Extracellular vesicle composition for use in the treatment of long covid

Abstract

Long COVID or Post Acute Sequelae of COVID-19 (PASC), is a prolonged, debilitating syndrome that follows acute SARS-CoV-2 infection in >10% of cases. Human bone marrow mesenchymal stem cell derived extracellular vesicles (hBM-MSC EVs) can present a new therapeutic option.

Description

EXTRACELLULAR VESICLE COMPOSITION FOR USE IN THE TREATMENT OF LONG COVIDCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No.63 / 596,955, filed on November 7, 2023; U.S. Provisional Patent Application Serial No.63 / 631,680, filed on April 9, 2024; and U.S. Provisional Patent Application Serial No.63 / 712,052, filed on October 25, 2024; each of which is incorporated by reference herein in its entirety.BACKGROUND

[0002] Although the COVID-19 pandemic has receded, the highly mutable and transmissible nature of the SARS-CoV-2 virus presents a constant threat for continued infection. This may manifest acutely or as a chronic condition known as Post- Acute Sequelae of COVID-19 (PASC), or Long COVID, that lasts beyond the initial 30 days of infection. The causes of Long COVID are not fully understood, complicating diagnosis and treatment. The condition raises policy questions, such as how best to support patients. Long COVID, now defined as those affected >30 days, affects at least 10% of all those who contract the SARS-CoV-2 virus, even those with mild to no acute symptoms upon presentation. The individual health consequences of Long COVID, regardless of age, can vary from moderate and transient to severe and sustained; lost employment and increased costs of care have resulted in a substantial societal cost. There are no proven pharmaceutical therapies for the treatment of Long COVID although some are under investigation. Currently patients simply wait for the symptoms to recede, if ever, or pursue treatments that are directed at symptom relief rather than treating the underlying disease.

[0003] The lack of targeted therapeutics underscores both the lack of understanding around the specific effects of the virus on human physiology and the highly heterogeneous nature of symptoms across multiple organ systems including immune, vascular and nervous system functions in different Long COVID patients. There is a need for therapeutics for Long COVID patients.SUMMARY

[0004] Long COVID illness (e.g, Post Acute Sequalae of COVID-19, PASC) can present a wide array of symptoms that limit quality of life. Provided herein are human bone marrow mesenchymal stem cell-derived extracellular vesicles (hBM-MSC EVs) that may possess immunomodulatory and other regenerative functions for the treatment of Long COVID. Studiesdescribed herein including, but not limited to, patient-reported outcome measures (PROMs), indicate the safety and efficacy of hBM-MSC EV for the treatment ofLong COVID. Treatment includes treating symptoms of a subject experiencing Long COVID, such as fatigue and / or pain.

[0005] Disclosed herein is a method of treating fatigue in a subject previously infected with SARS-CoV-2. In some embodiments, the method comprises administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein at least 80% of the EVs are CD63+, CD9-, CD81-. In some embodiments, the method comprises administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR- 23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof. In some embodiments, the method comprises administering to the subject a composition comprising Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein- coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gamma-glutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenolpyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin- 4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof. In some embodiments, the subject is negative for SARS- CoV-2 for at least four weeks prior to the administering. In some embodiments, the subject is SARS-CoV-2 negative if a first biological sample from the subject is negative for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR). In someembodiments, the subject was previously infected with SARS-CoV-2 if a second biological sample from the subject was positive for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR). In some embodiments, treating fatigue in the subject comprises a reduction in a Fatigue Severity Scale (FSS) score after the administering as compared to the FSS score prior the administering. In some embodiments, after the administering, the subject’s FSS score is three or less. In some embodiments, prior to the administering, the subject’s FSS score is four or greater. In some embodiments, the fatigue is chronic fatigue. In some embodiments, the subject experienced chronic fatigue for at least six months prior to the administering. In some embodiments, treating the fatigue comprises reducing the post-COVID-19 Functional Status (PCFS) score of the subject after the administering as compared to prior the administering. In some methods wherein the composition comprises one or more EVs, the one or more EVs comprise hsa-miR-125b-5p, hsa- miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR- 222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR- 423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof. In some methods, the composition comprises Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein- coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gamma-glutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenolpyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin- 4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

[0006] Disclosed herein is a method of treating pain in a subject previously infected with SARS- CoV-2. In some embodiments, the method comprises administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein at least 80% of the EVs are CD63+, CD9-, CD81-. In some embodiments, the method comprises administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR- 23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof. In some embodiments, the method comprises administering to the subject a composition comprising Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulinlike binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gamma-glutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenolpyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP -2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof. In some embodiments, the subject is negative for SARS-CoV-2 for at least four weeks prior to the administering. In some embodiments, the subject is SARS-CoV-2 negative if a first biological sample from the subject is negative for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR). In some embodiments, the subject was previously infected with SARS-CoV-2 if a second biological sample from the subject was positive for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR). In some embodiments, treating the pain comprises reducing the post-COVID-19 Functional Status (PCFS) score of the subject after theadministering as compared to prior the administering. In some embodiments, treating pain comprises reducing the pain in the subject after the administering as compared to prior the administering. In some methods wherein the composition comprises one or more EVs, the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR- 23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof. In some methods, the composition comprises Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF -2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin- like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gammaglutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenolpyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP- 2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

[0007] Disclosed herein is a method of treating Long COVID in a subject previously infected with SARS-CoV-2. In some embodiments, the method comprises administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein at least 80% of the EVs are CD63+, CD9-, CD81-. In some embodiments, the method comprises administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR- 23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof. In some embodiments, the method comprisesadministering to the subject a composition comprising Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulinlike binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gamma-glutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenolpyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP -2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof. In some embodiments, the subject is negative for SARS-CoV-2 for at least four weeks prior to the administering. In some embodiments, the subject is SARS-CoV-2 negative if a first biological sample from the subject is negative for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR). In some embodiments, the subject was previously infected with SARS-CoV-2 if a second biological sample from the subject was positive for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR). In some embodiments, treating the Long COVID comprises reducing the post-COVID-19 Functional Status (PCFS) score of the subject after the administering as compared to prior the administering. In some embodiments, treating the LONG COVID comprises reducing the pain in the subject after the administering as compared to prior the administering. In some methods wherein the composition comprises one or more EVs, the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191- 5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa- miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR- 29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof. In some methods, the composition comprises Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3(Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocytemacrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein- glutamine gamma-glutamyltransf erase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof. In some embodiments, the Long COVID is chronic COVID, post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, chronic post-COVID-19 syndrome, post- COVID conditions (PCC), long-haul COVID, post-acute COVID-19, long-term effects of COVID, or a combination thereof.

[0008] In some embodiments, the treating comprises improving the quality of life (QoL) of the subject, increasing cognitive functioning of the subject, decreasing fatigue in the subject, or decreasing pain in the subject, or a combination of two or more thereof.

[0009] In some embodiments, the subject is suffering from or suffered from: post exertional malaise, fatigue, brain fog, cough, headache, body aches, fever, chills, dizziness, gastrointestinal symptoms, palpitations, dementia, hair loss, diarrhea, congestion, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, changes in sexual desire or capacity, loss of or change in smell, loss of or change in taste, thirst, chronic cough, chest pain, neuropsychiatric abnormalities, pulmonary abnormalities, cardiovascular abnormalities, abnormal movements, sore throat, abdominal pain, overreactive immune response, highly dysregulated innate immune system, highly dysregulated adaptive immune system, confusion, or vomiting, or a combination of two or more thereof.

[0010] In some embodiments, after the administering the subject experiences an improvement in a Patient-Reported Outcome Measure (PROM), optionally wherein the subject shows statistically significant improvement in the PROM after treatment.

[0011] In some embodiments, after the administering the subject experiences improvement in one or more of the following: Euro quality of life (QoL) 5 Dimension 5 Level (EQ-5D-5L), Impact of Event Scale - Revised (IES-R), Post-COVID-19 Functional Status Scale (PCFS), Fatigue Severity Scale (FSS), 36-Item Short Form Health Survey (SF-36), a brief cognitive screening test (Mini-Cog), Mini-Mental State Examination (MMSE), or Montreal Cognitive Assessment (MOCA), or a combination of two or more thereof.

[0012] In some embodiments, administering reduces the level of one or more acute phase biomarkers in a sample from the subject. In some embodiments, the one or more acute phase biomarkers comprise C-Reactive Protein (CRP), ferritin, D-dimer, neutrophils, or combinations of two or more thereof.

[0013] In some embodiments, administering comprises intravenous administration.

[0014] In some embodiments, the composition is prepared by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition.

[0015] In some embodiments, the method comprises preparing the composition prior to the administering, wherein preparing the composition occurs by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition. In some embodiments, the culture media is serum-free. In some embodiments, the culture media has a glucose concentration below 4.5 g / L. In some embodiments, formulating the MSC conditioned media comprises exchanging the conditioned media for a pharmaceutically acceptable formulation. In some embodiments, the pharmaceutically acceptable formulation comprises saline.

[0016] In some embodiments, the composition comprises at least 6x1010to 8x1010extracellular vesicles per ml and is administered at a dose of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ml.

[0017] Disclosed herein is a method of treating Long COVID in a subject, the method comprising administering to the subject a composition comprising a therapeutic MSC secretome composition made by a method comprising: (a) culturing bone marrow-derived MSCs under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the therapeutic MSC secretomecomposition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a).

[0018] In some embodiments, the Long COVID comprises chronic COVID, post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, chronic post-COVID-19 syndrome, post-COVID conditions (PCC), long-haul COVID, post-acute COVID-19, long-term effects ofCOVID, or a combination thereof. In some embodiments, the subject has COVID or COVID symptoms that lasted for over 30 days.

[0019] In some embodiments, the subject is suffering or suffered from diminished quality of life (QoL), reduced cognitive functioning, increased fatigue, increased pain, or a combination thereof. In some embodiments, the subject is suffering or suffered from post exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, abnormal movements, or a combination thereof. In some embodiments, the subject is suffering or suffered from dementia, hair loss, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, malaise, fatigue, or a combination thereof. In some embodiments, the subject is suffering or suffered from neuropsychiatric abnormalities, pulmonary abnormalities, cardiovascular abnormalities, other abnormalities, or a combination thereof. In some embodiments, the subject is suffering or suffered from fatigue, cough, headache, body aches, fever, chills, loss of taste, loss of smell, diarrhea, congestion, dyspnea, sore throat, chest pain, abdominal pain, confusion, vomiting, or a combination thereof. In some embodiments, any one of the symptoms disclosed herein is moderate in severity based on a CDC symptom questionnaire.

[0020] In some embodiments, the subject is or was diagnosed with chronic fatigue, cognitive impairments, or a combination thereof. In some embodiments, the subject has overreactive immune responses, highly dysregulated innate immune systems, highly dysregulated adaptive immune systems, or a combination thereof.

[0021] In some embodiments, the subject experiences improvement after treatment in Patient- Reported Outcome Measures (PROMs). In some embodiments, the subject shows statistically significant improvement in PROM scores after treatment.

[0022] In some embodiments, the subject experiences improvement after treatment in one or more of the following aspects selected from the group consisting of: Euro quality of life (QoL) 5 Dimension 5 Level (EQ-5D-5L), Impact of Event Scale - Revised (IES-R), Post-COVID-19 Functional Status Scale (PCFS), Fatigue Severity Scale (FSS), 36-Item Short Form Health Survey (SF-36), a brief cognitive screening test (Mini-Cog), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), and a combination thereof. In someembodiments, the subject shows statistically significant improvement in Patient-Reported Outcomes Measurement Information System (PROMIS) scores after treatment.

[0023] In some embodiments, the subject experiences improvement after treatment in one or more of the following Long COVID symptoms selected from the group consisting of quality of life (QoL), cognitive functioning, fatigue, pain, and a combination thereof. In some embodiments, administering reduces the level of one or more acute phase biomarkers. In some embodiments, the one or more acute phase biomarkers comprise C-Reactive Protein (CRP), ferritin, D-dimer, neutrophils, or combinations thereof. In some embodiments, administering comprises intravenous administration.

[0024] In some embodiments, the dosage of the therapeutic MSC secretome composition administered to the subject is a cell-equivalent dosage of 0.7 to 7 million cells / kg. In some embodiments, the culture media is serum-free. In some embodiments, the culture media has a glucose concentration below 4.5 g / L.

[0025] In some embodiments, at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+CD9 CD81 . In some embodiments, the therapeutic MSC secretome composition comprises one or more of the following proteins: Ferritin, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD 109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP-A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD- L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl30, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1,TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A, NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, R0B04, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR- Al, TAFA2, N-Cadherin, IL- 17B, IL-17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo- A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM-A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA13, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA,0X40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, ROR2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt- 3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU. l, ED AR, AD AMTS 13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, S0X15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA- total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-lb, FGF-17, IL-6R, IL- 8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13.

[0026] In some embodiments, the therapeutic MSC secretome composition comprises one or more of the following nucleic acids: 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-lOb, 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-l'7-5p, 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-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-l, 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, or hsa-miR-99b-5p.

[0027] Also disclosed is a method of treating Long COVID, the method comprising administering to the subject a composition comprising a therapeutic MSC secretome composition comprising extracellular vesicles, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+CD9 CD81 .

[0028] In some embodiments, the therapeutic MSC secretome composition further comprises one or more of the following proteins: Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM- C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7 A, NKp80, Cy statin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan- 4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD 109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP -A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD- L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl,THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl3O, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, S0X9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF RI, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A, NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR- Al, TAFA2, N-Cadherin, IL- 17B, IL-17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo- A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30,Lymphotactin, Cystatin SN, JAM-A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA13, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITRL, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt- 3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.l, ED AR, AD AMTS 13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA- total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-lb, FGF-17, IL-6R, IL- 8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13.

[0029] In some embodiments, the extracellular vesicles comprise one or more of the following nucleic acids: 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-lOb, 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-l'7-5p, 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-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-l, 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, or hsa-miR-99b-5p.

[0030] In some embodiments, the Long COVID comprises chronic COVID, post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, chronic post-COVID-19 syndrome, post-COVID conditions (PCC), long-haul COVID, post-acute COVID-19, long-term effects of COVID, or a combination thereof. In some embodiments, the subject has COVID or COVID symptoms that lasted for over 30 days.

