisting of liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles) and a secretome-specific agonist (hereinafter referred to as hsa-let-7a-5p, hsa-let-7b- 5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-10 6a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hs a-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-14 5-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa- miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR -199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21,hsa-miR-21-3p, hsa-miR-21-5p, hsa-miR-221, hsa-miR-221-3p, hsa-miR-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-24-1, hsa-miR-24-2, hsa-miR-24-3p, hsa-miR-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-miR-27b, hsa-miR-27b-3p sa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-miR-30d, hsa-miR-30d-5p, hsa-miR-3 0e、hsa-miR-30e-5p、hsa-miR-31-3p、hsa-miR-31-5p、hsa-miR-320a、hsa -miR-342-3p、hsa-miR-345-5p、hsa-miR-34a-5p、hsa-miR-361-5p、hsa-mi R-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-miR-486-1, hsa-miR-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-miR-92a-1, hsa-miR-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-miR- 93、hsa-miR-93-5p、hsa-miR-940、hsa-miR-99a-5p、hsa-miR-99b-5p、HBI I-202、U26、U29、HBII-420、U30、U18A、U81、GSKIP、IFT88、PCDH11X、PCDH11Y 、KIAA0226L、PDE11A、PHACTR1、TEX14、DCUN1D2、SIM1、FILIP1、FAM107B、CH ADL、ZNF365、MNAT1、CYSTM1、GAS7、HOXB7、ASTN2、LGR5、ZFHX3、MCM7、GRIK1、MAP2, LHFPL3, PTER, STAMBP, CCDC135, PAX9, RPL13, ABCA13, DAAM1, OPN1LW, OPN1MW2, CNOT6L, MTRNR2L10, SMC4, RP L4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2, NANS, LOC100129335-5, ZNF238, CADM2-7, SALL1-6, VWA5A, RF00019 .441, RF00019.451, RF00019.621, RF00019.646, RF00019.413, piR-33044, piR-33043, piR-31703, RNY4, LOC4416 66. SNHG1, RNU11, LOC80154, LOC727751, LOC388152, GOLGA2P2Y, GOLGA2P3Y, SNHG12, RNU12, ASMTL-AS1, LOC284454 U2:RF00004.39, U2:RF00004.22, U2:RF00004.35, U2:RF00004.71, U2:RF00004.66 U2:RF00004.91, U2:RF00004.89, U2:RF00004.67, U1:RF00003.5, U1:RF00003.1 09. U1:RF00003.110, U1:RF00003.8, U1:RF00003.3, U1:RF00003.6, U1:RF00003. 38. U1:RF00003.20, U1:RF00003.24, U1:RF00003.73, U1:RF00003.11, U1:RF0000 3.27, U1:RF00003.40, U1:RF00003.107, U1:RF00003.62, U1:RF00003.45, U1:RF0 0003.116, U1:RF00003.126, U1:RF00003.81, U1:RF00003.100, U1:RF00003.57, U 1:RF00003.95, U1:RF00003.31, U1:RF00003.61, U1:RF00003.25, U1:RF00003.90 , U1:RF00003.46, U1:RF00003.123, U2:RF00004.42, U2:RF00004.61, U2:RF00004 .51、U1:RF00003.122、U1:RF00003.22、U1:RF00003.9、snoMBII-202:RF00324.2、let-7:RF00027.7, U2:RF00004.75, U1:RF00003.69, U2:RF00004.88, U12:RF00007.1, U7:RF00066.141, U1:RF00003. 85, U7:RF00066.49, U2:RF00004.77, U1:RF00003.113, U1:RF00003.112, U1:RF00003.70, U1:RF00003.83, U7:RF0006 6.89, U7:RF00066.124, U7:RF00066.75, U7:RF00066.77, U7:RF00066.118, U7:RF00066.103, U7:RF00066.79, U7:RF00066.200, and / or U7:RF00066.146, UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX 31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, HS3ST 41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141 and two or more RNA molecules comprising TMEM132E1, GAGE131, GAGE2D1, GAGE2D:copy21, ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and / or HNRNPU-AS1.

[0120] For example, provided herein are methods of modulating an immune response, where the modulation increases inflammation, and where two or more RNAs of the composition are selected from the group consisting of HBII-202, U26, U29, HBII-420, U30, U18A, U81, GSKIP, IFT88, PCDH11X, PCDH11Y, KIAA0226L, PDE11A, PHACTR1, TEX14, DCUN1D2, SIM1, FILIP1, FAM107B, CHADL, ZNF365, MNAT1, CYSTM1, GAS7, HO The method includes detecting at least one mRNA selected from the group consisting of XB7, ASTN2, LGR5, ZFHX3, MCM7, GRIK1, MAP2, LHFPL3, PTER, STAMBP, CCDC135, PAX9, RPL13, ABCA13, DAAM1, OPN1LW, OPN1MW2, CNOT6L, MTRNR2L10, SMC4, RPL4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2, and NANS. Also provided herein, for example, is a method of modulating an immune response, wherein the modulation reduces inflammation, and wherein two or more RNAs of the composition are selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR ... -125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hs a-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hs a-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p , hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2,hsa-miR-16-5p、hsa-miR-17-5p、hsa-miR-181a-5p、hsa-miR-191-5p、hsa -miR-193a-5p、hsa-miR-193b-3p、hsa-miR-197-3p、hsa-miR-199a-3p、hs a-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-miR-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-miR-221, hsa-miR-221-3p, hsa-miR-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, and hsa-miR -23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-miR-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hs a-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-mi R-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-miR-92a-1, hsa-miR-92a-2, hsa-miR-92a-3p, and hsa-miR-92b-3pA method is disclosed, comprising administering to the subject a therapeutically effective amount of at least one miRNA selected from the group consisting of hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR-99b-5p.

[0121] D. Methods of Treating Autoimmune Disease As mentioned above, the secretome and RNA compositions disclosed herein can regulate inflammation associated with diseases, including autoimmune diseases, and inhibit the destruction caused by inflammation. Thus, the disclosed compositions can be used to treat autoimmune diseases or their inflammatory symptoms. As used herein, "autoimmune disease" refers to a set of diseases, disorders, or illnesses that result from an adaptive immune response (T cell and / or B cell response) against the host organism. In such conditions, either due to mutation or other underlying causes, host T cells and / or B cells and / or antibodies can no longer distinguish host cells from non-self antigens and attack host cells bearing the antigens for which they are specific. Examples of autoimmune diseases include graft-versus-host disease, graft rejection, achalasia, acute disseminated encephalomyelitis, acute motor axonal neuropathy, Addison's disease, adipose tissue dolorosa, adult Still's disease, agammaglobulinemia, alopecia eriata, Alzheimer's disease, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, aplastic anemia, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune arthritis, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Baro's disease, Beich's disease, and Whett's disease, benign mucosal disease Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS), eosinophilic granulomatosis (EGPA), cerebrospinal fluid pemphigus, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis, dermatomyositis, Devic's disease (neuromyelitis optica), type 1 diabetes, discoid lupus erythematosus, Dressler's syndrome, endometriosis, enthesitis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, Felty's syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome,Granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid (PG), hidradenitis suppurativa (HS), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosis, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), inflammatory bowel disease (IBD), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis ( JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoplastic vasculitis, lichen planus, lichen planus, scleroderma, malignant conjunctivitis, linear immunoglobulin A disease (LAD), lupus nephritis, lupus vasculitis, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, acute pityriasis lichenoides, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia ophthalmos, pituitary gland, optic neuritis, ordothyroiditis, palindromic rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Perley-Romberg syndrome, planoplegia (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, acquired encephalomyelitis, Parneas anemia (PA), POEMS syndrome, polyarteritis nodosa, types I, II, and III polyglandular syndrome, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome group, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, athoracic leg syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, rheumatoid vasculitis, sarcoidosis, Schmidt's syndrome, Schnitzler's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm & testicular autoimmunity, Stiff-Pahn syndrome (SPS), Susac's syndrome, Sydenham's chorea, sympathetic ophthalmia (SO), systemic lupus erythematosus, systemic scleroderma, Takayasu's arteritis, cerebral arteritis / giant cell arteritis, thrombocytopenic purpura (TTP),These include, but are not limited to, Troza-Hunt syndrome (THS), transverse osteomyelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), urticaria, urticaria vasculitis, uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada syndrome, and Wegener's granulomatosis (or granulomatosis with polyangiitis). In one embodiment, one or more secretome (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition), and hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR -100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1 246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-13 6-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p , hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa -miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-203a, hsa-miR-203a-3p,hsa-miR-214-3p, hsa-miR-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-miR-221, hsa-miR-221-3p, hsa-miR-222, hsa-miR-222-3p, hsa-miR-22-3p, hs a-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-24-1, hsa-miR-24-2, hsa-miR-24-3p, hsa-miR-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-miR-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-miR-3 0d、hsa-miR-30d-5p、hsa-mir-30e、hsa-miR-30e-5p、hsa-miR-31-3p、hsa -miR-31-5p、hsa-miR-320a、hsa-miR-342-3p、hsa-miR-345-5p、hsa-miR-3 4a-5p、hsa-miR-361-5p、hsa-miR-376a-3p、hsa-miR-376c-3p、hsa-miR-4 23-3p、hsa-miR-423-5p、hsa-miR-424-5p、hsa-miR-484、hsa-mir-486-1、 hsa-mir-486-2、hsa-miR-486-5p、hsa-miR-570-3p、hsa-miR-574-3p、hsa -miR-663a、hsa-miR-874-3p、hsa-mir-92a-1、hsa-mir-92a-2、hsa-miR-92 a-3p、hsa-miR-92b-3p、hsa-mir-93、hsa-miR-93-5p、hsa-miR-940、hsa-m iR-99a-5p、hsa-miR-99b-5p、HBII-202、U26、U29、HBII-420、U30、U18A、U81 、GSKIP、IFT88、PCDH11X、PCDH11Y、KIAA0226L、PDE11A、PHACTR1、TEX14、DC UN1D2、SIM1、FILIP1、FAM107B、CHADL、ZNF365、MNAT1、CYSTM1、GAS7、HOXB7、ASTN2, LGR5, ZFHX3, MCM7, GRIK1, MAP2, LHFPL3, PTER, STAMBP, CCDC135, PAX9, RPL13, ABCA13, DAAM1, OPN1LW, OPN1MW2, CNO T6L, MTRNR2L10, SMC4, RPL4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2, NANS, LOC100129335-5, ZNF238, CADM2-7, SALL1-6 , VWA5A, RF00019.441, RF00019.451, RF00019.621, RF00019.646, RF00019.413, piR-33044, piR-33043, piR-31703, RNY4, LOC441666, SNHG1, RNU11, LOC80154, LOC727751, LOC388152, GOLGA2P2Y, GOLGA2P3Y, SNHG12, RNU12, ASMTL-AS1, LOC284454 U2:RF00004.39, U2:RF00004.22, U2:RF00004.35, U2:RF00004.71, U2:RF00004.66 U2:RF00004.91, U2:RF00004.89, U2:RF00004.67, U1:RF00003.5, U1:RF000 03.109, U1:RF00003.110, U1:RF00003.8, U1:RF00003.3, U1:RF00003.6, U1: RF00003.38, U1:RF00003.20, U1:RF00003.24, U1:RF00003.73, U1:RF00003 .11, U1:RF00003.27, U1:RF00003.40, U1:RF00003.107, U1:RF00003.62, U1: RF00003.45, U1:RF00003.116, U1:RF00003.126, U1:RF00003.81, U1:RF000 03.100, U1:RF00003.57, U1:RF00003.95, U1:RF00003.31, U1:RF00003.61, U 1:RF00003.25, U1:RF00003.90, U1:RF00003.46, U1:RF00003.123, U2:RF00 004.42, U2:RF00004.61, U2:RF00004.51, U1:RF00003.122, U1:RF00003.22,U1:RF00003.9、snoMBII-202:RF00324.2、let-7:RF00027.7、U2:RF00004.75、U1:RF00003.69、U2:RF00004.88、U12:RF00007.1、U7:RF00066.141、U1:RF00003.85、U7:RF00066.49、U2:、 RF00004.77, U1:RF00003.113, U1:RF00003.112, U1:RF00003.70, U1:RF00003.83, U7:RF00066.89, U7:RF00066.124, U7:RF00066.75, U7:RF00066.77, U7:RF00066.118, U7:RF00066.103, U7:RF00066.79, U7:RF00066.200, and / or or U7: RF00066.146, UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, HS3ST41, SLC 44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, T MEM132E1, GAGE131, GAGE2D1, GAGE2D:copy21, ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LIN Disclosed herein is a method for treating, inhibiting, decreasing, reducing, improving, and / or preventing an autoimmune disease or an inflammatory symptom associated with an autoimmune disease in a subject having an autoimmune disease, comprising administering to the subject a therapeutically effective amount of a composition comprising two or more RNA molecules, including C00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and / or HNRNPU-AS1. For example, disclosed herein is a method for treating, inhibiting, decreasing, reducing, improving, and / or preventing an autoimmune disease or an inflammatory symptom associated with an autoimmune disease in a subject having an autoimmune disease, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs are selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-5p, hsa-let-7e-5p, hsa-let-7f-5p, hsa-let-7g ...hsa-let-7b-5p、hsa-let-7c-5p、hsa-let-7d-3p、hsa-let-7e-5p、hsa-let-7g-5p、hsa-let-7i、hsa-let-7i-5p、hsa-miR-100-5p、hsa-miR-103a-3p、hsa-miR-106a-5p、hsa-miR-106b-5p、hsa-mir-10b、hsa-miR-10b-5p、hsa-mir-1246、hsa-miR-1246、hsa-miR-125a-5p、hsa-miR-125b-5p、hsa-miR-130a-3p、hsa-mir-130b、hsa-miR-130b-3p、hsa-miR-132-3p、hsa-miR-136-5p、hsa-miR-138-5p、hsa-miR-139-5p、hsa-mir-140、hsa-miR-140-3p、hsa-miR-145-5p、hsa-mir-146a、hsa-miR-146a-5p、hsa-miR-148a-3p、hsa-miR-152-3p、hsa-miR-15a-5p、hsa-miR-15b-5p、hsa-mir-16-1、hsa-mir-16-2、hsa-miR-16-5p、hsa-miR-17-5p、hsa-miR-181a-5p、hsa-miR-191-5p、hsa-miR-193a-5p、hsa-miR-193b-3p、hsa-miR-197-3p、hsa-miR-199a-3p、hsa-miR-199a-5p、hsa-miR-199b-5p、hsa-miR-19a-3p、hsa-miR-19b-3p、hsa-miR-20a-5p、hsa-miR-203a、hsa-miR-203a-3p、hsa-miR-214-3p、hsa-mir-21、hsa-miR-21-3p、hsa-miR-21-5p、hsa-mir-221、hsa-miR-221-3p、hsa-mir-222、hsa-miR-222-3p、hsa-miR-22-3p、hsa-miR-23a-3p、hsa-miR-23b-3p、hsa-mir-24-1、hsa-mir-24-2、hsa-miR-24-3p、hsa-mir-25、hsa-miR-25-3p、hsa-miR-26a-5p、hsa-miR-27a-3p、hsa-mir-27b、hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR -30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345- 5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423 hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR-99b-5p. Preferably, the composition disclosed herein comprises at least one miRNA selected from the group consisting of miR-92a-3p, let-7i-5p, miR-16-5p, miR-93-5p, miR-21-5p, miR-214-3p, miR-29c-3p, miR-34a-5p, mir-203a-3p, miR-27b-3p, miR-140-3p, miR-24-3p, miR-222-3p, miR-25-3p, miR-10b-5p, miR-221-3p, miR-17-5p, miR-30a-5p, and miR-30d-5p. 1. A method of treating, inhibiting, reducing, decreasing, ameliorating, and / or preventing an autoimmune disease or an inflammatory symptom associated with an autoimmune disease in a subject having an autoimmune disease, comprising administering to said subject one or more secretomes (compositions comprising liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes,Further disclosed herein are methods comprising administering to a subject a therapeutically effective amount of a composition comprising an MSC extract and / or extracellular vesicles (including, but not limited to, MSC extract and / or extracellular vesicles) and two or more RNA molecules, wherein the two or more RNAs are selected from the group consisting of HBII-202, U26, U29, HBII-420, U30, U18A, U81, GSKIP, IFT88, PCDH11X, PCDH11Y, KIAA0226L, PDE11A, PHACTR1, TEX14, DCUN1D2, SIM1, FILIP1, FAM107B, CHADL, ZNF365, MNA At least one mRNA selected from the group consisting of at least one mRNA selected from the group consisting of T1, CYSTM1, GAS7, H0XB7, ASTN2, LGR5, ZFHX3, MCM7, GRIK1, MAP2, LHFPL3, PTER, STAMBP, CCDC135, PAX9, RPL13, ABCA13, DAAM1, 0PN1LW, 0PN1MW2, CNOT6L, MTRNR2L10, SMC4, RPL4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2 and NANS. Further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing an autoimmune disease or an inflammatory symptom associated with an autoimmune disease in a subject having an autoimmune disease, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs comprise at least one y-RNA selected from the group consisting of RF00019.441, RF00019.451, RF00019.621, RF00019.646, and RF00019.413. 1. A method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing an autoimmune disease or an inflammatory symptom associated with an autoimmune disease in a subject having an autoimmune disease, comprising administering to a subject a composition comprising one or more secretomes (compositions including liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles,Further disclosed herein is a method for treating, inhibiting, decreasing, reducing, improving, and / or preventing an autoimmune disease or an inflammatory symptom associated with an autoimmune disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs comprise at least one pi-RNA selected from the group consisting of piR-33044, piR-33043, and piR-31703. In one embodiment, the RNA can be an antisense RNA. Accordingly, further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating and / or preventing an autoimmune disease or an inflammatory symptom associated with an autoimmune disease in a subject having an autoimmune disease, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretome (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs are selected from the group consisting of UBAP11, SMC51, TMX11, LTA4H1, KIF20B, KIF20C, KIF20D, KIF20E, KIF20F ... 1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, H S3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1,and at least one antisense mRNA selected from the group consisting of GAGE2D:copy21, an antisense lnRNA selected from the group consisting of ANKRD5-1, ZNF236-1, and ACP1, and / or UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRAN, B31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLCN51, ST6GALNA C51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE13 1, GAGE2D1, GAGE2D:copy21, ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and / or HNRNPU-AS1.

[0122] E. Methods of Treating Autoinflammatory Disease The compositions comprising secretomes and RNAs disclosed herein are not limited in treating inflammation resulting from adaptive immune responses, but are also effective in abrogating the destruction caused by inflammation associated with congenital abnormalities of the innate immune response (i.e., the constitutive inflammation that underlies autoinflammatory diseases). As used herein, "autoinflammatory disease" refers to a disorder in which the innate immune response attacks host cells. Examples of autoinflammatory disorders include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), neonatal-onset multisystem inflammatory disease (NOMID) (also known as chronic infantile neurological skin and articular syndrome (CINCA)), familial Mediterranean fever (FMF) and other cryopyrin-associated periodic syndromes (CAPS)-tumor necrosis factor (TNF)-associated periodic syndromes (TRAPS)), TNFRSF11A-associated hereditary fever disorder (TRAPS11), hyperimmunoglobulinemia D with periodic fever syndromes (HIDS) (mevalonic aciduria (MA) / mevalonate kinase deficiency (MKD)), interleukin-1 receptor (IL-1α) receptor antagonist (DIRA) deficiency (also known as sterile multifocal with osteomyelitis, staphylococcal inflammation), hypertrophic syndrome-chronic nonbacterial osteomyelitis (CNO)-early onset inflammatory bowel disease-arthritis-interleukin-36 receptor antagonist deficiency (DITRA), familial psoriasis (PSORS2) / pustular psoriasis (15) / suppurative sterile arthritis / pyoderma gangrenosum / acne syndrome (PAPA) / congenital lateral cytoplasmic anemia with immune deficiency, fever, and developmental delay (SIFD), childhood granulomatous arthritis (PGA)-familial Behçet-like autoinflammatory syndrome / NLRP12-associated periodic fever syndrome / proteasome-associated autoinflammatory syndrome (PRAAS), spondylochondrodysplasia with immune dysregulation (SPENCDI)-STING-associated infarct-onset vasculopathy (SAVI)-Acardi-Gautieres syndrome and other type 1 interferonopathies, acute neutrophilic dermatosis, X-linked familial hemophagocytic lymphohistiocytosis, Lyn kinase-associated autoinflammatory disease (LAID), and inflammatory disorders of the gut and skin caused by deletion mutations in the carboxy-terminal segment of NF-AB essential modulator (NEMO).One or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition), as well as hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-107a-5p, hsa-miR-108a-5p, hsa-miR-109a-5p, hsa-miR-200a-5p, hsa-miR-201a-5p, hsa-miR-202a-5p, hsa-miR-203a-5p, hsa-miR-204a-5p, hsa-miR-205a-5p, hsa-miR-206a-5p, hsa-miR-207b-5p, hsa-miR-208a-5p, hsa-miR-209a-5p, hsa-miR-210b-5p, hsa-miR-211b-5p, hsa-miR-212a-5p, hsa-miR-213a-5p, hsa-miR-214a-5p, hsa-miR-215a-5p, hsa-miR-216a-5p, hsa-miR-217a-5p, hsa-miR-218a-5p, hsa-miR-219a-5p, hsa-miR-22 R-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, h sa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir- 146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa -miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa- miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p , hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1,hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-miR-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e- 5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-m iR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-miR-486-1, hsa-miR-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-miR-92a-1, hsa-miR-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-miR-93, hsa-miR-93-5 p、hsa-miR-940、hsa-miR-99a-5p、hsa-miR-99b-5p、HBII-202、U26、U29、H BII-420、U30、U18A、U81、GSKIP、IFT88、PCDH11X、PCDH11Y、KIAA0226L、PDE1 1A、PHACTR1、TEX14、DCUN1D2、SIM1、FILIP1、FAM107B、CHADL、ZNF365、MNAT 1、CYSTM1、GAS7、HOXB7、ASTN2、LGR5、ZFHX3、MCM7、GRIK1、MAP2、LHFPL3、PTE R、STAMBP、CCDC135、PAX9、RPL13、ABCA13、DAAM1、OPN1LW、OPN1MW2、CNOT6L 、MTRNR2L10、SMC4、RPL4、PSAP、ASIC4、AHCYL1、RD3L、SIGLEC1、SYCE2、NANS、LOC100129335-5、ZNF238、CADM2-7、SALL1-6、VWA5A、RF00019.441、RF00019.451、RF00019.621、RF00019.646、RF00019.413、piR-33044、piR-33043、piR-31703、RNY4、LOC441666、SNHG1、RNU11、LOC80154、LOC727751、LOC388152、GOLGA2P2Y、GOLGA2P3Y、SNHG12、RNU12、ASMTL-AS1、LOC284454 U2:RF00004.39、U2:RF00004.22、U2:RF00004.35、U2:RF00004.71、U2:RF00004.66 U2:RF00004.91、U2:RF00004.89、U2:RF00004.67、U1:RF00003.5、U1:RF00003.109、U1:RF00003.110、U1:RF00003.8、U1:RF00003.3、U1:RF00003.6、U1:RF00003.38、U1:RF00003.20、U1:RF00003.24、U1:RF00003.73、U1:RF00003.11、U1:RF00003.27、U1:RF00003.40、U1:RF00003.107、U1:RF00003.62、U1:RF00003.45、U1:RF00003.116、U1:RF00003.126、U1:RF00003.81、U1:RF00003.100、U1:RF00003.57、U1:RF00003.95、U1:RF00003.31、U1:RF00003.61、U1:RF00003.25、U1:RF00003.90、U1:RF00003.46、U1:RF00003.123、U2:RF00004.42、U2:RF00004.61、U2:RF00004.51、U1:RF00003.122、U1:RF00003.22、U1:RF00003.9、snoMBII-202:RF00324.2、let-7:RF00027.7、U2:RF00004.75、U1:RF00003.69、U2:RF00004.88、U12:RF00007.1、U7:RF00066.141、U1:RF00003.85、U7:RF00066.49、U2:RF00004.77、U1:RF00003.113、U1:RF00003.112, U1:RF00003.70, U1:RF00003.83, U7:RF00066.89, U7:RF00066.124, U7:RF00066.75, U7:RF00066.77, U7:RF00066.118, U7:RF00066.103, U7:RF00066.79, U7:RF00066.200, and / or U7:RF00066.146, UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61 , CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLC Disclosed herein are methods of treating, inhibiting, decreasing, reducing, ameliorating and / or preventing an autoinflammatory disease or an inflammatory symptom associated with an autoinflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising two or more RNA molecules comprising N51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, GAGE2D:copy21, ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and / or HNRNPU-AS1. For example, disclosed herein are methods of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing an autoinflammatory disease or an inflammatory symptom associated with an autoinflammatory disease in a subject having an autoinflammatory disease, the method comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretome (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs are selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-5p, hsa-let-7e-5p, hsa-let-7f-5p, hsa-let-7g-5p, hsa-let-7h-5p, hsa-let-7i ...hsa-let-7d-3p、hsa-let-7e-5p、hsa-let-7g-5p、hsa-let-7i、hsa-let-7i-5p、hsa-miR-100-5p、hsa-miR-103a-3p、hsa-miR-106a-5p、hsa-miR-106b-5p、hsa-mir-10b、hsa-m、 iR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-13 2-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-miR-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-miR-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1, hsa-miR-16-2, hsa-miR-16-5p, hsa-miR-17-5p, and hsa-miR-181a -5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19 a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-miR-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-mi R-24-3p、hsa-mir-25、hsa-miR-25-3p、hsa-miR-26a-5p、hsa-miR-27a-3p 、hsa-mir-27b、hsa-miR-27b-3p、hsa-miR-29a-3p、hsa-miR-29c-3p、hsa- miR-30a-5p、hsa-miR-30a-5p、hsa-miR-30b-5p、hsa-miR-30c-5p、hsa-mi r-30d、hsa-miR-30d-5p、hsa-mir-30e、hsa-miR-30e-5p、hsa-miR-31-3p、hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-m iR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486- The present invention relates to a method for the preparation of a nucleic acid sequence encoding a nucleic acid fragment of a human miR-93, comprising administering to a mammalian subject the nucleic acid sequence of the present invention, the nucleic acid sequence of the present invention being selected from the group consisting of hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR-99b-5p. Preferably, the composition disclosed herein comprises at least one miRNA selected from the group consisting of miR-92a-3p, let-7i-5p, miR-16-5p, miR-93-5p, miR-21-5p, miR-214-3p, miR-29c-3p, miR-34a-5p, mir-203a-3p, miR-27b-3p, miR-140-3p, miR-24-3p, miR-222-3p, miR-25-3p, miR-10b-5p, miR-221-3p, miR-17-5p, miR-30a-5p, and miR-30d-5p.