[0031] In some embodiments, the subject is suffering or suffered from diminished quality of life (QoL), reduced cognitive functioning, increased fatigue, increased pain, or a combination thereof. In some embodiments, the subject is suffering or suffered from post exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, abnormal movements, or a combination thereof. In some embodiments, the subject is suffering or suffered from dementia, hair loss, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, malaise, fatigue, or a combination thereof. In some embodiments, the subject is suffering or suffered from neuropsychiatric abnormalities,pulmonary abnormalities, cardiovascular abnormalities, other abnormalities, or a combination thereof. In some embodiments, the subject is suffering or suffered from fatigue, cough, headache, body aches, fever, chills, loss of taste, loss of smell, diarrhea, congestion, dyspnea, sore throat, chest pain, abdominal pain, confusion, vomiting, or a combination thereof.

[0032] In some embodiments, the subject is or was diagnosed with chronic fatigue, cognitive impairments, or a combination thereof. In some embodiments, the subject has overreactive immune responses, highly dysregulated innate immune systems, highly dysregulated adaptive immune systems, or a combination thereof.

[0033] In some embodiments, the subject experiences improvement after treatment in Patient- Reported Outcome Measures (PROMs). In some embodiments, the subject shows statistically significant improvement in PROM scores after treatment.

[0034] In some embodiments, the subject experiences improvement after treatment in one or more of the following aspects selected from the group consisting of: Euro quality of life (QoL) 5 Dimension 5 Level (EQ-5D-5L), Impact of Event Scale - Revised (IES-R), Post-COVID-19 Functional Status Scale (PCFS), Fatigue Severity Scale (FSS), 36-Item Short Form Health Survey (SF-36), a brief cognitive screening test (Mini-Cog), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), and a combination thereof. In some embodiments, the subject shows statistically significant improvement in Patient-Reported Outcomes Measurement Information System (PROMIS) scores after treatment.

[0035] In some embodiments, the subject experiences improvement after treatment in one or more of the following Long COVID symptoms selected from the group consisting of: quality of life (QoL), cognitive functioning, fatigue, pain, and a combination thereof. In some embodiments, administering reduces the level of one or more acute phase biomarkers. In some embodiments, the one or more acute phase biomarkers comprise C-Reactive Protein (CRP), ferritin, D-dimer, neutrophils, or combinations thereof. In some embodiments, administering comprises intravenous administration.BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0037] FIGS. 1A-1F show PROMIS scores. FIGS. 1A-1D show raw PROMIS scores over the study period. Thick center bars are means and whiskers are 95% confidence intervals. P valuesderived from paired t test: *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, ns = not significant (p>0.05). FIGS. 1C and ID are continuous plots of individual subject scores over time. FIGS. IE and F show the T-scores for comparison to the US population reference set.

[0038] FIGS. 2A-2F show SF-36 (FIGS. 2A-2B), EQ-SD (FIGS. 2C-2D) and IES-R (FIGS. 2E-2F) scores over the study period. Thick center bars are means and whiskers are 95% confidence intervals. P values derived from paired t test: *p<0.05, **p<0.01, ns = not significant (p>0.05). FIGS. 2B, 2D and 2F are continuous plots of individual subject scores over time.

[0039] FIGS. 3A-3H show PCFS, FSS, Average Pain and Overall Health scores over the study period. Thick center bars are means and whiskers are 95% confidence intervals. P values derived from paired t test: *p<0.05, **p<0.01, ***p<0.001, ns not significant (p>0.05). FIGS. 3B, 3D, 3F, and 3H are continuous plots of individual subject scores (FIGS. 3A, 3C, 3E, and 3G) over time.

[0040] FIGS. 4A-4C show Mini-Cog, MMSE and MOCA scores over the study period. Thick center bars are means and whiskers are 95% confidence intervals. P values derived from paired t test: ns, not significant (p>0.05).DETAILED DESCRIPTION

[0041] Provided herein are compositions, systems, and methods for treating Long COVID illness (e.g., Post Acute Sequalae of COVID-19, PASC), including symptoms of Long COVID illness. Symptoms include fatigue and pain.

[0042] In some embodiments, a PASC score can be used to identify patients based on symptoms. Non-limiting examples of commonly reported symptoms that can be used to develop the score can include post exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. In some embodiments, commonly reported symptoms can also comprise dementia, hair loss, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, malaise, or fatigue. In some embodiments, six generalizable subclassifications can be developed based on symptoms including neuropsychiatric, pulmonary, cardiovascular, or other abnormalities. In some embodiments, mechanistic insight can be obtained through comparison of PASC with other virally initiated syndromes. In some embodiments, other virally initiated syndromes can comprise myalgiac encephalomyelitis / chronic fatigue syndrome or postural orthostatic tachycardia syndrome.

[0043] In some embodiments, overactive immune responses can characterize acute COVID. In some embodiments, highly dysregulated innate and adaptive immune systems can be implicatedin Long COVID. In some embodiments, an immunomodulatory therapy that can minimize hyperinflammation and repolarize the immune system towards a homeostatic state may be effective against both acute and Long COVID. In some embodiments, such therapy can arise from immunomodulatory properties of mesenchymal stem cells (MSCs), in particular human bone marrow MSCs (hBM-MSCs). Alternatively, in some embodiments, paracrine extracellular vesicles (EVs) derived from hBM-MSCs can be used. In some embodiments, paracrine EVs derived from hBM-MSCs can contain bioactive molecules that can convey the reparative functionality of intact hBM-MSC. In some embodiments, paracrine EVs derived from hBM- MSCs can be manufactured, stored and applied under appropriate conditions and can be utilized as an off the shelf therapeutic.

[0044] Provided herein are hBM-MSC EVs useful for treating chronic fatigue and cognitive impairments in a subject suffering from Long Covid-19. In some embodiments, the safety, and secondarily the efficacy, of intravenous (IV) infusions of a hBM-MSC EV investigational product (IP) candidate can be evaluated to treat subjects with a diagnosis of chronic fatigue and cognitive impairments from Long Covid- 19. In some embodiments, subjects can be treated with 2 doses of hBM-MSC EV. In some embodiments, each dose can comprise 15 mL of hBM-MSC EV. In some embodiments, the second dose can be administered to a subject 7 days or 1 week after the administration of the first dose. In some embodiments, a subject can be a human subject over 21 years of age. In some embodiments, a subject can be a human subject between 30 and 65 years of age. In some embodiments, a subject can be a male or a female. In some embodiments, the safety and preliminary efficacy can be measured using patient-reported outcome measures (PROMs). In some embodiments, PROMs can address general quality of life (QoL), response to stress, fatigue, generalized pain and cognitive function. In some embodiments, safety and preliminary efficacy can be measured at 3, 6, 12, and / or 24 weeks after IV infusion of the first dose of hBM-MSC EV IP candidate.

[0045] Provided herein are hBM-MSC EVs useful for treating post-acute COVID-19 and / or chronic post-COVID-19 syndrome. In some embodiments, hBM-MSC EV can be administered to a subject in need thereof as a single dose via IV infusion. In some embodiments, the single dose can comprise 15 mL of hBM-MSC EV. In some embodiments, a subject can be a human subject between 18 and 85 years of age. In some embodiments, a subject can be a male or a female. In some embodiments, Increased distance on Six Minute Walk Test (6MWT) can measured to evaluate fatigue. In some embodiments, EuroQol-5D (EQ-5D) can be measured to evaluate QoL. In some embodiments, Medical Research Council (MRC) Dyspnea Scale can be measured to evaluate activity -related dyspnea. In some embodiments, C-Reactive Protein (CRP), D-dimer, Atrial Natriuretic Peptides (ANP) can be measured to evaluate serum biomarkers ofinflammation. In some embodiments, outcome measures can be evaluated 61 days after the IV infusion of hBM-MSC EV.I. Definitions

[0046] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise. The terms “and / or” and “any combination thereof’ and their grammatical equivalents as used herein, can be used interchangeably. These terms can convey that any combination is specifically contemplated. Solely for illustrative purposes, the following phrases “A, B, and / or C” or “A, B, C, or any combination thereof’ can mean “A individually; B individually; C individually; A and B; B and C; A and C; and A, B, and C.” The term “or” can be used conjunctively or disjunctively, unless the context specifically refers to a disjunctive use.

[0047] The term “about” or “approximately” can mean within an acceptable error range for the particular value, which may depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation. About can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. About can mean within an order of magnitude, within 5-fold, or within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0048] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the present disclosure, and vice versa. Furthermore, compositions of the present disclosure can be used to achieve methods of the present disclosure.

[0049] Reference in the specification to “some embodiments,” “an embodiment,” “one embodiment” or “other embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the present disclosures.II. Compositions

[0050] Disclosed are the components to be used to prepare the disclosed compositions as well as the compositions themselves to be used within the methods disclosed herein. These and othermaterials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular MSC secretome (including, but not limited to a MSC exosome (with or without growth factors) referred to herein as an extracellular vesicle isolate product (EVIP)) is disclosed and discussed and a number of modifications that can be made to a number of molecules including the MSC secretome are discussed, specifically contemplated is each and every combination and permutation of MSC secretome and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods.

[0051] A primary trophic property of MSCs is the secretion of growth factors and exosomes to induce cell proliferation and angiogenesis. Exosomes may contain mitogenic proteins such as transforming growth factor-alpha (TGF-a), TGFP, hepatocyte growth factor (HGF), epithelial growth factor (EGF), basic fibroblast growth factor (FGF-2) and insulin-like growth factor-1 (IGF-1). These increase fibroblast, epithelial and endothelial cell division. Vascular endothelial growth factor (VEGF), IGF-1, EGF and angiopoietin-1 are released to recruit endothelial lineage cells and initiate vascularization. MSCs assist via paracrine mechanisms and modulate the regenerative environment via anti-inflammatory and immunomodulatory mechanisms. In response to inflammatory molecules such as interleukin- 1 (IL-P), IL-6, IL-2, IL- 12, tumor necrosis factor-a (TNF-a) and interferon-gamma (INF-y), MSCs secrete an array of growth factors and antiinflammatory proteins with complex feedback mechanisms among the many types of immune cells. The key immunomodulatory cytokines include prostaglandin 2, TGF-131, HGF, SDF-1, nitrous oxide, indol eamine 2, 3 -dioxygenase, IL-4, IL-10, IL-P receptor antagonist and soluble tumor necrosis factor-a receptor. MSCs prevent proliferation and function of many inflammatory immune cells, including T-cells, natural killer cells, B-cells, monocytes,macrophages, and dendritic cells. Although MSCs across species are able to regulate T-cell activity, the mechanisms are not identical across mammalian species.

[0052] A characteristic of chronically inflamed environments is a persistent imbalance in the types of helper T-cells and macrophages. MSC exosomes indirectly promote the transition of TH1 to TH2 cells by reducing INF-y and increasing IL-4 and IL-10. The restored TH1 / TH2 balance has been shown to improve tissue regeneration in cartilage, muscle, and other soft tissue injuries, alleviate symptoms of autoimmune diseases, and have an anti-diabetic effect. Similarly, reduction in INF-y and secretion of IL-4 promotes a shift in macrophages from Ml (proinflammatory, anti-angiogenic and tissue growth inhibition) to M2 (anti-inflammatory, proremodeling and tissue healing) type, an effect required for skeletal, muscular, and neural healing and regeneration.

[0053] Example compositions herein comprise an extracellular vesicle (EV) and / or a protein. The EV may originate from a mesenchymal stem cell (MSC). The protein may originate from a MSC. In an exemplary embodiment, the MSC is a bone marrow MSC (BM-MSC). The EV and / or protein may be purified or otherwise separated from the MSC growth and / or culturing condition from which the EV and / or protein was secreted into. Purified may include partially purified, such that some of the MSC growth and / or culturing condition is present in the composition. The composition may be formulated into an aqueous solution for intravenous administration.

[0054] Extracellular Vesicles

[0055] Extracellular vesicles (EV) are small membrane bound spheres containing proteins and RNA (of which exosomes are a subset). Exosomes are small lipid bilayer vesicles secreted by cells that lack a nucleus and cannot replicate. Other EV populations are derived directly from the plasma membrane or are formed during apoptosis (apoptotic bodies). Disclosed herein are compositions comprising an EV. In example embodiments, the EV is an exosome.

[0056] In some embodiments, the EV has a phenotype of CD63+CD9 and CD81 . In some embodiments, at least 70, 75, 80, 85, 90, 91, 92, 93, 94, or 95% of the EVs are CD63+CD9 and CD81 . In some embodiments, at least 50, 60, 70, 80, 85, 90, 91, 92, 93, 94, or 95% of the EVs are CD9 . In some embodiments, at least 50, 60, 70, 80, 85, 90, 91, 92, 93, 94, or 95% of the EVs are CD81 .

[0057] In some embodiments, the EV is produced from a MSC. The MSC may be a bone marrow MSC. The MSC may be a human MSC. In some embodiments, the EV is produced from a MSC that has the capacity to undergo trilineage differentiation in vitro toward adipocyte, osteoblast, and chondrocyte phenotypes. In some embodiments, the MSC is positive for CD73, CD105, CD166, and CD90 and is negative for CD14, CD31, CD34, and CD45.

[0058] In some embodiments, the EV comprises a peptide or protein. In some embodiments, the EV comprises a nucleic acid. Nucleic acids include ribonucleic acids (RNA), such as siRNA, shRNA, and microRNA (miRNA).

[0059] In some embodiments, the EV comprises one or more proteins (e.g., 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, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100). Non-limiting examples of the one or more proteins include: Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocytemacrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein- glutamine gamma-glutamyltransf erase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic) CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), and the proteins of Table 1. An EV that comprises the one or more of the proteins may include the one or more proteins within the EV. An EV that comprises one or more of the proteins may include the one or more proteins anchored within the EV. An EV that comprises the one or more of the proteins may be associated with the outside of the EV.

[0060] In some embodiments, the EV comprises one or more nucleic acids (e.g., 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, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100). Non-limiting examples of the one or more nucleic acids include: hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR- 199a-3p, hsa-miR-21-5p,hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa- miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940.miRNA sequences may be obtained from https: / / www.mirbase.org / . An EV that comprises the one or more of the nucleic acids may include the one or more nucleic acids within the EV.

[0061] Proteins

[0062] Disclosed herein are compositions comprising a protein. The protein may be independent of an EV. For instance, the protein may not be present within the EV or within the membrane of the EV. The composition may comprises one or more proteins (e.g., 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, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100). The protein may be present as a monomer or multimer. Non-limiting examples of the one or more proteins include: Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-betainduced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gammaglutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenolpyruvate carboxykinase, cytosolic) CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP- 2 (Tissue Inhibitor of MMPs 2), and the proteins of Table 1.

[0063] Secre tomes

[0064] Disclosed herein is a complex composition of secreted biomolecules (proteins, lipids, and ribonucleic acids) and / or extracellular vesicles comprising biomolecules, originating from mesenchymal lineage cells. In one aspect, disclosed herein are compositions comprising a therapeutically effective amount of a MSC secretome (such as, for example, including, but not limited to MSC growth factor, MSC exosome, MSC extracts and / or extracellular vesicle comprising compositions) and one or more biomolecules (such as, for example, a peptide, polypeptide, protein, siRNA, shRNA, and / or microRNA (miRNA)).

[0065] In some embodiments, the secretome composition can comprise 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, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 or more of the following proteins, in any combination, or all of the following proteins: Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM- C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7 A, NKp80, Cy statin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan- 4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD 109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP -A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD- L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl30, C-myc, LILRB4, BMP-2, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6, ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A, NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, R0B04, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR- Al, TAFA2, N-Cadherin, IL- 17B, IL-17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo- A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM-A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA13, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL-10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I,Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITRL, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, R0B03, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt- 3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.l, ED AR, AD AMTS 13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA- total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-lb, FGF-17, IL-6R, IL- 8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13. Non-limiting examples of a selection of growth factors or growth factor proteins is shown in Table 1 below.Table 1

[0066] Disclosed herein are compositions comprising a therapeutically effective amount of an MSC secretome (such as, for example, including, but not limited to MSC growth factor, MSC exosome, MSC extracts and / or extracellular vesicle comprising compositions). In someembodiments, the secretome composition can comprise 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, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 or more of the following nucleic acids, in any combination, or all of the following nucleic acids: 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-lOb, 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-l'7-5p, 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-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-l, 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, or hsa-miR-99b-5p.

[0067] Exemplary microRNA content may include human miRNA sequences hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let-7g-5p, hsa-let-7i-5p, hsa-miR-214-3p, and hsa-miR-27a-3p, which all have binding sites in mRNA for TMPRSS2.

[0068] It is understood and herein contemplated that the MSC secretome comprises exosomes and growth factors. The growth factors and exosomes can be allogenic or autogenic. The growth factors and exosomes can be derived from any cell in the human body, such as from ectodermal cells, endodermal cells, or mesodermal cells. For example, the MSC secretomes may comprise mesenchymal stem cell (MSC) derived growth factors, MSC derived exosomes, or both MSC derived growth factors and exosomes. In some embodiments, the method further comprises adding at least one additive with the exosomes and growth factors. Specifically, MSCs under appropriate wound healing conditions may produce suitable therapeutic agents, such as exosomes and growth factors, that can provide therapy for inflammatory lung diseases. In one aspect,disclosed herein are compositions, wherein the MSC secretome composition further comprises prostaglandin E2 (PGE2), transforming growth factor 131 (TGF-I31), hepatocyte growth factor (HGF), stromal cell derived factor-1 (SDF-1), nitric oxide, indoleamine 2,3 -dioxygenase, interleukin-4 (IL-4), IL-6, interleukin- 10 (IL-10), IL-1 receptor antagonist and soluble TNF-a receptor, insulin-like growth factors, fibroblast growth factors (FGF) 1-23 (especially, FGF1 and FGF2), bone morphogenetic proteins (BMPs) 1-15, epidermal growth factor (EGF), transforming growth factor-a (TGF-a) 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 estrogen, and / or thyroid hormones.

[0069] Embodiments of a secretome composition described herein may comprise proteins and microRNAs, some of which may be embedded in or surrounded by a lipid membrane to create vesicles in the size range of about >20 nm to about 200 nm in size. The number of vesicles within the composition may be between about 1 million to about 100 billion vesicles per mL when suspended or about 10 million to about 1 trillion when formulated as a lyophilized powder. The number of EVs within the composition may be about 10 million to about 1 trillion. About 10 million to about 1 trillion EVs may be administered to a subject in a pharmaceutical composition.A. Pharmaceutical carriers / Delivery of pharmaceutical products

[0070] Compositions described herein (protein, EV, secretome) may be administered in vivo in a pharmaceutically acceptable carrier. By “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, ie., the material may be administered to a subject, along with the nucleic acid or vector, without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art. The compositions may be administered orally, parenterally (e.g., intravenously), by intramuscular injection, by intraperitoneal injection, transdermally, extracorporeally, topically or the like, including topical intranasal administration or administration by inhalant. As used herein, “topical intranasal administration” means delivery of the compositions into the nose and nasal passages through one or both of the nares and can comprise delivery by a spraying mechanism or droplet mechanism, or through aerosolization of the nucleic acid or vector.

[0071] Administration of the compositions by inhalant can be through the nose or mouth via delivery by a spraying or droplet mechanism such as, for example, a metered-dose inhaler, a drypowder inhaler, a nebulizer, a vaporization device, or the like. Delivery can also be directly to any area of the respiratory system (e.g., lungs) via intubation. The exact amount of the compositions required will vary from subject to subject, depending on the species, age, weight and general condition of the subject, the severity of the disorder being treated, mode of administration and the like.

[0072] Parenteral administration of the composition, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions. Parenteral administration may involve use of a slow release or sustained release system such that a constant dosage is maintained.

[0073] Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA 1995. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of the pharmaceutically-acceptable carrier include, but are not limited to, saline, Ringer’s solution, and dextrose solution. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered.

[0074] Pharmaceutical carriers are known to those skilled in the art. These most typically would be standard carriers for administration of drugs to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. The compositions can be administered intramuscularly or subcutaneously. Other compounds will be administered according to standard procedures used by those skilled in the art.

[0075] Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice. Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like.

[0076] The pharmaceutical composition may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topically (including ophthalmically, vaginally, rectally, intranasally), orally, by inhalation, or parenterally, for example by intravenous drip, subcutaneous, intraperitoneal or intramuscularinj ection. The disclosed antibodies can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.

[0077] Preparations 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), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like. Formulations for topical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0078] Compositions for oral administration may 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.

[0079] Some of the compositions may potentially be administered as a pharmaceutically acceptable acid- or base- addition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, trialkyl and aryl amines and substituted ethanolamines.B. Therapeutic Uses

[0080] Effective dosages for the administration of the compositions are those large enough to produce the desired effect in which the symptoms of the disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days, and / or one or more dose administrations monthly, or once every 1, 2, or 3 or more months.

[0081] In some embodiments, compositions described herein can safely target one or more (e.g., more than hundreds) different biomolecular interactions or signaling pathways. In some embodiments, compositions described herein can treat one or more injuries or diseases caused bymultiple etiologies. In some embodiments, compositions described herein can be used for treating a disease or condition without identifying the pathogen underlying the disease or condition, thus offering an advantage for treating a disease or condition caused by an emerging or previously unknown pathogen.C. Secretome Compositions

[0082] Certain compositions disclosed herein comprise MSC secretomes and / or growth factors derived from mesenchymal stem cells (MSCs). In one aspect, disclosed herein are MSC secretome compositions (including, but not limited to MSC growth factor, MSC exosome, MSC extracts and / or extracellular vesicle comprising compositions). The treatment compositions may be used in the treatment, inhibition, decrease, reduction, amelioration, and / or prevention of conditions such as, for example, Long COVID.

[0083] MSCs are multipotent cells that have the ability to differentiate into a multitude of 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 tissue. As used herein, “MSC” refers to non-terminally differentiated cells including but not limited to multipotential stem cell, multipotential stromal cell, stromal vascular cells, pericytes, perivascular cells, stromal cells, pluripotent cells, multipotent cells, adipose- derived fibroblast-like cells, adipose-derived stromal vascular fraction, adipose-derived MSC, bone marrow-derived fibroblast-like cells, bone marrow-derived stromal vascular fraction, bone marrow-derived MSC, tissue-derived fibroblast-like cells, adult stem cells, adult stromal cells, keratinocytes, and / or melanocytes.

[0084] MSCs, in addition to their differentiation potential, have immunomodulatory abilities resulting in the expression of many different cytokines and growth factors. As used herein, a “MSC preparation” or “MSC secretome composition” refers to a composition comprising MSC growth factors, MSC exosomes, extracellular vesicles, extracellular vesicle isolate product (EVIP), or acellular extracts of MSCs and / or MSC lysates obtained from human MSCs, fibroblast-like cells, and 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 which the composition will be applied (autologous) or derived from another individual (allogeneic). The MSCs may be culture expanded to collect the conditioned media or to increase the quantity of cells for the lysate or used freshly prior to incorporation into the composition of the present disclosure. The MSC secretome compositions (including, but not limited to MSC growth factor, MSC exosome, MSC extracts and / or extracellular vesicle comprising compositions) may comprise about 0.00001 to about 20 wt.%, such as from about 0.01 to about 10 wt.%, of a mesenchymal stem cell (MSC)extract, MSC exosome, or MSC growth factor preparation. The MSC preparation may comprise either MSC conditioned media or MSC lysate from cell culture expanded MSCs. In some embodiments, the composition may further comprise from about 0.01 to about 10 wt.% of a cell- free medium conditioned by growth of MSCs or MSC lineage cells, wherein the cells are cultured under normal hyperoxic culturing conditions or under artificial wound healing conditions.

[0085] As disclosed herein the MSCs used to produce the disclosed MSC additives (including growth factor secretome composition either frozen or powdered 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. The growth factors and exosomes may be derived from any cell in the human body, such as from ectodermal cells, endodermal cells, or mesodermal cells. As used herein, MSC growth factors include but are not limited to prostaglandin E2 (PGE2), transforming growth factor 131 (TGF-(31), hepatocyte growth factor (HGF), stromal cell derived factor-1 (SDF-1), nitric oxide, indoleamine 2,3 -dioxygenase, interleukin-4 (IL-4), IL-6, interleukin- 10 (IL-10), IL-1 receptor antagonist and soluble TNF-a receptor, insulin-like growth factors, fibroblast growth factors (FGF) 1-23 (especially, FGF1 and FGF2), bone morphogenetic proteins (BMPs) 1-15, epidermal growth factor (EGF), transforming growth factor-a (TGF-a) 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), as well as hormones including estrogen, and thyroid hormones.

[0086] Culturing the MSCs may occur under wound healing and / or hypoxic conditions. Hypoxic conditions may comprise about 1% to about 5% oxygen, reduced or no serum, reduced glucose, or these elements in various combinations. The combined reduced nutrient and metabolite environment may trigger the cultured cells to produce wound healing and antiinflammatory ECM proteins and growth factors to direct tissue healing. Direct tissue healing likely is in the form of new ECM proteins, such as collagen and glycosaminoglycans (GAGs), as well as growth factors and cytokines. In one aspect, the MSC preparation (such as, for example, a MSC secretome composition) comprises MSC growth factors, MSC exosomes, and / or cellular extracts of MSCs or MSC lysates obtained from MSCs cultured under standard hyperoxic culturing conditions (for example, 21% oxygen) or MSCs cultured under artificial wound healing conditions (such as, for example, 0.1% to about 5% oxygen).

[0087] As disclosed herein artificial wound healing conditions simulate growth conditions in real wounds where there is a reduction in nutrient supply and reduction of waste removal that isusually caused by a disruption in local blood circulation. This creates a harsh environment for cells until new blood vessels are created and blood circulation is restored. Accordingly, artificial wound healing conditions used to culture MSCs may include one or more of the following growth conditions reduction in glucose availability, reduction in oxygen tension, reduction in pH, and increased temperature.

[0088] In some embodiments, the glucose availability can be reduced relative to normal control (e.g., 4.5 g / L). Modified culture media to reduce glucose, but not damage the cells can be between 0 and 50% reduction in glucose, more preferably between about 5% and 40% reduction in glucose. For example, MSC artificial wound healing culture conditions can comprise glucose reduction of about 5% to about 15%, from about 10% to about 20%, from about 15% to about 25%, from about 20% to about 30%, or from about 25% to about 35%. In some embodiments, glucose is present at a concentration of about 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, or 4.0 g / L, or a range between any two of these values. In some embodiments, glucose is present at a concentration of less than or no more than 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, 1.8, 1.9, 2.0, 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, or 4.5 g / L.

[0089] In some embodiments, oxygen tension can be reduced to oxygen levels to hypoxic conditions. Normal atmospheric oxygen is approximately 21% and any reduction is considered hypoxic. Thus, in one aspect, MSCs can be cultured at between 0.0% and 20.9% oxygen, from about 0.1% to about 0.5% oxygen, from about 0.1% to about 2.0%, from about 0.1% to about 5.0% oxygen, from about 0.5% to 5.0%, from about 1.0% to about 10% oxygen, about 5.0% to about 10.0% oxygen, or from about 10.0% to about 15.0%. The hypoxic oxygen conditions may be an aspect of artificial wound healing conditions. Oxygen tension may be between about 0.5% and 20.5% oxygen when culturing MSCs to produce a therapeutic secretome composition comprising extracellular vesicles and / or MSC-secreted growth factors, such as, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4,2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7,4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7,7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3,9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1, 11.2,11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13,13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7,14.8, 14.9, 15, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16, 16.1, 16.2, 16.3, 16.4, 16.5,16.6, 16.7, 16.8, 16.9, 17, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18, 18.1, 18.2, 18.3,18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, or 20.0% oxygen, or a range between any two of these values.

[0090] The pH can also be reduced during MSC culturing. The pH can be from about 6.0 to about 7.4, for example, from 6.0 to about 6.4, from about 6.2 to about 6.4, from about 6.2 to about 6.6, from about 6.4 to about 6.6, from about 6.4 to about 6.8, or from about 6.6 to about 7.0, such as 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.