[0123] Further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing an autoinflammatory disease or an inflammatory symptom associated with an autoinflammatory disease in a subject having an autoinflammatory disease, the method comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretome (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs are selected from the group consisting of HBII-202, U26, U29, HBII-420, U30, U18A, U81, GSKIP, IFT88, PCDH11X, PCDH11Y, KIAA0226L, PDE 11A, PHACTR1, TEX14, DCUN1D2, SIM1, FILIP1, FAM107B, CHADL, ZNF365, MNAT1, CYSTM1, GAS7, H0XB7, ASTN2, LGR5, ZFHX3, MCM7, GRIK1, MAP2, LHFPL3, PTER, STAMBP, CCDC135, PAX9, RPL13, ABCA13, DAAM1, 0PN1LW, 0PN1MW2, CNOT6L, MTRNR2L10, SMC4, RPL4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2 and NANS. Further disclosed herein is a method of treating, inhibiting, reducing, ameliorating, and / or preventing an autoinflammatory disease or an inflammatory symptom associated with an autoinflammatory disease in a subject having an autoinflammatory disease, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs comprise at least one y-RNA selected from the group consisting of RF00019.441, RF00019.451, RF00019.621, RF00019.646, and RF00019.413.Further disclosed herein is a method for preventing and / or treating a disease comprising administering to a subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs comprise at least one lncRNA selected from the group consisting of LOC100129335-5, ZNF238, CADM2-7, SALL1-6, and VWA5A. Further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing an autoinflammatory disease or an inflammatory symptom associated with an autoinflammatory disease in a subject having an autoinflammatory disease, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs comprise at least one pi-RNA selected from the group consisting of piR-33044, piR-33043, and piR-31703. In one embodiment, the RNA can be an antisense RNA. Accordingly, further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating and / or preventing an autoinflammatory disease or an inflammatory symptom associated with an autoinflammatory disease in a subject having an autoinflammatory disease, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein Two or more RNAs were identified: UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11,At least one antisense mRNA selected from the group consisting of AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, and GAGE2D:copy21, an antisense lnRNA selected from the group consisting of ANKRD5-1, ZNF236-1, and ACP1, and / or UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR1 ... The antisense RNA is selected from the group consisting of NF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, GAGE2D:copy21, ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and / or HNRNPU-AS1.

[0124] F. Methods of Treating Physical Injury That Causes Physical Inflammation or Post-Traumatic Inflammation Many inflammatory diseases result from inflammation-mediated physical injuries (e.g., brain trauma, blunt injury, ischemia, surgery, transplantation, sunburn, chemical burn, high-temperature burn, low-temperature burn, radiation, abrasion, puncture, laceration, contusion, etc.). As described above, the compositions comprising secretome and RNA disclosed herein can regulate inflammation. Thus, the novel forms of immunotherapy disclosed herein can inhibit organ damage caused by inflammation associated with these physical injuries, which cause swelling, redness, elevated body temperature, pain, and loss of organ function. Thus, in one aspect, a method for treating, inhibiting, reducing, decreasing, ameliorating and / or preventing inflammation caused by physical injury (e.g., abrasion, puncture, laceration, contusion, blunt injury, ischemia, surgery, transplantation, sunburn, chemical burn, high temperature burn, low temperature burn, etc.), comprising administering to the patient one or more of the secretome and hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-5p, hsa-let-7e-5p, hsa-let-7f-5p, hsa-let-7g-5p, hsa-let-7h-5p, hsa-let-7i-5p, hsa-let-7j ... 3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-mi R-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5 p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR- 146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16- 2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p,hsa-miR-197-3p、hsa-miR-199a-3p、hsa-miR-199a-5p、hsa-miR-199b-5p 、hsa-miR-19a-3p、hsa-miR-19b-3p、hsa-miR-20a-5p、hsa-miR-203a、hsa- miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-mi R-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, and hsa-miR-30c-5p 、hsa-mir-30d、hsa-miR-30d-5p、hsa-mir-30e、hsa-miR-30e-5p、hsa-miR -31-3p、hsa-miR-31-5p、hsa-miR-320a、hsa-miR-342-3p、hsa-miR-345-5p hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-m IR-486-1, HSA-MIR-486-2, HSA-MIR-486-5P, HSA-MIR-570-3P, HSA-MIR-574-3P, HSA-MIR-663A, HSA-MIR-874-3P, HSA-MIR-92A-1, HSA-MIR-92A-2, H sa-miR-92a-3p, hsa-miR-92b-3p, hsa-miR-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, hsa-miR-99b-5p, HBII-202, U26, U29, HBII-420, U30U18A、U81、GSKIP、IFT88、PCDH11X、PCDH11Y、KIAA0226L、PDE11A、PHACTR1、TEX14 、DCUN1D2、SIM1、FILIP1、FAM107B、CHADL、ZNF365、MNAT1、CYSTM1、GAS7、HOXB7、AS TN2、LGR5、ZFHX3、MCM7、GRIK1、MAP2、LHFPL3、PTER、STAMBP、CCDC135、PAX9、RPL13 、ABCA13、DAAM1、OPN1LW、OPN1MW2、CNOT6L、MTRNR2L10、SMC4、RPL4、PSAP、ASIC4、A HCYL1、RD3L、SIGLEC1、SYCE2、NANS、LOC100129335-5、ZNF238、CADM2-7、SALL1-6、 VWA5A、RF00019.441、RF00019.451、RF00019.621、RF00019.646、RF00019.413、pi R-33044、piR-33043、piR-31703、RNY4、LOC441666、SNHG1、RNU11、LOC80154、LOC7 27751、LOC388152、GOLGA2P2Y、GOLGA2P3Y、SNHG12、RNU12、ASMTL-AS1、LOC284454 U2:RF00004.39、U2:RF00004.22、U2:RF00004.35、U2:RF00004.71、U2:RF00004.66 U2:RF00004.91、U2:RF00004.89、U2:RF00004.67、U1:RF00003.5、U1:RF00003.109、U1:RF00003.110、0U1:RF0003. .8、U1:RF00003.3、U1:RF00003.6、U1:RF00003.38、U1:RF00003.24、U1:RF00003.24、U1:RF00003.73、00:0U1 .11、U1:RF00003.27、U1:RF00003.40、U1:RF00003.107、U1:RF00003.62、U1:RF00003.45、U1:RF00000、U116 00003.126、U1:RF00003.81、U1:RF00003.100、U1:RF00003.57、U1:RF00003.95、U1:RF00003.31、U1:6:RF0000U1:RF00003.25, U1:RF00003.90, U1:RF00003.46, U1:RF00003.123, U2:RF00004.42, U2:RF00004.61, U2:RF00004.51, U1:RF00003.122, U1:RF000 03.22, U1:RF00003.9, snoMBII-202:RF00324.2, let-7:RF00027.7, U2:RF00004.75, U1:RF00003.69, U2:RF00004.88, U12:RF00007.1, U7:RF0006 6.141, U1:RF00003.85, U7:RF00066.49, U2:RF00004.77, U1:RF00003.113, U1:RF00003.112, U1:RF00003.70, U1:RF00003.83, U7:RF00066.89, U7:RF00066.124, U7:RF00066.75, U7:RF00066.77, U7:RF00066.118, U7:RF00066.103, U7:RF00066.79, U7:RF00066.200, and / or U7:RF00066.146, U BAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP Disclosed herein is a method for administering to a subject having a physical injury a therapeutically effective amount of a composition comprising two or more RNAs, including 21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, GAGE2D:copy21, ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and HNRNPU-AS1.

[0125] A method for treating, inhibiting, reducing, decreasing, ameliorating, and / or preventing inflammation caused by a physical injury (e.g., an abrasion, a puncture, a laceration, a contusion, a blunt injury, ischemia, surgery, a transplant, sunburn, a chemical burn, a high-temperature burn, a low-temperature burn, etc.), comprising administering to a subject having a physical injury a therapeutically effective amount of a composition comprising one or more secretomes and two or more RNAs, wherein the two or more RNAs are selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e -5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-mi R-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3 p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-mi R-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221,It contains at least one miRNA selected from the group consisting of hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR-99b-5p. Preferably, two or more RNAs are miR-92a-3p, let-7i-5p, miR-16-5p, miR-93-5p, miR-21-5p, miR-214-3p, miR-29c-3p, miR-34a-5p, mir-203a-3p, miR-27b-3p, miR-140-3p, miR-24-3p, miR-222-3p, miR-25-3p, miR-10b-5p, miR-221-3p, miR-17-5p,The method includes at least one miRNA selected from the group consisting of miR-30a-5p, and miR-30d-5p.