[0091] The temperature of the culture environment may be raised relative to physiologic homeostasis temperature (e.g., 37°C). In one aspect, the culture conditions for the MSCs can comprise from about 35°C to about 39°C, from about 35°C to about 36°C, from about 36°C to about 37°C, from about 37°C to about 38°C, from about 38°C to about 39°C, or from about 39°C to about 40°C. In one aspect, the temperature of the culture can be 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, or 40.0°C.

[0092] In some embodiments, the culture media is serum free. In some embodiments, the serum free culture media comprises platelet lysate. In some embodiments, the platelet lysate is human platelet lysate (HPL). In some embodiments, the serum free culture media comprises at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of HPL by volume, or a range between any two of these values. In some embodiments, the culture media comprises from 8% to 12%, 5% to 15%, or 9% to 11% of HPL by volume.

[0093] In one aspect, the MSC secretome compositions (including, but not limited to MSC growth factor, MSC exosome, MSC extracts and / or extracellular vesicle comprising compositions) can further comprise a protective coating (such as, for example, a cryoprotectant oligosaccharide and a protein solution) to reduce degradation of the growth factors. It is understood and herein contemplated that the protective coating can be engineered as a polymer. “Polymer” refers to a relatively high molecular weight organic compound, natural or synthetic, whose structure can be represented by a repeated small unit, the monomer. Non-limiting examples of polymers include polyethylene, rubber, 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. It is also contemplated that, in certain aspects, various block segments of a block copolymer can themselves comprise copolymers. The term “polymer” encompasses all forms of polymers including, but not limited to, natural polymers, synthetic polymers, homopolymers, heteropolymers or copolymers, additionpolymers, etc. In one aspect, the gel matrix can comprise copolymers, block copolymers, diblock copolymers, and / or triblock copolymers. In one aspect, the protective coating can comprise a biocompatible polymer. In one aspect, biocompatible polymer can be crosslinked. Such polymers can also serve to slowly release the adipose browning agent and / or fat modulating agent into tissue. 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 polyol); poly(olefinic alcohol); polyvinylpyrrolidone); poly(hydroxyalkylmethacrylamide); poly(hydroxyalkylmethacrylate); poly(saccharides); poly(hydroxy acids); poly(vinyl alcohol), polyhydroxyacids such as poly(lactic acid), poly (gly colic acid), and poly (lactic acid-co- glycolic acids); polyhydroxyalkanoates such as poly 3 -hydroxybutyrate or poly4- hydroxybutyrate; polycaprolactones; poly(orthoesters); polyanhydrides; poly(phosphazenes); poly(lactide-co-caprolactones); polycarbonates such as tyrosine polycarbonates; polyamides (including synthetic and natural polyamides), polypeptides, and poly(amino acids); polyesteramides; polyesters; poly(dioxanones); poly(alkylene alkylates); hydrophobic polyethers; polyurethanes; polyetheresters; polyacetals; polycyanoacrylates; polyacrylates; polymethylmethacrylates; polysiloxanes; poly(oxyethylene) / poly(oxypropylene) copolymers; polyketals; polyphosphates; polyhydroxyvalerates; polyalkylene oxalates; polyalkylene succinates; poly(maleic acids), as well as copolymers thereof. Biocompatible polymers can also include polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols (PVA), methacrylate PVA(m-PVA), polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof, alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose triacetate, cellulose sulphate sodium salt, poly (methyl methacrylate), poly(ethylmethacrylate), poly(butylmethacrylate), poly(isobutylmethacrylate), poly(hexlmethacrylate), poly(isodecylmethacrylate), poly(lauryl methacrylate), poly (phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene, poly(ethylene glycol), polyethylene oxide), poly(ethylene terephthalate), poly(vinyl alcohols), poly(vinyl acetate, poly vinyl chloride polystyrene and polyvinylpryrrolidone, derivatives thereof, linear andbranched copolymers and block copolymers thereof, and blends thereof. Exemplary biodegradable polymers include polyesters, poly(ortho esters), poly(ethylene amines), poly(caprolactones), poly(hydroxybutyrates), poly(hydroxyvalerates), polyanhydrides, poly(acrylic acids), polyglycolides, poly(urethanes), polycarbonates, polyphosphate esters, polyphospliazenes, derivatives thereof, linear and branched copolymers and block copolymers thereof, and blends thereof.

[0094] In some embodiments the protective coating comprises carbohydrate construction of monosaccharides as well as carbohydrate polymers such as di saccharides or polysaccharides including but not limited to non-reducing poly or disaccharides as well as any combination thereof. Examples of carbohydrates that can be used in the protective coating comprise Glucose, Aldoses (D-Allose, D-Altrose, D-Mannose, etc.), Glucopyranose, Pentahydroxyhexanal, a-D- Glucopyranosyl-D-glucose, a-D-Glucopyranosyl-dihydrate, Polymer of P-D-Glycopyranosyl units, P-D-Fructofuranosyl a-D-glucopyranoside (anhydrous / dihydrate), fi-D-Galactopyranosyl- D-glucose, a-D-Glucopyranosyl-a-D-glucopyranoside (anhydrous / dihydrate), Galactose, Pentoses (Ribose, xylose, lyxose), Dextrose, Dodecacarbon monodecahydrate, Fructose, Sucrose, Lactose, Maltose, Trehalose, Agarose, D-galactosyl-0-(l-4)-anhydro-L-galactosyl, Cellulose, Polymer of P-D-Glycopyranosyl units, and Starch, as well as, Polyhydric alcohols, Polyalcohols, Alditols, Erythritol, Glycitols, Glycerol, Xylitol, and Sorbitol.

[0095] In some embodiments the protective coating contains biocompatible and / or biodegradable polyesters or polyanhydrides such as poly(lactic acid), poly(glycolic acid), and poly(lactic-co-gly colic acid). The particles can contain one more of the following polyesters: homopolymers including glycolic acid units, referred to herein as “PGA”, and lactic acid 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-lactide5 collectively referred to herein as “PLA”, and caprolactone units, such as poly(e-caprolactone), collectively referred to herein as “PCL”; and copolymers including lactic acid and glycolic acid units, such as various forms of poly(lactic acid-co-glycolic acid) and poly(lactide-co-glycolide) characterized by the ratio of lactic acid:gly colic acid, collectively referred to herein as “PLGA”; and polyacrylates, and derivatives thereof. Exemplary polymers also include copolymers of polyethylene glycol (PEG) and 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 associated with polymer to yield “PEGylated polymers” by a cleavable linker. 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 acetal pendant groups.

[0096] The triblock copolymers disclosed herein comprise a core polymer such as, example, polyethylene glycol (PEG), polyvinyl acetate, polyvinyl alcohol, polyvinyl pyrrolidone (PVP), polyethyleneoxide (PEO), poly(vinyl pyrrolidone-co-vinyl acetate), polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oils, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-glycolic) acid, poly(lactic co-glycolic) acid (PLGA), cellulose derivatives, such as hydroxymethylcellulose, hydroxypropylcellulose and the like. Examples of diblock copolymers that can be used in the protective coatings disclosed herein comprise a polymer such as, example, polyethylene glycol (PEG), polyvinyl acetate, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyethyleneoxide (PEO), poly(vinyl pyrrolidone-co-vinyl acetate), polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oils, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-glycolic) acid, poly(lactic co- glycolic) acid (PLGA).

[0097] In one aspect, the protective coating contains (z.e., the encapsulated, the encapsulated compositions can further comprise lecithin or hydrolyzed lecithin as a carrier or as encapsulation material. As used herein, lecithin and / or hydrolyzed lecithin coatings include coatings comprising phosphatidyl choline, phosphatidyl inositol, phosphatidyl ethanolamine, phosphatidyl serine, and phosphatidic acid. Sources of the lecithin can be plant or animal sources.

[0098] In one aspect, any of the polymers, monosaccharides, disaccharides, or polysaccharides used to form the protective coating formed by placing the MSC additive in an encapsulating solution can be at an appropriate concentration for form the protective coating. For example, polymers, monosaccharides, disaccharides, or polysaccharides can be at any concentration between 0.01 mM and 10.0 M concentration, for example, from about 0.01 M to about 0.1 M, from about 0.1 mM to about 1.0 M, or from about 1.0 M to about 10.0 M.

[0099] In one aspect, the MSC secretome compositions (including, but not limited to MSC growth factor, MSC exosome, MSC extracts and / or extracellular vesicle comprising compositions) disclosed herein may comprise any known ingredients typically found pharmaceutical fields such as agents for combating free radicals; bactericides; sequestering agents; preservatives; basifying or acidifying agents; fragrances; surfactants; fillers; natural products or extracts of natural product, such as aloe or green tea extract; vitamins; or coloring materials. Other ingredients that may be combined with the powder may include an antioxidant, 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, Tetrahexyl decyl Ascorbate), Vitamin E (Tocotrienol), Vitamin A (retinol, retinal, retinoic acid, provitamin A carotenoids, such as beta-carotene), N-acetyl glucosamine, or other derivatives ofglucosamine. Other ingredients may include at least one essential fatty acid, such as S2-3, S2-6, and S2-9 polyunsaturated fatty acids, such as linoleic acid (LA), gamma-linoleic acid (GLA), alpha-linoleic acid (ALA), dihomo-y-linolenic acid (DGLA), arachidonic acid (ARA), and others. The fatty acids may be derived from various sources including evening primrose oil, black currant oil, borage oil, or GLA modified safflower seeds. Other ingredients may include a platelet rich fibrin matrix, at least one ingredient to support ECM production and production of hyaluronic acid, such as N-acetyl glucosamine or other derivatives of glucosamine, ultra-low molecular weight (ULMW) hyaluronic acid, chondroitin sulfate, or keratin sulfate.

[0100] Producing the MSC secretome compositions can comprise culturing MSCs collected from a donor to create a cultured media under culturing conditions including, in some embodiments, reduced oxygen and nutrition; stimulating the cultured cells to selectively secrete desired anti-inflammatory proteins, peptides, glycosaminoglycans, proteoglycans exosomes, and secretomes by adjusting the cell growth conditions; collecting, combining the conglomerate mixture with an encapsulation solution, and freezing the conglomerate mixture, wherein the conglomerate mixture comprises exosomes, peptides, proteins, cytokines, growth factors, extracellular matrix (ECM), proteoglycans, glycosaminoglycans; and chemokines selected from the group consisting of human MSCs, animal MSCs, multipotential stromal cells, fibroblasts, and fibroblast cells; combining the conglomerate mixture with an encapsulation solution, such as oligosaccharides, like a trehalose solution or protein solution and freezing the mixture; and lyophilizing or freeze-drying the frozen mixture, creating a dry powder. Alternatively, the MSCs may be lysed to collect all of the MSCs from the culture process, creating an extracted lysate; concentrating the extracted lysate and combining the extracted lysate with an encapsulation solution, such as oligosaccharides like a trehalose solution or protein solution and freezing the mixture; and lyophilizing or freeze-drying the frozen mixture, creating a dry powder. The powder contains a highly concentrated collection of analgesic MSC secretomes and exosomes and extracellular matrix components that are specific to anti-inflammation.

[0101] The method may also include filter-sterilizing, concentrating, freezing, or freeze drying the MSC conditioned culture medium. Additionally, the MSC culture medium may be combined with a cryoprotectant prior to freezing.

[0102] There are various methods for lysing the MSCs. Lysing may be achieved by the addition of a hypotonic solution or repeated freeze-thaw processes to disrupt the cell membranes. Moreover, the cells may be lysed while attached to the culture surface or in suspension. The cells may also be enzymatically released and / or lysed by mechanical homogenization.

[0103] Stimulating the MSC to selectively secrete the desired anti-inflammatory proteins, peptides, glycosaminoglycans, proteoglycans, exosomes and secretomes may be achieved byadjusting the cell growth conditions, such as cell confluency, culture media supplements, nutritional supplements, oxygen levels, length of culture in those conditions, cell passage number or combinations of those, and the like.

[0104] In some embodiments, compositions described herein can be lyophilized for packaging and storing. In some embodiments, treatment compositions described herein can be stored at ambient or room temperature (e.g., between 60°F and 75°F or between 15°C and 24°C). In some embodiments, the stability of treatment compositions described herein at ambient or room temperature can provide advantages for logistics and / or delivery.III. Methods of Treating Long COVID

[0105] In some embodiments, the compositions (e.g., protein, EV, secretome) disclosed herein are used in methods of treating Long COVID in a subject. Any of the compositions described herein may be used in such a method. A subject infected with the SARS-CoV-2 virus that causes coronavirus disease (COVID-19) can experience long-term effects from the infection, known as Long COVID or Post-COVID Conditions (PCC). Long COVID can be broadly defined as signs, symptoms, and conditions that continue or develop after acute COVID-19 infection. A subject can recover from COVID in from about a few days to about a few weeks after the SARS-CoV-2 virus infection. Accordingly, in some embodiments, a subject may be diagnosed with Long COVID about 4 weeks after the SARS-CoV-2 virus infection.

[0106] In some embodiments, Long COVID can comprise chronic COVID, post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, chronic post-COVID- 19 syndrome, post-COVID conditions (PCC), long-haul COVID, post-acute COVID-19, long-term effects of COVID, or a combination thereof. In some embodiments, a subject may have COVID that lasted for over 30 days. In some embodiments, a subject may have COVID symptoms that lasted for over 30 days.

[0107] In some embodiments, a subject with Long COVID can have a wide range of symptoms. In some embodiments, Long COVID symptoms can last weeks, months, or years after infection. In some embodiments, a subject may have Long COVID or Long COVID symptoms relapsed after treatment and / or recovery. Non-limiting examples of symptoms of Long COVID can include general symptoms (e.g., tiredness or fatigue that interferes with daily life; symptoms that get worse after physical or mental effort or post-exertional malaise; or fever), respiratory and heart symptoms (e.g., difficulty breathing or shortness of breath; cough; fast-beating / pounding heart or heart palpitations; or chest pain), neurological symptoms (e.g., difficulty thinking or concentrating or “brain fog”; headache; sleep problems; dizziness when you stand up or “lightheadedness”; pins-and-needles feelings; change in smell or taste; or depression or anxiety), digestive symptoms (e.g., diarrhea; or stomach pain), or other symptoms (e.g., joint or musclepain; rash; or changes in menstrual cycles). In some embodiments, Long COVID can be categorized to four types (e.g., Type 1, Type 2, Type 3, or Type 4). In some embodiments, a subject with Type 1 Long COVID can have heart, kidney, and / or circulatory symptoms. In some embodiments, a subject with Type 2 Long COVID can have lung conditions, sleep disorders, and / or anxiety. In some embodiments, a subject with Type 3 Long COVID can have muscle pain, connective tissue disorders, and / or nervous system disorders. In some embodiments, a subject with Type 4 Long COVID can have digestive and / or respiratory symptoms.