[0126] Further disclosed herein is a method of treating, inhibiting, reducing, decreasing, ameliorating, and / or preventing inflammation caused by physical injury (e.g., abrasion, puncture, laceration, contusion, blunt injury, ischemia, surgery, transplant, sunburn, chemical burn, hot burn, cold burn, etc.) or inflammatory symptoms associated with inflammation caused by physical injury (e.g., abrasion, puncture, laceration, contusion, blunt injury, ischemia, surgery, transplant, sunburn, chemical burn, hot burn, cold burn, etc.) in a subject having inflammation caused by physical injury (e.g., abrasion, puncture, laceration, contusion, blunt injury, ischemia, surgery, transplant, sunburn, chemical burn, hot burn, cold burn, etc.), comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules. wherein the two or more RNAs are selected from the group consisting of HBII-202, U26, U29, HBII-420, U30, U18A, U81, GSKIP, IFT88, PCDH11X, PCDH11Y, KIAA0226L, PDE11A, PHACTR1, TEX14, DCUN1D2, SIM1, FILIP1, FAM107B, CHADL, ZNF365, MNAT1, CYSTM1, GAS7, H0XB7, ASTN2, LGR5, ZFHX3, MCM7, At least one mRNA selected from the group consisting of at least one mRNA selected from the group consisting of GRIK1, MAP2, LHFPL3, PTER, STAMBP, CCDC135, PAX9, RPL13, ABCA13, DAAM1, 0PN1LW, 0PN1MW2, CNOT6L, MTRNR2L10, SMC4, RPL4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2 and NANS. Inflammation or physical injury caused by physical injury (e.g., abrasion, puncture, laceration, contusion, blunt injury, ischemia, surgery, transplant, sunburn, chemical burn, high temperature burn, low temperature burn, etc.) in a subject having inflammation caused by physical injury (e.g., abrasion, puncture, laceration, contusion, blunt injury, ischemia, surgery, transplant, sunburn, chemical burn, high temperature burn, low temperature burn, etc.)Further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing inflammatory symptoms associated with inflammation caused by inflammation such as chemical burns, high temperature burns, low temperature burns, etc., comprising administering to a subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs comprise at least one y-RNA selected from the group consisting of RF00019.441, RF00019.451, RF00019.621, RF00019.646, and RF00019.413. Treating, inhibiting, reducing, decreasing, ameliorating, or preventing inflammation caused by physical injury (e.g., abrasions, punctures, lacerations, contusions, blunt injury, ischemia, surgery, transplants, sunburn, chemical burns, hot burns, cold burns, etc.) or inflammatory symptoms associated with inflammation caused by physical injury (e.g., abrasions, punctures, lacerations, contusions, blunt injury, ischemia, surgery, transplants, sunburn, chemical burns, hot burns, cold burns, etc.) in a subject having inflammation caused by physical injury (e.g., abrasions, punctures, lacerations, contusions, blunt injury, ischemia, surgery, transplants, sunburn, chemical burns, hot burns, cold burns, etc.). Further disclosed herein is a method for improving and / or preventing a tumor in a subject, the method comprising administering to a subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs comprise at least one lncRNA selected from the group consisting of LOC100129335-5, ZNF238, CADM2-7, SALL1-6, and VWA5A. Inflammation or physical injury caused by physical injury (e.g., abrasion, puncture, laceration, contusion, blunt injury, ischemia, surgery, transplantation, sunburn, chemical burn, high temperature burn, low temperature burn, etc.) in a subject having inflammation caused by physical injury (e.g., abrasion, puncture, laceration, contusion, blunt injury, ischemia, surgery, transplantation, sunburn, chemical burn, high temperature burn, low temperature burn, etc.)Further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing inflammatory symptoms associated with inflammation caused by sunburn, chemical burn, high temperature burn, low temperature burn, etc., comprising administering to a subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs comprise at least one pi-RNA selected from the group consisting of piR-33044, piR-33043, and piR-31703. In one embodiment, the RNA can be an antisense RNA. Thus, there is provided a method of treating, inhibiting, decreasing, reducing, ameliorating and / or preventing inflammation caused by physical injury (e.g., abrasion, puncture, laceration, contusion, blunt injury, ischemia, surgery, transplantation, sunburn, chemical burn, hot burn, cold burn, etc.) or inflammatory symptoms associated with inflammation caused by physical injury (e.g., abrasion, puncture, laceration, contusion, blunt injury, ischemia, surgery, transplantation, sunburn, chemical burn, hot burn, cold burn, etc.) in a subject having inflammation caused by physical injury (e.g., abrasion, puncture, laceration, contusion, blunt injury, ischemia, surgery, transplantation, sunburn, chemical burn, hot burn, cold burn, etc.), comprising administering to the subject one or more secretome (compositions, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition). Further disclosed herein are methods for administering to a subject a therapeutically effective amount of a composition comprising two or more RNA molecules, including, but not limited to, UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271,At least one antisense mRNA selected from the group consisting of NBPF141, TMEM132E1, GAGE131, GAGE2D1, and GAGE2D:copy21, an antisense lnRNA selected from the group consisting of ANKRD5-1, ZNF236-1, and ACP1, and / or UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, The antisense RNA is selected from the group consisting of HS3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, GAGE2D:copy21, ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and / or HNRNPU-AS1.

[0127] In one embodiment, it is understood and contemplated herein that one method of treating wounds is by subcutaneous, intramuscular, intravenous, local administration (e.g., by using an ointment, cream, and / or salve) of the secretome (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the composition) and RNA composition, but also by impregnating a stent, sponge, matrix, scaffold, bandage, dressing, suture, graft, surgical drape, surgical adhesive, and / or staple with the MSC secretome composition. Thus, in one embodiment, disclosed herein is a medicated stent, scaffold, sponge, matrix, adhesive dressing, wound dressing, graft, surgical drape, suture, ointment, cream, or wound adhesive comprising a therapeutically effective amount of the MSC secretome composition. The MSC secretome composition (including, but not limited to, the MSC growth factor, MSC exosome, MSC extract and / or extracellular vesicle containing composition) may be administered topically as described above and applied to the face, neck, hands or any other desired part of the body. When applied to an adhesive dressing, wound dressing, graft, surgical drape, suture, scaffold, matrix, sponge, or stent, the MSC secretome composition may be applied as a powder.

[0128] G. Methods of Treating Microbial Diseases In response to infection by microorganisms, such as viruses, bacteria, fungi, or parasites, the host immune system attempts to eliminate the infecting microorganism by employing the arms of the innate and adaptive immune system, including the generation of cytokines, antibodies, and effector mechanisms of granulocytes, monocytes, macrophages, dendritic cells, innate lymphoid cells, NK cells, NK T cells, T cells, B cells, and plasma cells. In any microbial inflammation, the inflammatory signaling cascade is initiated by the cellular response to microbial virulence factors and endogenous cytokines and terminates in the nuclear translocation of stress response transcription factors (SRTFs), which upregulate inflammatory gene networks. If left unchecked, this genomic reprogramming (genomic storm) leads to endothelial dysfunction, multiple organ failure, and ultimately a fatal shock known as septic shock, which represents the ultimate end stage of microbial inflammation, one of the top 10 leading causes of death in developed and developing countries.

[0129] "Microbial inflammation" refers to a disease associated with its cardinal symptoms such as redness, swelling, elevated temperature, pain, and impaired organ function such as respiratory failure as a result of epithelial damage with adjacent microvascular endothelial damage in the lungs (and other organs) due to microbial infections such as viruses, bacteria, fungi, or parasites. That is, "microbial inflammation" is the mechanism of disease ("microbial injury") caused by infection. Microbial inflammation results from the innate immune response to infection by microorganisms such as viruses, bacteria, fungi, or parasites. Thus, microbial injury caused by microbial pathogenicity factors is exacerbated by host-produced inflammatory mediators that impede clearance of the invading microorganism and add injury to organ injury. It is understood and contemplated herein that microbial inflammation and its final stage, sepsis, can result from any microbial injury induced by known (or unknown) pathogenicity factors and microbial antigens.

[0130] Innate and adaptive immune responses to infectious agents (disease-causing microorganisms) can include a burst in the production of cytokines, chemokines, and proteolytic enzymes by granulocytes, monocytes, macrophages, dendritic cells, mast cells, innate lymphoid cells, T cells, B cells, NK cells, and NK T cells. Microbial inflammation can be localized to a specific organ or can be systemic. Microbial inflammation can progress in stages from acute to subacute and chronic, with concomitant tissue destruction and subsequent fibrosis. If left unchecked, acute microbial inflammation can lead to sepsis and septic shock, the final stage of microbial inflammation.

[0131] A "pathogen" is an agent that causes infection or disease, particularly a virus, bacterium, fungus, protozoan, or parasite.

[0132] It is understood that the pathogen can be a virus. Thus, in one embodiment, the pathogen is selected from the group consisting of herpes simplex virus-1, herpes simplex virus-2, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, human herpes virus-6, variola virus, vesicular stomatitis virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, rhinovirus, coronaviruses (avian coronavirus (IBV), porcine coronavirus HKU15 (PorCoV), and the like. HKU15), porcine epidemic diarrhea virus (PEDV), HCoV-229E, HCoV-OC43, HCoV-HKU1, HCoV-NL63, SARS-CoV, SARS-CoV-2, or MERS-CoV), influenza virus A, influenza virus B, measles virus, polyomavirus, human papillomavirus, respiratory syncytial virus, adenovirus, coxsackievirus, chikungunya virus, dengue virus, mumps virus, poliovirus, rabies virus ... The virus may be selected from the group consisting of encephalitis virus, reovirus, yellow fever virus, Ebola virus, Marburg virus, Lassa fever virus, Eastern equine encephalitis virus, Japanese encephalitis virus, St. Louis encephalitis virus, Murray Valley fever virus, West Nile virus, Rift Valley fever virus, rotavirus A, rotavirus B, rotavirus C, Sindbis virus, simian immunodeficiency virus, human T-cell leukemia virus type 1, hantavirus, rubella virus, simian immunodeficiency virus, human immunodeficiency virus type 1, and human immunodeficiency virus type 2.

[0133] Also disclosed are methods in which the pathogen is a bacteria. The pathogen may be Mycobacterium tuberculosis, Mycobacterium bovis, BCG strains of Mycobacterium bovis, BCG, substrains, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium africanum, Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium ulcerans, Mycobacterium avium subsp. paratuberculosis, Mycobacterium chimera, Nocardia asteroides, other Nocardia species, Legionella pneumophila, other Legionella species, Acetinobacter baumannii, Mycobacterium tuberculosis ... baumanii, Salmonella typhi, Salmonella enterica, other Salmonella spp., Shigella boydii, Shigella sonnei, Shigella flexneri, other Shigella spp., Yersinia pestis, Pasteurella haemolytica, Pasteurella multocida, other Pasteurella spp., Actinobacillus pleuropneumoniae, Listeria monocytogenes, Listeria ivanovii, Brucella abortus, other Brucella spp., Coudrilia ruminantium, Borrelia burgdorferi, Bordetella avium, Bordetella pertussis, Bordetella bronchiseptica, Bordetella trematum, Bordetella hinzii, Bordetella puteri pteri, Bordetella parapertasis, Bordetella ansorpii, other Bordetella species, Burkholderia mallei, Burkholderia psuedomallei, Burkholderia cepacian, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydia psittaci, Coxiella burnetii, Rickettsial species, Ehrlichia species, Staphylococcus aureusaureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Vibrio cholerae, Campylobacter species, Neiserria meningitidis, Neiserria gonorrhea, Pseudomonas aeruginosa, other Pseudomonas species, Haemophilus influenzae, Haemophilus ducreyi, other Hemophilus species, Clostridium tetani The bacteria may be selected from the group consisting of Yersinia tetani, other Clostridium species, Yersinia enterolitica, and other Yersinia species, and Mycoplasma species.

[0134] Also disclosed are methods wherein the pathogen is a fungus selected from the group of fungi consisting of Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum, Aspergillus fumigatus, Coccidiodes immitis, Paracoccidiodes brasiliensis, Blastomyces dermitidis, Pneumocystis carinii, Penicillium marneffi, and Alternaria alternata.

[0135] The pathogens include Toxoplasma gondii, Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, other Plasmodium species, Entamoeba histolytica, Naegleria fowleri, Rhinosporidium seeberi, Giardia lamblia, Enterobius vermicularis, Enterobius gregorii, Ascaris lumbricoides, Ancylostoma duodenale, Necator americanus, Cryptosporidium spp., Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, other Leishmania species, Diphyllobothrium latum, Hymenolepis nana, Hymenolepis diminuta, Echinococcus granulosus, Echinococcus multilocularis, Echinococcus vogeli, Echinococcus oligarthrus, Diphyllobothrium latum, Clonorchis sinensis;Clonorchis viverrini, Fasciola hepatica, Fasciola gigantica, Dicrocoelium dendriticum, Fasciolopsis buski, Metagonimus yokogawai, Opisthorchis viverrini, Opisthorchis felineus, Clonorchis sinensis, Trichomonas vaginalis, Acanthamoeba species, Schistosoma intercalatum, Schistosoma haematobium, Schistosoma Also disclosed are methods in which the parasite is selected from the group of parasites consisting of Schistosoma japonicum, Schistosoma mansoni, other Schistosoma species, Trichobilharzia regenti, Trichinella spiralis, Trichinella britovi, Trichinella nelsoni, Trichinella nativa, and Entamoeba histolytica;

[0136] It is understood and contemplated herein that the microbial inflammation to be treated may be in any tissue, organ, or system of a subject where microbial infection may occur, including, but not limited to, blood, brain, paranasal sinuses, upper respiratory tract, or lungs, heart, bone marrow, spleen, liver, kidney, genitourinary tract, bladder, ear cavity, stomach, intestine, skin, eye, teeth, or gums, and musculoskeletal system.Therefore, in one aspect, disclosed herein is a method for treating, inhibiting, reducing, reducing, improving and / or preventing microbial inflammation in a subject at different stages (e.g., acute inflammation, subacute inflammation, chronic inflammation, organ-specific inflammation, systemic inflammation, and / or sepsis and septic shock as end stages of microbial inflammation), comprising administering to the subject a therapeutically effective amount of any of the compositions disclosed herein (i.e., a composition comprising one or more secretomes and two or more RNAs). Thus, in one embodiment, one or more secretomes, as well as hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b-5p, hsa-miR-130c-3p, hsa-miR-130d-3p, hsa-miR-130e-3p, hsa-miR-130f ... 0b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p , hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-mi R-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16 -2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p,hsa-miR-193b-3p、hsa-miR-197-3p、hsa-miR-199a-3p、hsa-miR-199a-5p 、hsa-miR-199b-5p、hsa-miR-19a-3p、hsa-miR-19b-3p、hsa-miR-20a-5p、h sa-miR-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-miR-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, and hsa-m iR-26a-5p, hsa-miR-27a-3p, hsa-miR-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, and hsa-miR-30b-5 p、hsa-miR-30c-5p、hsa-mir-30d、hsa-miR-30d-5p、hsa-mir-30e、hsa-mi R-30e-5p、hsa-miR-31-3p、hsa-miR-31-5p、hsa-miR-320a、hsa-miR-342-3 p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, h sa-miR-484, hsa-miR-486-1, hsa-miR-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, and hsa-miR-92a-1 hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, hsa-miR-99b-5p, HBII-202, U26U29、HBII-420、U30、U18A、U81、GSKIP、IFT88、PCDH11X、PCDH11Y、KIAA0226L、PDE11A 、PHACTR1、TEX14、DCUN1D2、SIM1、FILIP1、FAM107B、CHADL、ZNF365、MNAT1、CYSTM1、G AS7、HOXB7、ASTN2、LGR5、ZFHX3、MCM7、GRIK1、MAP2、LHFPL3、PTER、STAMBP、CCDC135、 PAX9、RPL13、ABCA13、DAAM1、OPN1LW、OPN1MW2、CNOT6L、MTRNR2L10、SMC4、RPL4、PSAP 、ASIC4、AHCYL1、RD3L、SIGLEC1、SYCE2、NANS、LOC100129335-5、ZNF238、CADM2-7、SA LL1-6、VWA5A、RF00019.441、RF00019.451、RF00019.621、RF00019.646、RF00019.41 3、piR-33044、piR-33043、piR-31703、RNY4、LOC441666、SNHG1、RNU11、LOC80154、LO C727751、LOC388152、GOLGA2P2Y、GOLGA2P3Y、SNHG12、RNU12、ASMTL-AS1、LOC284454 U2:RF00004.39、U2:RF00004.22、U2:RF00004.35、U2:RF00004.71、U2:RF00004.66 U2:RF00004.91、U2:RF00004.89、U2:RF00004.67、U1:RF00003.5、U1:RF00003.109、U1:RF00003.110、U1:RF0 0003.8、U1:RF00003.3、U1:RF00003.6、U1:RF00003.38、U1:RF00003.20、U1:RF00003.24、U1:RF00003.1:73、 RF00003.11、U1:RF00003.27、U1:RF00003.40、U1:RF00003.107、U1:RF00003.62、U1:RF00003.45、U1:RF0000 3.116、U1:RF00003.126、U1:RF00003.81、U1:RF00003.100、U1:RF00003.57、U1:RF00003.95、U1:RF000003.U1:RF00003.61, U1:RF00003.25, U1:RF00003.90, U1:RF00003.46, U1:RF00003.123, U2:RF00004.42, U2:RF00004.61, U2:RF00004.51, U1:RF00003. 122, U1:RF00003.22, U1:RF00003.9, snoMBII-202:RF00324.2, let-7:RF00027.7, U2:RF00004.75, U1:RF00003.69, U2:RF00004.88, U12:RF00007.1, U7:RF00066.141, U1:RF00003.85, U7:RF00066.49, U2:RF00004.77, U1:RF00003.113, U1:RF00003.112, U1:RF00003.70, U1:RF00003.83, U7:RF00066.89, U7:RF00066.124, U7:RF00066.75, U7:RF00066.77, U7:RF00066.118, U7:RF00066.103, U7:RF00066.79, U7:RF00066.200, and / or U7:RF00066.1 46, UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1 , ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP2 1, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, GAGE2D:copy21, ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and / or HNRNPU-AS1;Methods for improving and / or preventing are disclosed herein.

[0137] Disclosed herein is a method of treating, inhibiting, reducing, decreasing, ameliorating, and / or preventing inflammatory damage resulting from a microbial infection in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretome and two or more RNA molecules, wherein the two or more RNAs are selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-10 ... a-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-1 25b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa- mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197 -3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-203a, hsa-miR-203a-3 p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p,hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25- 3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa -miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-3 0e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa- miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-m iR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3 hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR-99b-5p. Preferably, the two or more RNAs comprise at least one miRNA selected from the group consisting of miR-92a-3p, let-7i-5p, miR-16-5p, miR-93-5p, miR-21-5p, miR-214-3p, miR-29c-3p, miR-34a-5p, mir-203a-3p, miR-27b-3p, miR-140-3p, miR-24-3p, miR-222-3p, miR-25-3p, miR-10b-5p, miR-221-3p, miR-17-5p, miR-30a-5p, and miR-30d-5p;Compositions are disclosed herein.

[0138] Further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing inflammatory damage resulting from a microbial infection or inflammatory symptoms associated with inflammatory damage resulting from a microbial infection in a subject having inflammatory damage resulting from a microbial infection, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretome (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs are selected from the group consisting of HBII-202, U26, U29, HBII-420, U30, U18A, U81, GSKIP, IFT88, PCDH11X, PCDH11Y, K At least one mRNA selected from the group consisting of IAA0226L, PDE11A, PHACTR1, TEX14, DCUN1D2, SIM1, FILIP1, FAM107B, CHADL, ZNF365, MNAT1, CYSTM1, GAS7, H0XB7, ASTN2, LGR5, ZFHX3, MCM7, GRIK1, MAP2, LHFPL3, PTER, STAMBP, CCDC135, PAX9, RPL13, ABCA13, DAAM1, 0PN1LW, 0PN1MW2, CNOT6L, MTRNR2L10, SMC4, RPL4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2 and NANS. Further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing inflammatory damage resulting from a microbial infection or inflammatory symptoms associated with inflammatory damage resulting from a microbial infection in a subject having inflammatory damage resulting from a microbial infection, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs are selected from the group consisting of RF00019.441, RF00019.451, RF00019.621, RF00019.646,and RF00019.413.Further disclosed herein is a method of treating, inhibiting, reducing, decreasing, ameliorating, and / or preventing inflammatory damage resulting from microbial infection or inflammatory symptoms associated with inflammatory damage resulting from microbial infection in a subject having inflammatory damage resulting from microbial infection, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs comprise at least one lncRNA selected from the group consisting of LOC100129335-5, ZNF238, CADM2-7, SALL1-6, and VWA5A. Further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing inflammatory damage resulting from microbial infection or inflammatory symptoms associated with inflammatory damage resulting from microbial infection in a subject having inflammatory damage resulting from microbial infection, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs comprise at least one pi-RNA selected from the group consisting of piR-33044, piR-33043, and piR-31703. In one embodiment, the RNA can be an antisense RNA. Thus, further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating and / or preventing inflammatory damage resulting from a microbial infection or inflammatory symptoms associated with inflammatory damage resulting from a microbial infection in a subject having inflammatory damage resulting from a microbial infection, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretome (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs are selected from the group consisting of UBAP11, SMC51, TMX11, LTA4H1, KIF20B1,OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11 , ZNF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, At least one antisense mRNA selected from the group consisting of FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, and GAGE2D:copy21, an antisense lnRNA selected from the group consisting of ANKRD5-1, ZNF236-1, and ACP1, and / or an antisense lnRNA selected from the group consisting of UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CD KL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A 1, NAA351, HS3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR2 71, NBPF141, TMEM132E1, GAGE131, GAGE2D1, GAGE2D:copy21, ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and / or HNRNPU-AS1.

[0139] In one aspect, the microbial inflammation is in the blood, brain, paranasal sinuses, upper respiratory tract, or lungs, heart, bone marrow, spleen, liver, kidneys, genitourinary tract, bladder, ear cavity, stomach, intestines, skin, eyes, teeth, or gums, and the musculoskeletal system.

[0140] It is understood and contemplated herein that, despite the disclosed composition's ability to inhibit microbial inflammation, the addition of an antimicrobial agent (either in the composition itself or administered separately) may be desirable for the treatment of actual infection.Therefore, disclosed herein is a method for treating, inhibiting, reducing or preventing microbial inflammation in a subject, further comprising administering an antimicrobial agent to the subject.Antimicrobial agents can include any antibiotic, antibody, small molecule, and functional nucleic acid (siRNA, RNAi, antisense oligonucleotide) that directly attacks the infecting microorganism or changes the host condition, making the host system invulnerable to microorganisms. Such agents include, but are not limited to, abacavir, acyclovir, adefovir, amantadine, amprenavir, Ampligen, arbidol, atazanavir, atripla, baravir, beta-D-N4-hydroxycytidine (NHC, EIDD-1931), cidofovir, combivir, dolutegravir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, Ecoliever, famciclovir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, hydroxy-chloroquine, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, lamivudine, lopinavir, loviride, maraviroc, moroxyvir, bromodi ... aztreonam, methisazone, nelfinavir, nevirapine, nexavir, nitazoxanide, norvir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, remdesivir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, sofosbuvir, stavudine, telaprevir, tenofovir, tenofovir Ludisoproxil, Tipranavir, Trifluridine, Trizivir, Tromantadine, Travada, Valaciclovir, Valganciclovir, Vicriviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir, Zidovudine, Clofazimine; Dapsone; Capreomycin; Cycloserine; Ethambutol (Bs); Ethionamide; Isoniazid; Pyrazinamide; Rifampicin; Rifabutin;Rifapentine;Streptomycin;Arsphenamine;Chloramphenicol (Bs);Fosfomycin;Fusidic acid;Metronidazole;Mupirocin;Platensimycin;Quinupristin / Dalfopristin;Thiamphenicol;Tigecycline (Bs);Tinidazole;Trimethoprim (Bs);Aminoglycosides, e.g., Amikacin, Gentamicin, Kanamycin, Meropenem, Neomycin, Netilma isin, tobramycin, paromomycin, streptomycin, spectinomycin, nitazoxanide, melarsoproline, eflornithine, metronidazole, tinidazole, miltefosine, mebendazole, pyrantel pamoate, thiabendazole, diethylcarbamazine, ivermectin, niclosamide, praziquantel, albendazole, praziquantel, rifampin, amphotericin B, fumagillin, amphotericin Syn B, Candicidin, Philippine, Hamycin, Natamycin, Nystatin, Rimocidin, Bifonazole, Butoconazole, Clotrimazole, Econazole, Fenticonazole, Isoconazole, Ketoconazole, Luliconazole, Miconazole, Omoconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole, Albaconazole, Efinaconazole, Epoxiconazole, Fluconazole, Isavuconazole, Itraconazole, Posaconazole, Propiconazole, Ravuconazole, Terconazole, Voriconazole, Abafungin, Anidulafungin, Caspofungin, Micafungin, Aurones, Benzoic Acid, Ciclopirox, Flucytosine, Griseofulvin, Haloprogin, Tolnaftate, Undecylenic Acid, Crystal Violet, Balsam of Peru of Peru), Orotomide, Miltefosine; Ansamycins such as Geldanamycin, Rifaximin, Herbimycin; Carbapenems such as Ertapenem, Doripenem, Imipenem / Cilastatin, and Meropenem;For example, cefadroxil, cefazolin, cephadine, cephapirin, cephalothin, cephalexin, cefaclor, cefoxitin, cefotetan, cefamandole, cefmetazole, cefonicid, loracarbef, cephalosporin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, moxalactam, ceftriaxone, cef ceftazidime, ceftaroline fosamil, and ceftobiprole; glycopeptides, such as teicoplanin, vancomycin, telavancin, dalbavancin, and oritavancin; lincosamides (B), such as clindamycin and lincomycin; lipopeptides, such as daptomycin; macrolides (B), such as azithromycin, clarithromycin, erythromycin, roxithromycin, telithromycin, and spiramycin; monobactams, such as Nitrofurans, such as Furazolidone and Nitrofurantoin (Bs); Oxazolidinones (Bs), such as Linezolid, Posizolid, Radezolid, and Trezolid; Penicillins, such as Amoxicillin, Ampicillin, Azocillin, Dicloxacillin, Flucloxacillin, Mezocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Penicillin polypeptides, such as bacitracin, colistin, and polymyxin B; quinolones / fluoroquinolones, such as ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin;Sulfonamides (Bs), such as Mafenide, Sulfacetamide, Sulfadiazine, Silver Sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide (Alkaline), Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (Co-Trimoxazole) (TMP-SMX), and Sulfonamide Chrysoidine (Alkaline); Tetracyclines (B), such as Demeclocycline, Doxycycline, Methacycline, Minocycline, Oxytetracycline, and Tetracycline; Monoclonal antibodies, such as Actoxumab, Atidortoxumab, Berlimatoxumab, Bezlotoxine, and Bezlotoxine; Xumab, Cosfroviximab, Edobacomab, Felvizumab, Filibumab, Foravirumab, Larcaviximab, Motavizumab, Navivumab, Panobacumab, Palivizumab, Porgaviximab, CR6261, Rafivirumab, Pagibaximab, Obiltoxaximab, Ibalizumab, Regavirumab, Rmab, Sevirumab, Rivabazumab pegol pegol, tefibazumab, subratoxumab, and tuvirumab; and checkpoint inhibitors; such as pembrolizumab, nivolumab, atezolizumab, avelumab, daruvalumab, pidilizumab, AMP-224, AMP-514, PDR001, cemilimab, and ipilimumab.