[0108] In some embodiments, a subject may be suffering or suffered from diminished quality of life (QoL), reduced cognitive functioning, increased fatigue, increased pain, or a combination thereof. In some embodiments, a subject may be suffering or suffered from post exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, abnormal movements, or a combination thereof. In some embodiments, a subject may be suffering or suffered from dementia, hair loss, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, malaise, fatigue, or a combination thereof. In some embodiments, a subject may be suffering or suffered from neuropsychiatric abnormalities, pulmonary abnormalities, cardiovascular abnormalities, other abnormalities, or a combination thereof. In some embodiments, a subject may be suffering or suffered from fatigue, cough, headache, body aches, fever, chills, loss of taste, loss of smell, diarrhea, congestion, dyspnea, sore throat, chest pain, abdominal pain, confusion, vomiting, or a combination thereof.

[0109] In some embodiments, a subject may be or may have been diagnosed with chronic fatigue, cognitive impairments, or a combination thereof. In some embodiments, a subject may have overreactive immune responses, highly dysregulated innate immune systems, highly dysregulated adaptive immune systems, or a combination thereof.

[0110] In some embodiments, a subject can experience improvement after treatment in Patient- Reported Outcome Measures (PROMs). PROMs are tools that can be used to collect and capture patient’s reports of their outcomes, which can be used as the basis for patient-reported outcomebased performance measures (PRO-PMs). Non-limiting examples of PROMs include Patient- Reported Outcomes Measurement Information System (PROMIS®), Medicare Health Outcomes Survey (HOS), or FOTO Patient Outcomes. PROMIS® is a set of person-centered measures that can evaluate and monitor physical, mental, and / or social health in adults and children. PROMIS® can be used with the general population or with individuals living with chronic conditions. In some embodiments, a subject can show statistically significant improvement in PROM scores after treatment. In some embodiments, a subject can show statistically significant improvement in PROMIS® scores after treatment.[OHl] In some embodiments, a subject can experience improvement after treatment in one or more of the following aspects selected from the group consisting of: Euro quality of life (QoL) 5 Dimension 5 Level (EQ-5D-5L), Impact of Event Scale - Revised (IES-R), Post-COVID-19 Functional Status Scale (PCFS), Fatigue Severity Scale (FSS), 36-Item Short Form Health Survey (SF-36), a brief cognitive screening test (Mini-Cog), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), and a combination thereof.

[0112] In some embodiments, a subject can experience improvement after treatment in one or more of the following Long COVID symptoms selected from the group consisting of: quality of life (QoL), cognitive functioning, fatigue, pain, and a combination thereof.

[0113] In some embodiments, a primary efficacy endpoint, Improvement in partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2 / FiO2) ratio from pre-infusion baseline (Day 0) to Day 7, is analyzed using the Analysis of Variance (ANOVA) adjusting for an intubation status. No improvement (+0 mmHg) is assigned to subjects who die or have negative change in P / F ratio from baseline. The PaO2 / FiO2 ratio of patients discharged prior to Day 7 is imputed as 380. A difference between 2 mean changes from the baseline to Day 7 is tested at one-sided significance level of 0.075 (overall Type I error rate < 0.1) and estimated with 85% confidence interval.

[0114] In some embodiments, time to recovery is defined by from the first study treatment until return of oxygenation saturation (SpO2) > 93% on room air (or PaO2 / FiO2 > 300 mmHg) and is estimated using the Kaplan-Meier (KM) method and 95% confidence interval by arm. Median time to recovery and a percentage of recovered patients at Days 14 and 28 is displayed by arm. A recovery odds ratio between the selected IP and control arm is also estimated using a cox regression model.

[0115] In some embodiments, the incidence of Serious Adverse Events (SAEs) is estimated by arm and displayed by severity and relationship to the study drug. Incidence of SAEs that lead to not receiving full doses of the study treatment (IP+saline or saline alone) is also summarized by arm.

[0116] In some embodiments, all-cause mortality (or overall survival) is estimated using the KM method as survival rates at Day 14, 28 and 60 by arm. The hazard ratio (HR) between the selected IP and control arms is also estimated using a cox regression model.

[0117] Disclosed herein is a method of treating Long COVID in a subject, the method comprises administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein at least 80% of the EVs are CD63+, CD9-, CD81-. In some methods wherein the composition comprises one or more EVs, the one or more EVs comprise hsa-miR-125b-5p, hsa- miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR- 423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof. In some methods, the composition comprises Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein- coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gamma-glutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenolpyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin- 4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

[0118] Disclosed herein is a method of treating Long COVID in a subject, the method comprises administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR- 23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR- 940, or a combination of two or more thereof. In some methods, the composition comprises Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O- sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2(Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocytemacrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein- glutamine gamma-glutamyltransf erase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

[0119] Disclosed herein is a method of treating Long COVID in a subject, the method comprises administering to the subject a composition comprising Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulinlike binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gamma-glutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenolpyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

[0120] In some embodiments, the subject is negative for SARS-CoV-2 for at least four weeks prior to the administering. In some embodiments, the subject is SARS-CoV-2 negative if a first biological sample from the subject is negative for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR). In some embodiments, the subject was previously infected with SARS-CoV-2 if a second biological sample from the subject waspositive for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT- PCR).

[0121] In some embodiments, treating the Long COVID comprises reducing the post-COVID- 19 Functional Status (PCFS) score of the subject after the administering as compared to prior the administering. In some embodiments, treating the LONG COVID comprises reducing the pain in the subject after the administering as compared to prior the administering.

[0122] In some embodiments, the Long COVID is chronic COVID, post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, chronic post-COVID-19 syndrome, post- COVID conditions (PCC), long-haul COVID, post-acute COVID-19, long-term effects of COVID, or a combination thereof.

[0123] In some embodiments, the treating comprises improving the quality of life (QoL) of the subject, increasing cognitive functioning of the subject, decreasing fatigue in the subject, or decreasing pain in the subject, or a combination of two or more thereof.

[0124] In some embodiments, the subject is suffering from or suffered from: post exertional malaise, fatigue, brain fog, cough, headache, body aches, fever, chills, dizziness, gastrointestinal symptoms, palpitations, dementia, hair loss, diarrhea, congestion, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, changes in sexual desire or capacity, loss of or change in smell, loss of or change in taste, thirst, chronic cough, chest pain, neuropsychiatric abnormalities, pulmonary abnormalities, cardiovascular abnormalities, abnormal movements, sore throat, abdominal pain, overreactive immune response, highly dysregulated innate immune system, highly dysregulated adaptive immune system, confusion, or vomiting, or a combination of two or more thereof.

[0125] In some embodiments, after the administering the subject experiences an improvement in a Patient-Reported Outcome Measure (PROM), optionally wherein the subject shows statistically significant improvement in the PROM after treatment.

[0126] In some embodiments, after the administering the subject experiences improvement in one or more of the following: Euro quality of life (QoL) 5 Dimension 5 Level (EQ-5D-5L), Impact of Event Scale - Revised (IES-R), Post-COVID-19 Functional Status Scale (PCFS), Fatigue Severity Scale (FSS), 36-Item Short Form Health Survey (SF-36), a brief cognitive screening test (Mini-Cog), Mini-Mental State Examination (MMSE), or Montreal Cognitive Assessment (MOCA), or a combination of two or more thereof.

[0127] In some embodiments, administering reduces the level of one or more acute phase biomarkers in a sample from the subject. In some embodiments, the one or more acute phase biomarkers comprise C-Reactive Protein (CRP), ferritin, D-dimer, neutrophils, or combinations of two or more thereof.

[0128] In some embodiments, administering comprises intravenous administration.

[0129] In some embodiments, the composition is a secretome composition comprising the protein and / or one or more EVs.

[0130] In some embodiments, the composition is prepared by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition.

[0131] In some embodiments, the method comprises preparing the composition prior to the administering, wherein preparing the composition occurs by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition. In some embodiments, the culture media is serum-free. In some embodiments, the culture media has a glucose concentration below 4.5 g / L. In some embodiments, formulating the MSC conditioned media comprises exchanging the conditioned media for a pharmaceutically acceptable formulation. In some embodiments, the pharmaceutically acceptable formulation comprises saline.

[0132] Also disclosed herein are methods of treating Long COVID in a subject comprising administering to the subject a composition comprising secreted extracellular vesicles that contain a composition that includes any combination of composition proteins and / or miRNAs, selected from the following: Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TEMP -2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7A, NKp80, Cystatin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM-A, MCSF, LEMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan-4, Ferritin, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD 109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TEMP-1, PAPP-A, Decorin, PCK1, Arylsulfatase A, CD99, CA2,PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP- 1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Folli statin-like 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP- 1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl30, C-myc, LILRB4, BMP-2 MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM Rbeta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6 ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A, NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin-1, CD51, Notch- 1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, Rai A, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin,Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR- AI, TAFA2, N-Cadherin, IL-17B, IL- 17 RC, MIP-3b, Cy statin C, Cy statin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo- A, HSD17B1, IL- 19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM- A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA13, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha-1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmogl ein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL- 28A, FGF-12, METAP2, ASAHL, EDIL3, NTAL, EGF R, TAFA5, Galectin-9, vWF-A2, TACE, Activin RUB, Cathepsin S, LDL R, BMPR-IA, 0X40, IL- 3 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1 A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDT5, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL- 10 Rb, XEDAR, IL-22, PILR-alpha, NRGl-bl, FABP4, RGM-A, RELT, TrkC, C5a, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIG02, HCC-1, TFPI-2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RH, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 MI, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.l, ED AR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase,NPDC-1, MCP-4, EG-VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP- lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, IL-13, 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-lOb, 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-l'7-5p, 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-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-l, 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.

[0133] In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered at a cell-equivalent dose range of 0.7 to 7 million cells / kg. In some embodiments, the composition is administered at a cell-equivalent dose of at least about, at most about, or about 0.2, 0.5, 0.7, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, or 12.0 million cells / kg, or a range between any two of these values. In some embodiments, the product is administered at a dose that provides 9xlOnto 1.2xl012extracellular vesicles or 5xl0nto 1.5xl012, 6xlOnto 1.4xl012, 7xlOnto 1.3xl012, 8xl0nto 1.2xl012, or 8xl0nto 1.3xl012extracellular vesicles. In some embodiments, the product is administered at a dose that provides at least or at most 5xl0n, 6xlOn, 7xlOn, 8xl0n, 9xlOn, IxlO12, LlxlO12, 1.2xl012, 1.3xl012, 1.4xl012, or 1.5xl012extracellular vesicles. In some embodiments, the composition comprises 6xlO10to 8xl010, 5xl010to 9xlO10, 4xlO10to 10xl010, 5.5xl010to 8.5xl010, or 6xlO10to 8.5xl010cells / ml. Insome embodiments, the composition comprises 6xlO10to 8xlO10extracellular vesicles per ml and is administered at a dose of 10 to 20 ml. In some embodiments, the composition comprises 6xlO10to 8xlO10extracellular vesicles per ml and is administered at a dose of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ml, or a range between any two of these values. In some embodiments, the composition comprises at least 6xlO10to 8xlO10extracellular vesicles per ml and is administered at a dose of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ml.

[0134] Fatigue

[0135] Disclosed herein is a method of treating fatigue in a subject previously infected with SARS-CoV-2, wherein the method comprises administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein at least 80% of the EVs are CD63+, CD9-, CD81-. In some methods, the one or more EVs comprise hsa-miR-125b-5p, hsa- miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR- 222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR- 423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof. In some methods, the composition comprises Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein- coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gamma-glutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenolpyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin- 4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

[0136] In some embodiments, the subject is negative for SARS-CoV-2 for at least four weeks prior to the administering. In some embodiments, the subject is SARS-CoV-2 negative if a firstbiological sample from the subject is negative for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR). In some embodiments, the subject was previously infected with SARS-CoV-2 if a second biological sample from the subject was positive for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT- PCR).

[0137] Disclosed herein is a method of treating fatigue in a subject previously infected with SARS-CoV-2, wherein the method comprises administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa- miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a- 3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa- miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof. In some methods, the composition comprises Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome- associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gammaglutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenolpyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP- 2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

[0138] Disclosed herein is a method of treating fatigue in a subject previously infected with SARS-CoV-2, wherein the method comprises administering to the subject a composition comprising Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupledreceptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocytemacrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein- glutamine gamma-glutamyltransf erase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

[0139] In some embodiments, treating fatigue in the subject comprises a reduction in a Fatigue Severity Scale (FSS) score after the administering as compared to the FSS score prior the administering. In some embodiments, after the administering, the subject’s FSS score is three or less. In some embodiments, prior to the administering, the subject’s FSS score is four or greater. In some embodiments, the fatigue is chronic fatigue. In some embodiments, the subject experienced chronic fatigue for at least six months prior to the administering. In some embodiments, treating the fatigue comprises reducing the post-COVID-19 Functional Status (PCFS) score of the subject after the administering as compared to prior the administering.

[0140] In some embodiments, the treating comprises improving the quality of life (QoL) of the subject, increasing cognitive functioning of the subject, decreasing fatigue in the subject, or decreasing pain in the subject, or a combination of two or more thereof.

[0141] In some embodiments, the subject is suffering from or suffered from: post exertional malaise, fatigue, brain fog, cough, headache, body aches, fever, chills, dizziness, gastrointestinal symptoms, palpitations, dementia, hair loss, diarrhea, congestion, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, changes in sexual desire or capacity, loss of or change in smell, loss of or change in taste, thirst, chronic cough, chest pain, neuropsychiatric abnormalities, pulmonary abnormalities, cardiovascular abnormalities, abnormal movements, sore throat, abdominal pain, overreactive immune response, highly dysregulated innate immune system, highly dysregulated adaptive immune system, confusion, or vomiting, or a combination of two or more thereof.