[0141] H. Methods of Treating Cancer The disclosed secretome and RNA compositions can be used to treat any disease in which uncontrolled cell proliferation occurs, such as cancer. A representative, but non-limiting list of cancers that can be treated using the disclosed compositions is as follows: lymphomas, such as B-cell lymphoma and T-cell lymphoma; mycosis fungoides; Hodgkin's disease; myeloid leukemia (including, but not limited to, acute myeloid leukemia (AML) and / or chronic myeloid leukemia (CML)); bladder cancer; brain cancer; nervous system cancer; head and neck cancer; head and neck squamous cell carcinoma; kidney cancer; small cell lung cancer, non-small ... Lung cancer, such as small cell lung cancer (NSCLC), lung squamous cell carcinoma (LUSC), and lung adenocarcinoma (LUAD); neuroblastoma / glioblastoma; ovarian cancer; pancreatic cancer; prostate cancer; skin cancer; liver cancer; melanoma; squamous cell carcinoma of the mouth, throat, larynx and lung; cervical cancer; breast cancer, including but not limited to triple-negative breast cancer; genitourinary cancer; lung cancer; esophageal cancer; head and neck cancer; colorectal cancer; hematopoietic cancer; testicular cancer; and colon and rectal cancer. Thus, in one aspect, a method of treating, inhibiting, reducing, decreasing, ameliorating and / or preventing inflammatory damage resulting from cancer and / or metastasis in a subject is provided, comprising administering to a subject one or more secretome (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising compositions), and one or more of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-10 ... R-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hs a-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5 p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a,hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1, hsa-miR-16-2, hsa-miR-16-5p, and hsa-miR -17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR- 199b-5p、hsa-miR-19a-3p、hsa-miR-19b-3p、hsa-miR-20a-5p、hsa-miR-2 03a、hsa-miR-203a-3p、hsa-miR-214-3p、hsa-mir-21、hsa-miR-21-3p、hs a-miR-21-5p, hsa-miR-221, hsa-miR-221-3p, hsa-miR-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-24-1, hsa-miR-24-2, hsa-miR-24-3p, hsa-miR-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-miR-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hs a-miR-29c-3p、hsa-miR-30a-5p、hsa-miR-30a-5p、hsa-miR-30b-5p、hsa- miR-30c-5p、hsa-mir-30d、hsa-miR-30d-5p、hsa-mir-30e、hsa-miR-30e-5 p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-mi R-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-miR-486-1, hsa-miR-486-2, hsa-miR-486-5p, and hsa-miR-570-3phsa-miR-574-3p、hsa-miR-663a、hsa-miR-874-3p、hsa-miR-92a-1、hsa-mir-92a-2、hsa-miR-92a-3p、hsa-mi R-92b-3p、hsa-mir-93、hsa-miR-93-5p、hsa-miR-940、hsa-miR-99a-5p、hsa-miR-99b-5p、HBII-202、U26、U29、 HBII-420、U30、U18A、U81、GSKIP、IFT88、PCDH11X、PCDH11Y、KIAA0226L、PDE11A、PHACTR1、TEX14、DCUN1D2、SIM 1, FILIP1, FAM107B, CHADL, ZNF365, MNAT1, CYSTM1, GAS7, HOXB7, ASTN2, LGR5, ZFHX3, MCM7, GRIK1, MAP2, LHFPL3 、PTER、STAMBP、CCDC135、PAX9、RPL13、ABCA13、DAAM1、OPN1LW、OPN1MW2、CNOT6L、MTRNR2L10、SMC4、RPL4、PSAP、 ASIC4、AHCYL1、RD3L、SIGLEC1、SYCE2、NANS、LOC100129335-5、ZNF238、CADM2-7、SALL1-6、VWA5A、RF00019.441、 RF00019.451、RF00019.621、RF00019.646、RF00019.413、piR-33044、piR-33043、piR-31703、RNY4、LOC441666、 SNHG1、RNU11、LOC80154、LOC727751、LOC388152、GOLGA2P2Y、GOLGA2P3Y、SNHG12、RNU12、ASMTL-AS1、LOC284454 U2:RF00004.39、U2:RF00004.22、U2:RF00004.35、U2:RF00004.71、U2:RF00004.66 U2:RF00004.91、U2:RF00004.89、U2:RF00004.67、U1:RF00003.5、U1:RF00003.109、U1:RF00003.110、U1:RF 00003.8、U1:RF00003.3、U1:RF00003.6、U1:RF00003.38、U1:RF00003.20、U1:RF00003.24、U1:RF00003.73、U1:RF00003.11, U1:RF00003.27, U1:RF00003.40, U1:RF00003.107, U1:RF00003.62, U1:RF00003.45, U1:RF00003.116, U1:RF00003.126, U1:RF0000 3.81, U1:RF00003.100, U1:RF00003.57, U1:RF00003.95, U1:RF00003.31, U1:RF00003.61, U1:RF00003.25, U1:RF00003.90, U1:RF00003.46, U1:RF0 0003.123, U2:RF00004.42, U2:RF00004.61, U2:RF00004.51, U1:RF00003.122, U1:RF00003.22, U1:RF00003.9, snoMBII-202:RF00324.2, let-7:RF0 0027.7, U2:RF00004.75, U1:RF00003.69, U2:RF00004.88, U12:RF00007.1 , U7:RF00066.141, U1:RF00003.85, U7:RF00066.49, U2:RF00004.77, U1:RF 00003.113, U1:RF00003.112, U1:RF00003.70, U1:RF00003.83, U7:RF00066.89, U7:RF00066.124, U7:RF00066.75, U7:RF00066.77, U7:RF00066.118, U7:RF00066.103, U7:RF00066.79, U7:RF00066.200, and / or U7:RF00066.146, UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10 orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLC N51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, GAGE2D:copy21,Disclosed herein are methods comprising administering to a subject a therapeutically effective amount of a composition comprising two or more RNA molecules, including ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and / or HNRNPU-AS1.

[0142] For example, disclosed herein are methods of treating, inhibiting, decreasing, reducing, ameliorating and / or preventing cancer and / or cancer-associated metastasis or inflammatory symptoms in a subject having cancer, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretome (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs are selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-5p, hsa-let-7e-5p, hsa-let-7f-5p, hsa-let-7g-5p, hsa-let-7i ... et-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir -130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p , hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR -16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR- 199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21,It contains at least one miRNA selected from the group consisting of hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486-2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR-99b-5p. Preferably, two or more RNAs are miR-92a-3p, let-7i-5p, miR-16-5p, miR-93-5p, miR-21-5p, miR-214-3p, miR-29c-3p, miR-34a-5p, mir-203a-3p, miR-27b-3p, miR-140-3p, miR-24-3p, miR-222-3p,Further disclosed herein are methods comprising at least one miRNA selected from the group consisting of miR-25-3p, miR-10b-5p, miR-221-3p, miR-17-5p, miR-30a-5p, and miR-30d-5p. Further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing cancer and / or cancer-associated metastasis or inflammatory symptoms in a subject having cancer, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretome (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs are selected from the group consisting of HBII-202, U26, U29, HBII-420, U30, U18A, U81, GSKIP, IFT88, PCDH11X, PCDH11Y, KIAA0226L, PDE11A, and the like. , PHACTR1, TEX14, DCUN1D2, SIM1, FILIP1, FAM107B, CHADL, ZNF365, MNAT1, CYSTM1, GAS7, H0XB7, ASTN2, LGR5, ZFHX3, MCM7, GRIK1, MAP2, LHFPL3, PTER, STAMBP, CCDC135, PAX9, RPL13, ABCA13, DAAM1, 0PN1LW, 0PN1MW2, CNOT6L, MTRNR2L10, SMC4, RPL4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2 and NANS. Further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing cancer and / or cancer-associated metastasis or inflammatory symptoms in a subject having cancer, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretome (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs are selected from the group consisting of RF00019.441, RF00019.451, RF00019.621, RF00019.646,and RF00019.413.Further disclosed herein is a method of treating, inhibiting, reducing, decreasing, ameliorating, and / or preventing cancer and / or cancer-associated metastasis or inflammatory symptoms in a subject having cancer, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs comprise at least one lncRNA selected from the group consisting of LOC100129335-5, ZNF238, CADM2-7, SALL1-6, and VWA5A. Further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing cancer and / or cancer-associated metastasis or inflammatory symptoms in a subject having cancer, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretomes (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts, and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs comprise at least one pi-RNA selected from the group consisting of piR-33044, piR-33043, and piR-31703. In one embodiment, the RNA can be an antisense RNA. Accordingly, further disclosed herein is a method of treating, inhibiting, decreasing, reducing, ameliorating and / or preventing cancer and / or cancer-associated metastasis or inflammatory symptoms in a subject having cancer, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more secretome (including, but not limited to, liposomes, lipid nanoparticles, MSC growth factors, MSC exosomes, MSC extracts and / or extracellular vesicles comprising the composition) and two or more RNA molecules, wherein the two or more RNAs are selected from the group consisting of UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11,TACR11, ZNF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, and GAGE2D:copy21. at least one antisense mRNA selected from the group consisting of: ANKRD5-1, ZNF236-1, and ACP1; and / or an antisense lnRNA selected from the group consisting of: UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP 51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, HS3ST41, SLC44A51, CLCN51, ST6 GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAG The antisense RNA is selected from the group consisting of E131, GAGE2D1, GAGE2D:copy21, ANKRD5-1, ZNF236-1, ACP1, EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and / or HNRNPU-AS1.