[0142] In some embodiments, after the administering the subject experiences an improvement in a Patient-Reported Outcome Measure (PROM), optionally wherein the subject shows statistically significant improvement in the PROM after treatment.

[0143] In some embodiments, after the administering the subject experiences improvement in one or more of the following: Euro quality of life (QoL) 5 Dimension 5 Level (EQ-5D-5L), Impact of Event Scale - Revised (IES-R), Post-COVID-19 Functional Status Scale (PCFS), Fatigue Severity Scale (FSS), 36-Item Short Form Health Survey (SF-36), a brief cognitive screening test (Mini-Cog), Mini-Mental State Examination (MMSE), or Montreal Cognitive Assessment (MOCA), or a combination of two or more thereof.

[0144] In some embodiments, administering reduces the level of one or more acute phase biomarkers in a sample from the subject. In some embodiments, the one or more acute phase biomarkers comprise C-Reactive Protein (CRP), ferritin, D-dimer, neutrophils, or combinations of two or more thereof.

[0145] In some embodiments, administering comprises intravenous administration.

[0146] In some embodiments, the composition is a secretome composition comprising the protein and / or one or more EVs. In some embodiments, the composition comprises at least 6xlO10to 8xl010extracellular vesicles per ml and is administered at a dose of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ml.

[0147] In some embodiments, the composition is prepared by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition.

[0148] In some embodiments, the method comprises preparing the composition prior to the administering, wherein preparing the composition occurs by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition. In some embodiments, the culture media is serum-free. In some embodiments, the culture media has a glucose concentration below 4.5 g / L. In some embodiments, formulating the MSC conditioned media comprises exchanging the conditioned media for a pharmaceutically acceptable formulation. In some embodiments, the pharmaceutically acceptable formulation comprises saline.

[0149] Pain

[0150] Disclosed herein is a method of treating pain in a subject previously infected with SARS- CoV-2, wherein the method comprises administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein at least 80% of the EVs are CD63+, CD9-, CD81-. In some methods, the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa- miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a- 3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa- miR-424-5p, or hsa-miR-940, or a combination of two or more thereof. In some methods, the composition comprises Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocytemacrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein- glutamine gamma-glutamyltransf erase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

[0151] In some embodiments, the subject is negative for SARS-CoV-2 for at least four weeks prior to the administering. In some embodiments, the subject is SARS-CoV-2 negative if a first biological sample from the subject is negative for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR). In some embodiments, the subject was previously infected with SARS-CoV-2 if a second biological sample from the subject was positive for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT- PCR).

[0152] Disclosed herein is a method of treating pain in a subject previously infected with SARS- CoV-2, wherein the method comprises administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein the one or more EVs comprise hsa-miR-125b- 5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa- miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b- 3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa-miR-34a-5p, hsa- miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof. In some methods, the composition comprises Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein- coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O-sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gamma-glutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenolpyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin- 4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

[0153] Disclosed herein is a method of treating pain in a subject previously infected with SARS- CoV-2, wherein the method comprises administering to the subject a composition comprising Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-O- sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor- 1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF(Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocytemacrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein- glutamine gamma-glutamyltransf erase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP-2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

[0154] In some embodiments, the subject is negative for SARS-CoV-2 for at least four weeks prior to the administering. In some embodiments, the subject is SARS-CoV-2 negative if a first biological sample from the subject is negative for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR). In some embodiments, the subject was previously infected with SARS-CoV-2 if a second biological sample from the subject was positive for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT- PCR).

[0155] In some embodiments, treating the pain comprises reducing the post-COVID-19 Functional Status (PCFS) score of the subject after the administering as compared to prior the administering. In some embodiments, treating pain comprises reducing the pain in the subject after the administering as compared to prior the administering.

[0156] In some embodiments, the treating comprises improving the quality of life (QoL) of the subject, increasing cognitive functioning of the subject, decreasing fatigue in the subject, or decreasing pain in the subject, or a combination of two or more thereof.

[0157] In some embodiments, the subject is suffering from or suffered from: post exertional malaise, fatigue, brain fog, cough, headache, body aches, fever, chills, dizziness, gastrointestinal symptoms, palpitations, dementia, hair loss, diarrhea, congestion, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, changes in sexual desire or capacity, loss of or change in smell, loss of or change in taste, thirst, chronic cough, chest pain, neuropsychiatric abnormalities, pulmonary abnormalities, cardiovascular abnormalities, abnormal movements, sore throat, abdominal pain, overreactive immune response, highly dysregulated innate immune system, highly dysregulated adaptive immune system, confusion, or vomiting, or a combination of two or more thereof.

[0158] In some embodiments, after the administering the subject experiences an improvement in a Patient-Reported Outcome Measure (PROM), optionally wherein the subject shows statistically significant improvement in the PROM after treatment.

[0159] In some embodiments, after the administering the subject experiences improvement in one or more of the following: Euro quality of life (QoL) 5 Dimension 5 Level (EQ-5D-5L), Impact of Event Scale - Revised (IES-R), Post-COVID-19 Functional Status Scale (PCFS), Fatigue Severity Scale (FSS), 36-Item Short Form Health Survey (SF-36), a brief cognitive screening test (Mini-Cog), Mini-Mental State Examination (MMSE), or Montreal Cognitive Assessment (MOCA), or a combination of two or more thereof.

[0160] In some embodiments, administering reduces the level of one or more acute phase biomarkers in a sample from the subject. In some embodiments, the one or more acute phase biomarkers comprise C-Reactive Protein (CRP), ferritin, D-dimer, neutrophils, or combinations of two or more thereof.

[0161] In some embodiments, administering comprises intravenous administration.

[0162] In some embodiments, the composition is a secretome composition comprising the protein and / or one or more EVs. In some embodiments, the composition comprises at least 6xlO10to 8xl010extracellular vesicles per ml and is administered at a dose of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ml.

[0163] In some embodiments, the composition is prepared by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition.

[0164] In some embodiments, the method comprises preparing the composition prior to the administering, wherein preparing the composition occurs by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition. In some embodiments, the culture media is serum-free. In some embodiments, the culture media has a glucose concentration below 4.5 g / L. In some embodiments, formulating the MSC conditioned media comprises exchanging the conditioned media for a pharmaceutically acceptable formulation. In some embodiments, the pharmaceutically acceptable formulation comprises saline.

[0165] Non-limiting example embodiments1. A method of treating Long COVID in a subject, the method comprising administering to the subject a composition comprising a therapeutic MSC secretome composition made by a method comprising:(a) culturing bone marrow-derived MSCs under the following conditions to produce an MSC conditioned media:(i) oxygen tension below 5%; and(ii) culture media having a pH below 7;(b) harvesting the MSC conditioned media; and(c) formulating the MSC conditioned media to produce the therapeutic MSC secretome composition, wherein the therapeutic MSC secretome composition comprises proteins and extracellular vesicles produced by the bone marrow-derived MSCs in step (a).2. The method of embodiment 1, wherein the Long COVID comprises chronic COVID, postacute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, chronic post- COVID-19 syndrome, post-COVID conditions (PCC), long-haul COVID, post-acute COVID-19, long-term effects of COVID, or a combination thereof.3. The method of embodiment 1 or 2, wherein the subject has COVID or COVID symptoms that lasted for over 30 days.4. The method of any one of embodiments 1 to 3, wherein the subject is suffering or suffered from diminished quality of life (QoL), reduced cognitive functioning, increased fatigue, increased pain, or a combination thereof.5. The method of any one of embodiments 1 to 3, wherein the subject is suffering or suffered from post exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, abnormal movements, or a combination thereof.6. The method of any one of embodiments 1 to 3, wherein the subject is suffering or suffered from dementia, hair loss, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, malaise, fatigue, or a combination thereof.7. The method of any one of embodiments 1 to 3, wherein the subject is suffering or suffered from neuropsychiatric abnormalities, pulmonary abnormalities, cardiovascular abnormalities, other abnormalities, or a combination thereof.8. The method of any one of embodiments 1 to 3, wherein the subject is suffering or suffered from fatigue, cough, headache, body aches, fever, chills, loss of taste, loss of smell, diarrhea, congestion, dyspnea, sore throat, chest pain, abdominal pain, confusion, vomiting, or a combination thereof.9. The method of any one of embodiments 1 to 8, wherein the subject is or was diagnosed with chronic fatigue, cognitive impairments, or a combination thereof.10. The method of any one of embodiments 1 to 9, wherein the subject has overreactive immune responses, highly dysregulated innate immune systems, highly dysregulated adaptive immune systems, or a combination thereof.11. The method of any one of embodiments 1 to 10, wherein the subject experiences improvement after treatment in Patient-Reported Outcome Measures (PROMs).12. The method of any one of embodiments 1 to 11, wherein the subject shows statistically significant improvement in PROM scores after treatment.13. The method of any one of embodiments 1 to 12, wherein the subject experiences improvement after treatment in one or more of the following aspects selected from the group consisting of: Euro quality of life (QoL) 5 Dimension 5 Level (EQ-5D-5L), Impact of Event Scale - Revised (IES-R), Post-COVID-19 Functional Status Scale (PCFS), Fatigue Severity Scale (FSS), 36-Item Short Form Health Survey (SF-36), a brief cognitive screening test (Mini-Cog), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), and a combination thereof.14. The method of any one of embodiments 1 to 13, wherein the subject shows statistically significant improvement in Patient-Reported Outcomes Measurement Information System (PROMIS) scores after treatment.15. The method of any one of embodiments 1 to 14, wherein the subject experiences improvement after treatment in one or more of the following Long CO VID symptoms selected from the group consisting of: quality of life (QoL), cognitive functioning, fatigue, pain, and a combination thereof.16. The method of any one of embodiments 1 to 15, wherein administering reduces the level of one or more acute phase biomarkers.17. The method of embodiment 16, wherein the one or more acute phase biomarkers comprise C -Reactive Protein (CRP), ferritin, D-dimer, neutrophils, or combinations thereof.18. The method of any one of embodiments 1 to 17, wherein administering comprises intravenous administration.19. The method of any one of embodiments 1 to 18, wherein the dosage of the therapeutic MSC secretome composition administered to the subject is a cell-equivalent dosage of 0.7 to 7 million cells / kg.20. The method of any one of embodiments 1 to 19, wherein the culture media is serum-free.21. The method of any one of embodiments 1 to 20, wherein the culture media has a glucose concentration below 4.5 g / L.22. The method of any one of embodiments 1 to 21, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+CD9 CD81 .23. The method of any one of embodiments 1 to 22, wherein the therapeutic MSC secretome composition comprises one or more of the following proteins: Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7 A, NKp80, Cystatin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan-4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP-A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL- 18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL- 2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Follistatin-like 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 Rbeta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl30, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM Rbeta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2,PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin- 2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A, NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL- 21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, R0B04, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL- 17 RC, MIP-3b, Cy statin C, Cy statin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo- A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM-A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA13, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha- 1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I- TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF- 12, METAP2, ASAHL, EDIL3, NT AL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2,TROP-2, NUDTS, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RC0R1, IL- 10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL- 15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIG02, HCC-1, TFPI- 2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITR L, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIE R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CDS 8, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU. l, ED AR, AD AMTS 13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP- 1b, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13.24. The method of any one of embodiments 1 to 23, wherein the therapeutic MSC secretome composition comprises one or more of the following nucleic acids: 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-lOb, 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-l'7-5p, 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-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-l, 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, or hsa-miR-99b-5p.25. A method of treating Long COVID in a subject, the method comprising administering to the subject a composition comprising a therapeutic MSC secretome composition comprising extracellular vesicles, wherein at least 80% of the extracellular vesicles in the therapeutic MSC secretome composition are CD63+CD9 CD81 .26. The method of embodiment 25, wherein the therapeutic MSC secretome composition further comprises one or more of the following proteins: Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF RI, htPAPP-A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7 A, NKp80, Cystatin B, Osteoadherin, Midkine, Calreticulin, Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan-4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, blG- H3, GPR115, TGFbl, Ephrin-A4, CD109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP-2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP-A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97,CT ACK, Integrin alpha 1, EXTL3, IL- 18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin DI, DNMT3A, BCL-2, CL-P1, Ephrin-B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3,Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, P0N1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Follistatin-like 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL-20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC- II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF- CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl3O, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM R beta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF-23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A, NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactom edin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2’7, Siglec-6, Dectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG- 2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, RalA, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, ROBO4, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL- 17 RC, MIP-3b, Cystatin C, Cystatin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo- A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E,TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM-A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA13, IL-9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha- 1, Smad4, ICAM-1, MEF2C, TREM-1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I- TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL-28A, FGF- 12, METAP2, ASAHL, EDIL3, NT AL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL-13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL- 10 Rb, XEDAR, IL-22, PILR-alpha, NRG1-131, FABP4, RGM-A, RELT, TrkC, Csa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL- 15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIG02, HCC-1, TFPI- 2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITRL, CD14, R-Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb, NKp46, MCP-3, IL-32 alpha, TGFb3 FOLR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP-2, PU.l, ED AR, AD AMTS 13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP-10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG- VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4-1BB, HO-1, SOST, S100A13, Kallikrein 7, or IL-13.27. The method of embodiment 25 or 26, wherein the extracellular vesicles comprise one or more of the following nucleic acids: 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-lOb, 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-1’7- 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-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-l, 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, or hsa-miR-99b-5p.28. The method of any one of embodiments 25 to 27, wherein the Long CO VID comprises chronic CO VID, post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, chronic post-COVID-19 syndrome, post-CO VID conditions (PCC), long-haul CO VID, post-acute COVID-19, long-term effects of CO VID, or a combination thereof.29. The method of any one of embodiments 25 to 28, wherein the subject has COVID or COVID symptoms that lasted for over 30 days.30. The method of any one of embodiments 25 to 29, wherein the subject is suffering or suffered from diminished quality of life (QoL), reduced cognitive functioning, increased fatigue, increased pain, or a combination thereof.31. The method of any one of embodiments 25 to 29, wherein the subject is suffering or suffered from post exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms,palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, abnormal movements, or a combination thereof.32. The method of any one of embodiments 25 to 29, wherein the subject is suffering or suffered from dementia, hair loss, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, malaise, fatigue, or a combination thereof.33. The method of any one of embodiments 25 to 29, wherein the subject is suffering or suffered from neuropsychiatric abnormalities, pulmonary abnormalities, cardiovascular abnormalities, other abnormalities, or a combination thereof.34. The method of any one of embodiments 25 to 29, wherein the subject is suffering or suffered from fatigue, cough, headache, body aches, fever, chills, loss of taste, loss of smell, diarrhea, congestion, dyspnea, sore throat, chest pain, abdominal pain, confusion, vomiting, or a combination thereof.35. The method of any one of embodiments 25 to 34, wherein the subject is or was diagnosed with chronic fatigue, cognitive impairments, or a combination thereof.36. The method of any one of embodiments 25 to 34, wherein the subject has overreactive immune responses, highly dysregulated innate immune systems, highly dysregulated adaptive immune systems, or a combination thereof.37. The method of any one of embodiments 25 to 36, wherein the subject experiences improvement after treatment in Patient-Reported Outcome Measures (PROMs).38. The method of any one of embodiments 25 to 37, wherein the subject shows statistically significant improvement in PROM scores after treatment.39. The method of any one of embodiments 25 to 38, wherein the subject experiences improvement after treatment in one or more of the following aspects selected from the group consisting of: Euro quality of life (QoL) 5 Dimension 5 Level (EQ-5D-5L), Impact of Event Scale - Revised (IES-R), Post-COVID-19 Functional Status Scale (PCFS), Fatigue Severity Scale (FSS), 36-Item Short Form Health Survey (SF-36), a brief cognitive screening test (Mini-Cog), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), and a combination thereof.40. The method of any one of embodiments 25 to 39, wherein the subject shows statistically significant improvement in Patient-Reported Outcomes Measurement Information System (PROMIS) scores after treatment.41. The method of any one of embodiments 25 to 40, wherein the subject experiences improvement after treatment in one or more of the following Long CO VID symptoms selected from the group consisting of: quality of life (QoL), cognitive functioning, fatigue, pain, and a combination thereof.42. The method of any one of embodiments 25 to 41, wherein administering reduces the level of one or more acute phase biomarkers.43. The method of embodiment 42, wherein the one or more acute phase biomarkers comprise C-Reactive Protein (CRP), ferritin, D-dimer, neutrophils, or combinations thereof.44. The method of any one of embodiments 25 to 43, wherein administering comprises intravenous administration.EXAMPLES