[0143] Disclosed treatment regimens include, alone or in combination with Abemaciclib-Abiraterone acetate-Abitrexate (Methotrexate)-Abraxane (paclitaxel albumin stabilized small particle formulation), ABVD, ABVE, ABVE-PC, AC, AC-T, Adcetris (Brentuximab vedotin)-ADE), Ado-trastuzumab Emtansine, Adriamycin (Doxorubicin hydrochloride), Afatinib maleate, Dimaleate, Afinitor (Everolimus), Akynzeo (Netupitant and Palonosetron Hydrochloride), Aldara (Imiquimod), Aldesleukin, Alectinib, Alemtuzumab, Alimta (Pemetrexed Disodium), Aliqopa (Copanlisib Hydrochloride), Alkeran for Injection (Melphalan Hydrochloride), Hydrochloride), Alkeran Tablets (Melphalan), Aloxi (Palonosetron Hydrochloride), Alumbrig (Brigtinib), Ambochlorin (Chlorambucil), Amboclorin (Chlorambucil), Amifostine, Aminolevulinic Acid, Anastrozole, Aprepitant, Aredia (Pamidronate Disodium), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arsenic Trioxide, Arzerra (Ofatumumab), Asparaginase Erwinia chrysanthemumiichrysanthemi), atezolizumab, Avastin (bevacizumab), avelumab, axitinib, azacitidine, BAVENCIO (avelumab), BEACOPP, Besenam (carmustine), Beloadaq (belinostat), belinstat, bendamustine hydrochloride (bendamustine hydrochloride), BEP, Besponsa (inotuzumab ozogamicin), bevacizumab, bexarotene, Bexar (tositumomab and iodine I 131 Tositumomab), bicalutamide, BiCNU (carmustine), bleomycin, blinatumomab, Blincyto (blinatumomab), bortezomib, Bosulif (bosutinib), bosutinib, brentuximab vedotin, brigutinib, BuMel, busulfan, Busulfex (busulfan), cabazitaxel, Cabometyx (cabozantinib-S-malate), cabozantinib-S-malate, CAF, Campus ( Alemtuzumab), Camptosar, (Irinotecan hydrochloride), Capecitabine, CAPOX, Carac (fluorouracil-topical), Carboplatin, Carboplatin-TAXOL, Carfilzomib, Carmubris (Carmustine), Carmustine, Carmustine implant, Casodex (Bicalutamide), CEM, Ceritinib, Cerubidine (Daunomycin hydrochloride Hydrochloride), Cervarix (Recombinant HPV Bivalent Vaccine), Cetuximab, CEV, Chlorambucil, Chlorambucil-Prednisone, CHOP, Cisplatin, Cladribine, Clafen (Cyclophosphamide), Clofarabine, Clofarex (Clofarabine), Clolar (Clofarabine), CMF, Cobimetinib, Cometriq (Cabozantinib-S-Malate), Copanlisib HydrochlorideHydrochloride), COPDAC, COPP, COPP-ABV, Cosmegen (Dactinomycin), Cotellic (Cobimetinib), Crizotinib, CVP, Cyclophosphamide, Cyfos (Ifosfamide), Cyramza (Ramucirumab), Cytarabine, Cytarabine Liposomal, Cytosar-U (Cytarabine), Cytoxan (Cyclophosphamide), Dabrafenib, Dacarbazine, Dacogen (Decitabine), Dactinomycin, Daratumumab, Darazalex (Daratumumab), Dasatinib, Daunorubicin Hydrochloride, Daunorubicin Hydrochloride and Cytarabine Liposomal, Decitabine, Defibrotide Sodium Sodium), Defitelio (Defibrotide Sodium), Degarelix, Denileukin Diftitox, Denosumab, Depocyte (Cytarabine Liposome), Dexamethasone, Dexrazoxane Hydrochloride Hydrochloride), Dinutuximab, Docetaxel, Doxil (Doxorubicin Hydrochloride Liposomal), Doxorubicin Hydrochloride, Doxorubicin Hydrochloride Liposomal, Dox-SL (Doxorubicin Hydrochloride Liposomal), DTIC-Dome (Dacarbazine), Durvalumab, Efudex (Fluorouracil-topical), Elitek (Rasburicase), Ellence (Epirubicin Hydrochloride), Elotuzumab, Eloxatin (Oxaliplatin), Eltrombopagolamine, Emend (Aprepitant), Empliciti (Elotuzumab), Enadeznib Mesylate Mesylate), Enzalutamide, Epirubicin Hydrochloride, EPOCH, Erbitux (Cetuximab), Eribulin Mesylate, Erivedge (Vismodegib), Erlotinib Hydrochloride, Erwinaze (Asparaginase Erwinia chrysanthemi), Ethyol (Amifostine), Etopophos (Etoposide Phosphate), Etoposide, Etoposide PhosphatePhosphate), Evacetrapib (Doxorubicin Hydrochloride Liposomal), Everolimus, Evista, (Raloxifene Hydrochloride), Evomela (Melphalan Hydrochloride), Exemestane, 5-FU (Fluorouracil Injection), 5-FU (Fluorouracil - Topical), Fairston (Toremifene), Faridak (Panobinostat), Faslodex (Fulvestrant), FEC, Femara (Letrozole), Filgrastim, Fludara (Fludarabine Phosphate), Fludarabine Phosphate, Fluoroplex (Fluorouracil - Topical), Fluorouracil Injection, Fluorouracil - Topical, Flutamide, Folex (Methotrexate), Folex PFS (methotrexate), FOLFIRI, FOLFIRI-bevacizumab, FOLFIRI-cetuximab, FOLFIRINOX, FOLFOX, FOLOTHIN (pralatrexate), FU-LV, fulvestrant, Gardasil (recombinant HPV quadrivalent vaccine), Gardasil 9 (recombinant HPV nonavalent vaccine), Gazyva (obinutuzumab), gefitinib, gemcitabine hydrochloride, gemcitabine-cisplatin, gemcitabine-oxaliplatin, gemtuzumab ozogamicin, Gemzar (gemcitabine hydrochloride), Gilotrif (Afatinib) Dimaleate, Gleevec (Imatinib Mesylate), Gliadel (Carmustine Implant), Gliadel Wafer (Carmustine Implant), Glucarpidase, Goserelin Acetate, Halaven (Eribulin Mesylate), Hemangeol (Propranolol Hydrochloride), Herceptin (Trastuzumab), HPV Bivalent Vaccine, Recombinant, HPV Nonavalent Vaccine, Recombinant, HPV Quadrivalent Vaccine, Recombinant, Hycamtin (Topotecan Hydrochloride), Hydrea (Hydroxyurea), Hydroxyurea, Hyper-CVAD, Ibrance (Palbociclib), Ibritumomab Tiuxetan, Ibrutinib, ICE, Iclusig (Ponatinib Hydrochloride), Idamycin (Idarubicin Hydrochloride)Hydrochloride), Idarubicin Hydrochloride, Idelalisib, Idhifa (Enasidenib Mesylate), Ifex (Ifosfamide), Ifosfamide, Ifosfamidum (Ifosfamide), IL-2 (Aldesleukin), Imatinib Mesylate, Imbruvica (Ibrutinib), Imfinzi (Durvalumab), Imiquimod, Imlygic (Talimogene Laherparepvec), Inlyta (Axitinib), Inotuzumab Ozogamicin, Interferon alpha-2b, Recombinant, Interleukin-2 (Aldesleukin), Intron A (Recombinant Interferon alpha-2b), Iodine I 131 Tositumomab and Tositumomab, Ipilimumab, Iressa (gefitinib), Irinotecan hydrochloride, Irinotecan hydrochloride liposomal, Istodax (romidepsin), Ixabepilone, Ixazomib citrate, Ixempra (ixabepilone), Jakafi (ruxolitinib phosphate), JEB, Jevtana (cabazitaxel), Kadcyla (Ado-trastuzumab emtansine) Emtansine), Keoxifene (Raloxifene Hydrochloride), Kepivans (Palifermin), Keytruda (Pembrolizumab), Kisqali (Ribociclib), Kymriah (Tisagenlecleucel), Kyprolis (Carfilzomib), Lanreotide Acetate, Lapatinib Ditosylate, Lartruvo (Olaratumab), Lenalidomide, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Letrozole, Leucovorin CalciumCalcium), Leukeran (Chlorambucil), Leuprolide Acetate, Leystatin (Cladribine), Levulan (Aminolevulinic Acid), Linfolizin (Chlorambucil), LipoDox (Doxorubicin Hydrochloride Liposomal), Lomustine, Lonsurf (Trifluridine and Trifluridine-Tipiracil Hydrochloride), Lupron (Leuprolide Acetate), Lupron Depot (Leuprolide Acetate), Lupron Depot-Ped (Leuprolide Acetate), Lynparza (Olaparib), Marqibo (Vincristine Sulfate Liposomal), Matulane (Procarbazine Hydrochloride), Mechlorethamine Hydrochloride, Megestrol Acetate, Mekinist (Trametinib), Melphalan, Melphalan Hydrochloride Hydrochloride), Mercaptopurine, Mesna, Mesnex (Mesna), Methazolastone (Temozolomide), Methotrexate, Methotrexate LPF (Methotrexate), Methylnaltrexone Bromide, Mexate (Methotrexate), Mexate-AQ (Methotrexate), Midostaurin, Mitomycin C, Mitoxantrone Hydrochloride, Mitozytrex (Mitomycin C), MOPP, Mozobil (Plerixafor), Mustargen (Mechlorethamine Hydrochloride), Mutamycin (Ma Mylostatin C), Myleran (Busulfan), Mylosar (Azacitidine), Mylotarg (Gemtuzumab Ozogamicin), Nanoparticle Paclitaxel (Paclitaxel Albumin Stabilized Small Particle Formulation), Navelbine (Vinorelbine Tartrate), Necitumumab, Nelarabine, Neosar (Cyclophosphamide), Neratinib Maleate, Nerlynx (Neratinib Maleate) Maleate), Netupitant and Palonosetron Hydrochloride, Neulasta (Pegfilgrastim), Neupogen (Filgrastim), Nexavar (Sorafenib Tosylate), Nilandron (Nilutamide), Nilotinib, Nilutamide, Ninlaro (Ixazomib Citrate), Niraparib Tosylate Monohydrate Monohydrate), Nivolumab, Nolvadex (Tamoxifen Citrate), Nplate (Romiplostim), Obinutuzumab, Odomzo (Sonidegib), OEPA, Ofatumumab, OFF, Olaparib, Olaratumab, Omacetaxine Mepesuccinate, Oncaspar (Pegaspargase), Ondansetron Hydrochloride, Onivyde (Irinotecan Hydrochloride Liposome), Ontak (Denileukin Diftitox), Opdivo (Nivolumab), OPPA, Osimertinib, Oxaliplatin, Paclitaxel, Pa Clitaxel albumin stabilized small particle formulation, PAD, palbociclib, palifermin, palonosetron hydrochloride, palonosetron hydrochloride and netupitant, pamidronate disodium, panitumumab, panobinostat, paraplatin (carboplatin), paraplatin (carboplatin), pazopanib hydrochloride, PCV, PEB, pegaspargase, pegfilgrastim, peginterferon alpha-2b, PEG-Intron (peginterferon alpha-2b), pembrolizumab, pemetrexed disodiumDisodium), Perjeta (Pertuzumab), Pertuzumab, Platinol (Cisplatin), Platinol-AQ (Cisplatin), Plerixafor, Pomalidomide, Pomalyst (Pomalidomide), Ponatinib Hydrochloride, Portraza (Necitumumab), Pralatrexate, Prednisone, Procarbazine Hydrochloride, Proleukin (Aldesleukin), Prolia (Denosumab), Promacta (Eltrombopagulamine), Propranolol Hydrochloride, Provenzi (Sipuleucel-T), Purinethol (Mercaptopurine), Purixan (Mercaptopurine), Radium-223 Chloride, Raloxifene Hydrochloride, Ramucirumab, Rasburicase , R-CHOP, R-CVP, recombinant human papillomavirus (HPV) bivalent vaccine, recombinant human papillomavirus (HPV) nonavalent vaccine, recombinant human papillomavirus (HPV) quadrivalent vaccine, recombinant interferon alpha-2b, regorafenib, Relistol (methylnaltrexone bromide), R-EPOCH, Revlimid (lenalidomide), Rheumatrex (methotrexate), ribociclib, R-ICE, Rituxan (rituximab), Rituxan Hycela (Rituximab and Hyaluronidase (Human Origin)), Rituximab, Rituximab and Hyaluronidase (Human Origin), Rolapitant Hydrochloride, Romidepsin, Romiplostim, Rubidomycin (Daunomycin Hydrochloride), Rubraca (Rucaparib Camsylate), Rucaparib Camsylate, Ruxolitinib Phosphate, Rydapt (Midostaurin), Sclerosol Intrapleural Aerosol (Talc), Siltuximab, Sipuleucel T, Somatuline Depot (Lanreotide Acetate) Acetate), Sonidegib, Sorafenib Tosylate, Sprycel (dasatinib), STANFORDV, Sterile Talc Powder (Talc), Steritalc (Talc), Stivarga (Regorafenib), Sunitinib Malate, Sutent (Sunitinib Malate), Sylatron (Peginterferon α-2b), Sylvant (Siltuximab), Synribo (Omacetaxine Mepesuccinate), Tabloid (Thioguanine), TAC, Tafinlar (Dabrafenib), Tagrisso (Osimertinib), Talc, Talimogene Laherparepvec, Tamoxifen Citrate, Tarabine PFS (Cytarabine), Tarceva (Erlotinib Hydrochloride), Targretin (Bexarotene), Tasigna (Nilotinib), Taxol (Paclitaxel), Taxotere (Docetaxel), Tecentriq (Atezolizumab), Temodar (Temozolomide), Temsirolimus, Thalidomid, Thalomid, Thioguanine, Thiotepa, Tisagenlecleucel, Tolak (Fluorouracil-Topical), Topotecan Hydrochloride, Toremifene, Torisel (Temsirolimus), Tositumomab and Iodine I 131 Tositumomab, Totect (Dexrazoxane Hydrochloride) Hydrochloride), TPF, Trabectedin, Trametinib, Trastuzumab, Treanda (Bendamustine Hydrochloride), Trifluridine and Trifluridine-Tipiracil Hydrochloride, Trisenox (Arsenic Acid), Tykerb (Lapatinib Ditosylate), Unituxin (Dinutuximab), Uridine Triacetate, VAC, Vandetanib, VAMP, Varubi (Rolapitant Hydrochloride) Hydrochloride), Vectibix (panitumumab), VeIP, Velban (vinblastine sulfate), Velcade (bortezomib), Velsar (vinblastine sulfate), vemurafenib, Venclexta (venetoclax), venetoclax, Verzenio (abemaciclib), Viadur (leuprolide acetate), Vidaza (azacitidine), vinblastine sulfate, VincasarPFS (Vincristine Sulfate), Vincristine Sulfate, Vincristine Sulfate Liposomal, Vinorelbine Tartrate, VIP, Vismodegib, Vistogard (Uridine Triacetate), Voraxaze (Glucarpidase), Vorinostat, Votrient (Pazopanib Hydrochloride), Vyxeos (Daunorubicin Hydrochloride and Cytarabine Liposomal), Wellcovorin (Leucovorin Calcium) Calcium), Xalkori (Crizotinib), Xeloda (Capecitabine), XELIRI, XELOX, Xgeva (Denosumab), Xofigo (Radium-223 Chloride), Xtandi (Enzalutamide), Yervoy (Ipilimumab), Yondelis (Trabectedin), Zaltrap (Ziv-Aflibercept), Zarxio (Filgrastim), Zejula (Niraparib Tosylate Monohydrate), Zelboraf (Vemurafenib), Zevalin (Ibritumomab Tiuxetan), Zinecard (Dexrazoxane Hydrochloride) (Abiraterone Acetate), Ziv-Aflibercept, Zofran (Ondansetron Hydrochloride), Zoladex (Goserelin Acetate), Zoledronic Acid, Zolinza (Vorinostat), Zometa (Zoledronic Acid), Zydelig (Idelalisib), Zykadia (Ceritinib), and / or Zytiga (Abiraterone Acetate)It is understood and contemplated herein that the present invention may be used in combination with any anti-cancer therapy known in the art, including, but not limited to, nivolumab (BMS-936558 or MDX1106), CT-011, MK-3475), PD-L1 (MDX-1105 (BMS-936559), MPDL3280A, or MSB0010718C), PD-L2 (rHIgM12B7), CTLA-4 (ipilimumab (MDX-010), tremelimumab (CP-675,206)), IDO, B7-H3 (MGA271), B7-H4, TIM3, LAG-3 (BMS-986016). EXAMPLES

[0144] I. Working Example The following examples are presented to provide those skilled in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely illustrative and are not intended to limit the disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, temperature is ° C. or at ambient temperature, and pressure is at or near atmospheric pressure.

[0145] Here, we compare the effects of naturally produced microRNA packaged in bone marrow mesenchymal stem cell-derived extracellular vesicles (BM-MSC EVs) with the effects of synthetic microRNA whose sequences have been shown to inhibit inflammasome formation and secretion of the pro-inflammatory cytokine interleukin-1-β (IL-1β).

[0146] THP-1 cells were differentiated into macrophage phenotype cells and exposed to LPS to induce IL-1β production by the cells. The cells were then transfected with either naturally produced RNA packaged in BM-MSC EVs or with a cocktail of synthetic RNA sequences associated with negative regulation of IL-1β. The miRNA cocktail included the following human miRNA sequences: miR-222-3p, miR-24-3p, miR-27b-3p, miR-221-3p, miR-21-5p. In one test condition, the microRNA hmiR21-5p was transfected alone since it is believed to be the main miRNA regulator of IL-1β. Twenty-four hours after adding LPS and test substances to the cells, conditioned medium was collected and IL-1β protein concentration was measured using a commercially available ELISA assay kit. The results of the test are shown in Figure 1. The percent inhibition of IL-1β in the test samples compared to LPS-stimulated cells alone is summarized in Table 1.

[0147] [Table 1]

[0148] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

Claims

1. A composition comprising one or more secretomes and two or more ribonucleic acid (RNA).

2. The composition of claim 1 , wherein the secretome comprises a liposome or a lipid nanoparticle.

3. 2. The composition of claim 1, wherein the secretome comprises exosomes or extracellular vesicles derived from mesenchymal stem cells (MSCs).

4. 4. The composition of any one of claims 1 to 3, wherein the two or more RNAs comprise microRNA (miRNA), messenger RNA (mRNA), long non-coding RNA (lncRNA), y-RNA, and / or pi-RNA.

5. The two or more RNAs are RNY4, LOC441666, SNHG1, RNU11, LOC80154, LOC727751, LOC388152, GOLGA2P2Y, GOLGA2P3Y, SNHG12, RNU12, ASMTL-AS1, LOC284454 U2: RF00004.39, U2: RF00004.22, U2: RF00004.35, U2: RF00004.71, U2: RF00004.66U2:RF00004.91, U2:RF00004.89, U2:RF00004.67, U1:RF00003.5, U1:RF00003.109, U1:RF00003.110, U1:RF00003.8, U1:RF00003.3, U 1: RF00003.6, U1: RF00003.38, U1: RF00003.20, U1: RF00003.24, U1: RF00003.73, U1: RF00003.11, U1: RF00003.27, U1: RF00003.40, U1: RF00003.107, U1:RF00003.62, U1:RF00003.45, U1:RF00003.116, U1:RF00003.126, U1:RF00003.81, U1:RF00003.100, U1:RF00003.57, U1:RF00003.95, U1:RF00003.31, U1:RF00003.61, U1:RF00003.25, U1:RF00003.90, U1:RF00003.46, U1:RF00003.123, U2:RF00004.42, U2:RF00004.61, U2:RF00004.51, U1:RF00003.122, U1:RF00003.22, U1:RF00003.9, snoMBII-202:RF00324.2, let-7:RF00027.7, U2:R F00004.75, U1:RF00003.69, U2:RF00004.88, U12:RF00007.1, U7:RF00066.141, U1:RF00003.85, U7:RF00066.49, U2:RF00004.77, U1:R 5. The composition of claim 4, comprising at least one RNA selected from the group consisting of: U7:RF00003.113, U1:RF00003.112, U1:RF00003.70, U1:RF00003.83, U7:RF00066.89, U7:RF00066.124, U7:RF00066.75, U7:RF00066.77, U7:RF00066.118, U7:RF00066.103, U7:RF00066.79, U7:RF00066.200, and U7:RF00066.

146.

6. The composition of claim 4, wherein the two or more RNAs comprise at least one antisense RNA selected from the group consisting of EPHA1-AS1, FLJ45974, ANKRD30BP2, LINC00340, GRIK1-AS1, LOC440300, CSPG4P8, ADARB2-AS1, MLLT4-AS1, and HNRNPU-AS1.

7. The two or more RNAs are hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p, hsa-miR-26a-5p,hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR- 30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR-30d-5p, hs a-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-342-3p , hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa -miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486- 2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mi The composition of claim 4, comprising at least one miRNA selected from the group consisting of hsa-mir-92a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR-99b-5p.

8. 7. The composition of claim 6, wherein the two or more RNAs comprise at least one miRNA selected from the group consisting of miR-92a-3p, let-7i-5p, miR-16-5p, miR-93-5p, miR-21-5p, miR-214-3p, miR-29c-3p, miR-34a-5p, mir-203a-3p, miR-27b-3p, miR-140-3p, miR-24-3p, miR-222-3p, miR-25-3p, miR-10b-5p, miR-221-3p, miR-17-5p, miR-30a-5p, and miR-30d-5p.

9. The two or more RNAs are HBII-202, U26, U29, HBII-420, U30, U18A, U81, GSKIP, IFT88, PCDH11X, PCDH11Y, KIAA0226L, PDE11A, PHACTR1, TEX14, DCUN1D2, SIM1, FILIP1, FAM107B, CHADL, ZNF365, MNAT1, CYSTM1, GAS7, HOXB7, ASTN2, LGR5, ZFHX3, 5. The composition of claim 4, comprising at least one mRNA selected from the group consisting of MCM7, GRIK1, MAP2, LHFPL3, PTER, STAMBP, CCDC135, PAX9, RPL13, ABCA13, DAAM1, OPN1LW, OPN1MW2, CNOT6L, MTRNR2L10, SMC4, RPL4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2, and NANS.

10. The two or more RNAs are selected from the group consisting of UBAP11, SMC51, TMX11, LTA4H1, KIF20B1, OPCML1, RNLS1, CDKL21, C10orf531, ACOX31, GPC51, GATA41, EPHA61, CNTNAP51, ZRANB31, KIAA17151, TOX1, ALPK11, TACR11, ZNF6521, FAM154A1, NAA351, HS3ST41, SL The composition of claim 4, comprising at least one antisense mRNA selected from the group consisting of C44A51, CLCN51, ST6GALNAC51, ABCA41, COL5A11, AKIP11, UGT81, DRP21, AMOTL11, FGFR1OP21, WBSCR271, NBPF141, TMEM132E1, GAGE131, GAGE2D1, and GAGE2D:copy21.

11. 5. The composition of claim 4, wherein the two or more RNAs comprise at least one lncRNA selected from the group consisting of LOC100129335-5, ZNF238, CADM2-7, SALL1-6, and VWA5A.

12. 5. The composition of claim 4, wherein the two or more RNAs comprise at least one antisense lncRNA selected from the group consisting of ANKRD5-1, ZNF236-1, and ACP1.

13. 5. The composition of claim 4, wherein the two or more RNAs comprise at least one y-RNA selected from the group consisting of RF00019.441, RF00019.451, RF00019.621, RF00019.646, and RF00019.

413.

14. 5. The composition of claim 4, wherein the two or more RNAs comprise at least one pi-RNA selected from the group consisting of piR-33044, piR-33043, and piR-31703.

15. The composition of any one of claims 1 to 14, wherein the RNA comprises a modification to reduce degradation.

16. The composition of claim 15, wherein the modification comprises the addition of a 2'-O methyl group, a 2'-fluoro group, or a 2'-hydro group.

17. A method of modulating an immune response to inflammatory injury in a subject, comprising administering to said subject any of the compositions of any one of claims 1 to 17.

18. The modulation increases inflammation, and the two or more RNAs of the composition are selected from the group consisting of HBII-202, U26, U29, HBII-420, U30, U18A, U81, GSKIP, IFT88, PCDH11X, PCDH11Y, KIAA0226L, PDE11A, PHACTR1, TEX14, DCUN1D2, SIM1, FILIP1, FAM107B, CHADL, ZNF365, MNAT1, CYSTM1, GAS7, HOXB7, ASTN2, LGR5, Z 20. The method of claim 17, comprising at least one mRNA selected from the group consisting of FHX3, MCM7, GRIK1, MAP2, LHFPL3, PTER, STAMBP, CCDC135, PAX9, RPL13, ABCA13, DAAM1, OPN1LW, OPN1MW2, CNOT6L, MTRNR2L10, SMC4, RPL4, PSAP, ASIC4, AHCYL1, RD3L, SIGLEC1, SYCE2, and NANS.

19. The regulation reduces inflammation, and the two or more RNAs of the composition are hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7e-5p, hsa-let-7g-5p, hsa-let-7i, hsa-let-7i-5p, hsa-miR-100-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-mir-10b, hsa-miR-10b-5p, hsa-mir-1246, hsa-mir-1246, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-130a-3p, hsa-mir-130b, hsa-miR-130b-3p, hsa-miR-132-3p, hsa-miR-136-5p, hsa-miR-138-5p, hsa-miR-139-5p, hsa-mir-140, hsa-miR-140-3p, hsa-miR-145-5p, hsa-mir-146a, hsa-miR-146a-5p, hsa-miR-148a-3p, hsa-miR-152-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-mir-16-1, hsa-mir-16-2, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-193a-5p, hsa-miR-193b-3p, hsa-miR-197-3p, hsa-miR-199a-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-203a, hsa-miR-203a-3p, hsa-miR-214-3p, hsa-mir-21, hsa-miR-21-3p, hsa-miR-21-5p, hsa-mir-221, hsa-miR-221-3p, hsa-mir-222, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-mir-24-1, hsa-mir-24-2, hsa-miR-24-3p, hsa-mir-25, hsa-miR-25-3p,hsa-miR-26a-5p, hsa-miR-27a-3p, hsa-mir-27b, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c -3p, hsa-miR-30a-5p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-mir-30d, hsa-miR- 30d-5p, hsa-mir-30e, hsa-miR-30e-5p, hsa-miR-31-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR- 342-3p, hsa-miR-345-5p, hsa-miR-34a-5p, hsa-miR-361-5p, hsa-miR-376a-3p, hsa-miR-376c-3p, hsa-miR-423-3p, hsa-miR-423-5p, hsa-miR-424-5p, hsa-miR-484, hsa-mir-486-1, hsa-mir-486- 2, hsa-miR-486-5p, hsa-miR-570-3p, hsa-miR-574-3p, hsa-miR-663a, hsa-miR-874-3p, hsa-mir-9 The method of claim 17, comprising at least one miRNA selected from the group consisting of miR-2a-1, hsa-mir-92a-2, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-mir-93, hsa-miR-93-5p, hsa-miR-940, hsa-miR-99a-5p, and hsa-miR-99b-5p.

20. A method of treating an autoimmune disease in a subject, comprising administering to the subject any of the compositions of claims 1-17.

21. A method of treating an autoinflammatory disease in a subject, comprising administering to the subject any of the compositions of claims 1-17.

22. 20. A method of treating inflammatory damage resulting from physical injury in a subject, comprising administering to the subject any of the compositions of claims 1-17.

23. 20. A method of treating inflammatory damage resulting from microbial infection in a subject, comprising administering to the subject any of the compositions of claims 1-17.

24. A method of treating inflammatory damage resulting from cancer in a subject, comprising administering to the subject any of the compositions of claims 1-17.

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