[0166] The following examples are put forth so as to provide those of ordinary skill 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 exemplary 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. These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.Example 1 - Production of Therapeutic Composition

[0167] An MSC secretome therapeutic composition was made by the following method: human bone marrow-derived MSCs were cultured in culture vessels with growth media to expand the MSC population. Growth media was then removed, and the cells were washed with PBS. The MSCs were then cultured in reduced glucose media with a pH below 7.0 under hypoxic conditions. The conditioned media was then collected and subjected to diafiltration followed by filter sterilization. The production process for the therapeutic product was done under current Good Manufacturing Practices and Current Good Tissue Practices.

[0168] The tetraspanin profile of extracellular vesicles present in the therapeutic composition was determined, and it was found that greater than 95% of the extracellular vesicles present in the therapeutic composition were CD63+CD9 CD81 .

[0169] Protein content of the therapeutic product was determined, and the following proteins were found to be present: Ferritin, NUP85, LAMP2, GPR115, Serpin Fl, OPN, PAI-1, DAPP1, Cathepsin B, Semaphorin 6C, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, Thrombomodulin, PF4, MIF, Periostin, Furin, TIMP-1, Decorin, PCK1, CD99, CD63, CD9, CD81, Transferrin, DcR3, Lumican, TIMP-2, SLITRK5, FAP, Artemin, DPPII, cIAP-1, Pentraxin 3, Visfatin, Neprilysin, Albumin, Galectin-1, UNC5H3, IL-20 R beta, SREC-II, JAM-C, TNF RI, htPAPP- A, eNOS, MSP R, TPP1, LAMP1, B2M, NCAM-1, HIF-1 alpha, ST6GAL1, CD99-L2, Plexin A4, EMMPRIN, p53, Semaphorin 7A, NKp80, Cystatin B, Osteoadherin, Midkine, Calreticulin,Osteoactivin, Legumain, TAZ, Cathepsin L, RBP4, Serpin A4, JAM-A, MCSF, LIMPII, OPG, IL-22, Galectin-3, MOG, Trypsin 3, SIRP alpha, Syndecan-4, IGFBP-4, IL-1 R6, GSTM1, NUP85, LAMP2, MeprinA, IL-1 F10, bIG-H3, GPR115, TGFbl, Ephrin-A4, CD109, Serpin Fl, IGFBP-6, HS3ST4, Aminopeptidase LRAP, OPN, PAI-1, DAPP1, GDF-9, Cathepsin B, IGFBP- 2, Semaphorin 6C, IGF-2, PDGF R alpha, Sortilin, Serpin B6, Dkk-3, CNTF, TSP-1, GM-CSF Ra, Thrombomodulin, Endoglycan, IGFBP-3, RGM-C, PF4, MIF, TGM4, Periostin, Furin, TIMP-1, PAPP-A, Decorin, PCK1, Arylsulfatase A, CD99, CA2, PRDX4, Transferrin, DcR3, GP73, LAIR2, ULBP-4, Lumican, TIMP-2, TFPI, SOX2, SLITRK5, FAP, Spinesin, ENPP-2, CD97, CTACK, Integrin alpha 1, EXTL3, IL-18 BPa, PD-L2, PSMA, IL-20 Ra, Glyoxalase II, Trypsin 1, IGF-2R, ADAMTSL-1, Erythropoietin, Plexin Dl, DNMT3A, BCL-2, CL-P1, Ephrin- B3, FABP6, CHI3L1, FCRLS, TFF3, Artemin, DPPII, cIAP-1, PDGF Rb, Pentraxin 3, Angiotensinogen, Follistatin, CF VII, Persephin, TRAIL Rl, THAP11, CD200, CLEC-2, AMIGO, IGFBP-5, PON1, SOX7, GALNT10, Visfatin, Progranulin, PCSK2, GKN1, IL-18, Neprilysin, Stabilin-2, IL-17 RD, Albumin, Follistatin-like 1, MMP-10, FKBP51, LRRC4, Pref-1, Galectin-1, Troponin C, UNC5H3, FLRT2, CD314, Semaphorin 6B, Netrin-4, CD27 Ligand, IL- 20 R beta, Semaphorin 6A, TSK, Cytokeratin-8, CHST3, Mcl-1, DPPIV, SREC-II, Norrin, JAM-C, Bcl-10, Wnt-4, LSECtin, Kell, TNF RI, PTP1B, htPAPP-A, IDO, PDGF-CC, Galanin, Activin A, TLR2, SCCA2, FABP1, eNOS, SHP-1, ICOS, ClqTNF9, MMP-1, TC-PTP, IL-24, gpl3O, C-myc, LILRB4, BMP-2,, MIA, CD34, CD63, CD9, CD81, IFNab R2, Glypican 2, MSP R, DSCAM, Matriptase, KIR2DL3, CD30, Siglec-10, CLEC-1, TPP1, Ubiquitin+1, ANGPTL4, TWEAK R, Nidogen-1, CD2, Kallikrein 1, TSLP R, LAMP1, TROY, VCAM-1, Siglec-11, S100A1, PARI, Thyroid Peroxidase, Aminopeptidase P2, IL-1 RI, ADAMS, OSM Rbeta, Thrombospondin-2, SMPD1, B2M, MFRP, LRP-6„ST3GAL1, NCAM-1 (CD56), Granzyme B, Adiponectin, IL-22BP, TPST2, PD-ECGF, LH, LEDGF, Cyr61, ULBP-3, IFNb, THSD1, FGF- 23, LAMA4, Adipsin, AIF, SorCS2, SULT2A1, CD39L2, Insulin R, HIF-1 alpha, 0X40 Ligand, Pax3, UCH-L3, cMASP3, Langerin, Desmin, SOX9, ST6GAL1, MEP1B, CD99-L2, Plexin A4, Semaphorin 4D, ROBO2, PDX-1, APRIL, Neurturin, Kremen-2, EMMPRIN, Activin RIB, Neuroligin 2, Epiregulin, CASA, MMP-12, GALNT2, CEACAM-5, VEGF Rl, DSPG3, SorCSl, Matrilin-2, sFRP-3, p53, EphB3, NCK1, Semaphorin 7A, NKp80, Prolactin, Cystatin B, Sirtuin 1, FGF-16, FGF R5, NQO-1, Semaphorin 6D, FGF-3, GATA-4, VAP-A, CHST2, Pappalysin-2, Syndecan-3, Jagged 1, AKR1C4, Olfactomedin-2, Osteoadherin, NKp44, Thyroglobulin, IL-21R, Chemerin, EphAl, CD48, MICB, FGF-5, TRANCE, CES2, ULBP-1, Integrin alpha 5, VAMP-2, FLRG, Ret Midkine, CD73, TRACP, proGRP, Granzyme H, PRX2, p2'7, Siglec-6, Dectin-1, CD51, Notch-1, Calreticulin, DR3, DCTN1, CDC25B, Osteoactivin, ACE, CA125, HAO-1, PSMA1, FCRLB, BMP-9, CRIM1, LIF, SPINK1, EphB6, RGM-B, HS3ST1, R0R1, CMG-2, 4-1BB Ligand, L1CAM-2, p63, Cathepsin V, Testican 2, Glypican 5, CD6, Siglec-2, Legumain, PRELP, CES1, TAZ, NSE, TECK, HTRA2, HIF-1 beta, TAFA1, Podocalyxin, Rai A, CRELD2, GRAP2, SP-D, BID, GFR alpha-2, Notch-3, VEGF R3, DLL4, TGFb2, LIGHT, XIAP, ST8SIA1, Cathepsin L, 6Ckine, MIS RII, Kallikrein 5, TGM3, FCAR, Contactin-2, CD83, IL-1 R3, SALM4, GBA3, R0B04, OSCAR, VEGF, IGSF3, Biglycan, Neudesin, ILT4, uPAR, Axl, WIF-1, IL-7 R alpha, GPR56, CEACAM-3, MCEMP1, FABP2, Plexin B3, MEPE, Activin RIIA, ANG-2, Cochlin, Presenilin 1, NPTXR, SLAM, COMT, SPHK1, RBP4, Nectin-1, GUSB, Nidogen-2, IL-17F, SR-AI, TAFA2, N-Cadherin, IL-17B, IL-17 RC, MIP-3b, Cystatin C, Cy statin D, AMSH, FcERI, CLEC10A, HGF R, ANG-1, Prolactin R, FGF-20, CD28, Nogo- A, HSD17B1, IL-19, Enteropeptidase, Cathepsin E, TSLP, TCN2, GDF-15, Epimorphin, GRKS, PD-1, Serpin A4, ADAM23, NOV, Galectin-2, Neurexin 3 beta, TLR3, Sirtuin 2, Numb, IL-28 R alpha, IL-33, Lin28, FCRL1, KLF4, NKp30, Lymphotactin, Cystatin SN, JAM-A, Calreticulin-2, ErbB4, BMP-8, IL-27 Ra, Fas, IL-4 Ra, Kallikrein 14, Matrilin-3, Olig2, Kallikrein 12, CA13, IL- 9, Nectin-3, MPIF-1, Cystatin S, ADA, IL-2 Rb, GFR alpha- 1, Smad4, ICAM-1, MEF2C, TREM- 1, L-Selectin, Hepsin, CD42b, MCSF, RANK, CHST4, CA8, FCRL3, ASAH2, CF XIV, PYY, HGF, I-TAC, Semaphorin 4C, SorCS3, Tie-1, IL-31 RA, Arginase 1, POGLUT1, IL-lra, Podoplanin, TIM-3, CREG, CD300f, uPA, EphA2, LRRTM4, LIMPII, Tenascin R, CPE, PECAM-1, DNAM-1, DKK-1, OPG, CPB1, TSH, MMP-2, Siglec-9, ICAM-3, Cystatin SA, Galectin-4, Pepsinogen II, Desmoglein-3, Nectin-4, SCF, Serpin A5, PTH, FGF-19, MSP, IL- 28 A, FGF-12, METAP2, AS AHL, EDIL3, NT AL, EGF R, TAFAS, Galectin-9, vWF-A2, TACE, Activin RIM, Cathepsin S, LDL R, BMPR-IA, 0X40, IL- 13 R2, B7-H4, MMP-13, ANGPTL7, TRAIL R4, IGSF4B, Sirtuin 5, PEAR1, SH2D1A, Cerberus 1, GDF-11, Nrf2, TROP-2, NUDTS, R0R2, EphB4, Glypican 1, LAP(TGFbl), Gash, Contactin-1, IL-27, UNC5H4, ICAM-2, MBL, HS3ST3B1, RCOR1, IL- 10 Rb, XEDAR, IL-22, PILR-alpha, NRG1- 131, FABP4, RGM-A, RELT, TrkC, CSa, SREC-I, Nestin, TPO, ErbB3, Kirrel3, FLRT1, Galectin-3, CXCL16, JAM-B, DR6,Nogo Receptor, TLR4, VEGF R2, Tie-2, IL-15 R, Caspr2, LTbR, LAMP, ALCAM, GLP-1, NG2, IL-22 R alpha 1, AMIGO2, HCC-1, TFPI-2, ULBP-2, Desmoglein 2, Aggrecan, Syntaxin 4, VAMP-1, Nectin-2, FGF-21, Flt-3, GFAP, TIM-1, Inhibin A, Cadherin-4, P1GF-2, Neurogranin, HE4, IL-23 R, Galectin-7, GALNT3, GITRL, CD14, R- Spondin 2, CK19, Cardiotrophin-1, TREML1, HAPLN1, CD27, ANG-4, Siglec-7, CD155, VEGF-C, TNF RII, PGRP-S, SDF-la, PDGF-AB, GPVI, CD40, SCF R, Thrombospondin-5, IL-1 RII, Neuropilin-2, Cadherin-13, E-Selectin, GITR, WISP-1, Renin, AgRP, MDL-1, ROBO3, RANTES, Endocan, Granulysin, hCGb, Mesothelin, TLR1, TRAIL, MOG, DDR1, NGF R, TRAIL R3, Trypsin 3, ARSB, LIF R alpha, BAFF R, CD157, Granzyme A, 2B4, ESAM, IL-1 R4, CXCL14, IL-31, SIRP alpha, Uromodulin, CTRC, CEACAM-1, TARC, MIP-3a, SDF-lb,NKp46, MCP-3, IL-32 alpha, TGFb3 F0LR2, CD58, IL-23, CD36, TNFb, Shh-N, Ficolin-1, Reg4, ILT2, Mer, TREM-2, Flt-3L, CDS, IL-6, CD229, Insulin, Syntaxin 6, GRO, Bcl-w, Lipocalin-2, PDGF-AA, IL-2 Ra, Angiogenin, LYVE-1, CD4, RAGE, CDNF, Brevican, NAP -2, PU.l, ED AR, ADAMTS13, Kynureninase, PTH1R, IFN-gamma Rl, CrkL, B7-1, PARC, Draxin, VE-Cadherin, Procalcitonin, SOX15, Kallikrein 11, BCMA, Dectin-2, EpCAM, HCC-4, TGFa, IP- 10, BLAME, CILP-1, PIGF, LOX-1, MCP-2, Resistin, HVEM, ENPP-7, Syndecan-4, IL-2 Rg, MICA, Dopa Decarboxylase, NPDC-1, MCP-4, EG-VEGF, Glycoprotein V, Semaphorin 4G, IL-12p40, PSA-total, IL-15, MAP1D, Clq, TNF4, Dtk, Endoglin, ENA-78, Reg3A, MIP-lb, FGF-17, IL-6R, IL-8, Galectin-8, CA4, Cystatin E M, FUT8, B7-H3, GCP-2, CD40L, MDC, 4- 1BB, HO-1, SOST, S100A13, Kallikrein 7, and IL-13.

[0170] The nucleic acid content of the therapeutic product was determined, and the following nucleic acids were found to be present: 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-lOb, 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-l'7-5p, 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-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-l, 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.Example 2 - Clinical Study of Bone Marrow Derived Mesenchymal Stem Cell Extracellular Vesicle Isolate as a Treatment for Long COVIDSummary

[0171] The safety profile and potential efficacy of an advanced hBM-MSC EV investigational product (IMP) in 10 Long COVID subjects was evaluated. 10 subjects with confirmed Long COVID symptoms were assessed for safety risks and indications of potential efficacy of a hBM- MSC EV preparation following intravenous administration of two 15 mL doses of IMP, 7 days apart. Subjects were then monitored for adverse events for over three months and were evaluated using a battery of 9 patient reported outcome measures (PROMs) before treatment and at weeks 3, 6 and 12 after treatment. No adverse events or serious adverse events were attributed to IMP throughout the study. Statistically significant improvements were measurable within 3 weeks after the first infusion and were sustained for the entire 12 weeks of the study for the following PROMs: PROMIS® (mental, physical, and average pain), EQ-5D-5L, IES-R, PCFS, and FSS. No improvement was detected by SF-36. No improvement was indicated by the cognitive assessments Mini-Cog®, MMSE, and MOCA, but this was likely explained by the normal cognitive functioning of all 10 subjects at the outset. The hBM-MSC EV preparation can be safe and can have potential efficacy in treatment of Long COVID. The efficacy results suggest that hBM-MSC EVs can be efficacious in the treatment of Long COVID symptoms such as diminished overall quality of life, reduced functioning, and increased fatigue and pain. hBM- MSC EVs can be further evaluated in randomized and controlled clinical studies as a therapy for Long COVID.MethodsInvestigational medicinal product (IMP)

[0172] The IMP is an allogeneic biologic produced from human hBM-MSCs cultured under hypoxic, low glucose, and low pH conditions. The IMP is manufactured from the banked hBM- MSCs of a single donor under CGMP conditions and according to FDA Master File protocols. Each lot of the IMP meets stringent release specifications, including proteomic, mRNA and miRNA characterization. Additionally, the size and quantity of EVs and the presence of a specific surface marker expression profile are confirmed. Identity assays are combined with validated potency assays to demonstrate the mechanism of action is functional.Subject enrollment and approvals

[0173] The study protocol was approved by the Institute of Regenerative and Cellular Medicine IRB. Subjects meeting the inclusion and exclusion criteria were enrolled. Informed consent was obtained from all subjects or their legal representatives. The study population was comprised of10 subjects, of any racial or ethnic origin, balanced by gender and over 21 years of age, who had Long Covid and who complained of chronic fatigue and mental status changes.

[0174] Subject Inclusion and Exclusion CriteriaINCLUSION CRITERIAAll candidates for this study met all of the following Inclusion Criteria to be eligible for enrollment:1. Voluntary signature of the approved Informed Consent by the patient or legal representative.2. Subject must be over 21 years old.3. A diagnosis of Long Covid-19.EXCLUSION CRITERIACandidates who met any of the following Exclusion Criteria at the time of the study procedure were not eligible for enrollment in the study:1. The subject is unable to conform to the study protocol follow-up procedures and visits.2. The subject has major risk factors such as a history of narcotic abuse, paucity of family support, unemployed, history of previous physical or mental abuse or severe medical comorbidities beyond Long Covid- 19.3. Patients with any other auto-immune disorder.4. Any patient with a previous positive test for tuberculosis.5. Patients with a history of chronic steroid use.6. Any patient with a history of any Cancer.7. Any patient requiring treatment for high blood pressure.8. Any patient requiring treatment for diabetes.9. Any patient with a history of cardiac, liver or renal disease.10. Any patient positive for HIV.11. Patients who have received any other investigational drugs for treatment.12. Any patient felt not to be a suitable study patient by the principal Investigator.Study design

[0175] The study was a prospective non-randomized study. The subjects received one 15 mL IV infusion of the IMP (15 mL of the IMP was mixed with 85 mL sterile saline for a total of 100 mL of infusion), and this was repeated one week later. Safety evaluation of all adverse events and complications was reported by the treating physician who performed daily safety evaluations during the one week infusion period.Quality of life assessments and other metrics

[0176] A battery of disease independent and disease dependent patient reported outcome measures (PROMs) to measure quality of life (QoL), fatigue, pain and cognitive functioning were administered before treatment with the IP (Week 0) and at intervals (Weeks 3, 6 and 12) after treatment. Assessments before treatment (Week 0) were given in person while the remainder were performed either in person or by videoconference according to the subject’s availability. The 9 assessments were as follows.

[0177] PROMIS-Global Health - Patient-Reported Outcomes Measurement Information System. PROMIS (promishealth.org) resulted from an NIH sponsored initiative to develop a PROM system that assess an individual’s physical, mental, and social health that is efficient, flexible, reproducible and precise in the measurement of generic symptoms. PROMIS scores herein are separated into Mental and Physical Health total scores. A T-score metric is also reported in which 50 is the mean of the reference US general population and 10 units is the standard deviation (SD) of that.

[0178] EQ-5D-5L - A short, easily administered, robust, reliable and responsive generic QoL questionnaire developed by the EuroQol Group that assess five parameters: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression (https: / / euroqol.org / ). It also includes a single visual analog scale to indicate the subject’s health status, and these are reported separately herein as an Overall Health Score.

[0179] SF-36 - 36-Item Short Form Health Survey. The SF-36 is a set of generic, coherent, and easily administered quality-of-life measures assessed by questionnaire developed by the Rand Corporation as part of an effort to explain variations in patient outcomes: 36-Item Short Form Survey (SF-36); RAND; rand.org. Eight scaled scores that assesses vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health or emotional wellbeing are reduced to a total score. SF-36 was used to assess the effects of COVID-19 on QoL.

[0180] IES-R - Impact of Event Scale-Revised. Originally developed to sensitively measure intrusion and avoidance responses following any type of stressful life event, IES can be used repeatedly to follow the response to a specific event over time. It was revised (IES-R) to also address persistent hyperarousal, the third major symptom cluster of posttraumatic stress disorder (PTSD).

[0181] PCFS - Post-COVID-19 Functional Status Scale. A PROM designed to complement other metrics, evaluate the ultimate consequences of COVID-19 on functional status and help identify patients undergoing incomplete recovery from SARS-CoV-2 infection. It consists of grades 0-4 assigned based on yes / no responses to four component questions. Grade 0 reflects the absence ofany functional limitation and grade 4 reflects requiring assistance with activities of daily living (severe functional limitations). Grade 0 reflects the absence of any functional limitation; grade 1 reflects the presence of symptoms, pain or anxiety without effect on activities (negligible functional limitations); grade 2 reflects the presence of symptoms, pain or anxiety requiring lower intensity of activities (slight functional limitations); grade 3 reflects the inability to perform certain activities (moderate functional limitations); and grade 4 reflects requiring assistance with activities of daily living (severe functional limitations). FSS - Fatigue Severity Scale. Originally developed to describe fatigue in multiple sclerosis (MS) and systemic lupus erythematosus (SLE) patients, FSS is an internally consistent metric that correlates well with visual analog measures, is largely independent of self-reported depressive symptoms, and could differentiate fatigue associated with MS from that associated with SLE. It consists of nine items scored on a sevenpoint Likert-type scale ranging from strongly disagree to strongly agree. The nine items are combined into a total score calculated as the average of the individual item responses. FSS consists of nine items scored on a seven-point Likert- type scale ranging from strongly disagree to strongly agree. The nine items are combined into a total score calculated as the average of the individual item responses. A higher score indicates greater fatigue severity.

[0182] Mini-Cog - a simple, brief (3-to-5-minutes) and easily administered test that includes recalling a three-word list of objects and drawing a clock to discriminate demented from nondemented individuals.

[0183] MMSE - Mini -Mental State Examination. A 7-to-10-minute screening tool used to detect and quantify the severity of cognitive impairment that includes naming the current date, counting backward, and identifying everyday objects like a pencil or watch.

[0184] MOCA - Montreal Cognitive Assessment. A 10-to- 15 -minute screening tool for detection of mild cognitive impairment (MCI) with superior sensitivity as compared to the MMSE that includes memorizing a short list of words, identifying a picture of an animal, and copying a drawing of a shape or object.Statistical analysis

[0185] All data sets were subjected to repeated measures one way ANOVA with a Geisser- Greenhouse correction using GraphPad Prism 9.5.1 software. Subsequent pairwise comparisons between Week 0 and subsequent weeks for each assessment metric employed a parametric paired t-test assuming a Gaussian distribution. For all plotted results *p<0.05, **p<0.01,***p<0.001, ****p<0.0001 and ns=not significant.ResultsDemographics

[0186] Subjects (6 female, 4 male) ranged in age from 39 to 80 years with a mean age of 60 (Table 1). Weights ranged from 122 to 252 pounds with a mean of 171 pounds. Subject vital signs at the two treatment visits are shown in Table 2 and were generally consistent at each time with no deviations resulting in an adverse or serious adverse event.Table 2. Subject demographicsTable 3. Subject Vital Statistics Prior to Each TreatmentSafety

[0187] No adverse events or serious adverse events related to IMP were reported during the infusion periods or the 12 week follow-up.(fol. and Stress

[0188] The PROMIS Mental Health and Physical Health raw scores for the subject pool show significant improvements by week 3 that are sustained for 12 weeks (FIGS. 1A and IB), and all subjects had progressed by week 12 (FIGS. 1C and ID). Compared to the US population reference set T-score (mean=50), the group had progressed from mean values of 38.9 to 51.1 for Mental Health by week 12 and from 36.0 to 51.4 for Physical Health placing them within one standard deviation (40-60) of the reference group (FIGS. IE and IF). EQ-5D-5L and IES-R scores achieved significance within the first follow-up, and significant improvements were measured at week 12 (FIGS. 2A-2F). All subjects improved in IES-R by week 12, while three of nine showed no change in EQ-5D-5L. No significant effect on the SF-36 scores was evident. Other

[0189] FIGS. 3A-H shows the results of the PCFS, FSS, Average Pain (queried in PROMIS) and Overall Health (EQ-5D-5L) metrics. All four metrics achieved significance within three weeks and those improvements were sustained and improved for the entire 12 weeks. By week 12 all but one subject improved in PCFS, all but two improved in Pain, and all but one improved in Overall Health.Cognition

[0190] No significant changes for Mini-Cog, MMSE and MOCA assessments of cognitive functioning were evident (FIGS. 4A-4C).Discussion

[0191] Patients suffering from Long COVID have no approved therapeutic options available and treatment is palliative. This prospective study was intended to assess the safety and explore thepotential efficacy of IV administration of a hBM-MSC EV preparation for the treatment of Long COVID. No adverse or serious adverse events either occurred or were attributable to the IMP, and significant improvements in subject symptoms were evident across most tests in a battery of nine PROMs.

[0192] This study employed multiple PROMs to assess the subjects’ conditions following the treatment, the adult study group represented a balance of gender, weight and age, and statistically significant and sustained improvement was observed for many of the metrics at the earliest time point as compared to before treatment, and this was sustained over the remainder of the study.

[0193] Significant improvements amongst the subjects over time was indicated for the COVID specific PCFS metric that quantifies Long COVID symptom severity, suggesting that their symptoms were diminishing over time. Similarly, significant (p<0.01) improvement in the FSS scores occurred within three weeks and this improved further over time suggesting that at least one very common specific symptom of Long COVID, fatigue, may be successfully targeted by the therapy. Regarding another specific symptom experienced by many patients, generalized pain, scores on the pain metric were also significantly reduced by the third week and this was sustained and improved over the 12-week study. This may be due to the documented ability of hBM-MSC and their EVs to modulate the immune system away from a proinflammatory response, which can otherwise promote neuropathic pain. Finally, the Overall Health Score results were consistent with the QoL and specific symptom assessment scores in that a highly significant improvement was observed within three weeks and sustained for 12 weeks.

[0194] As in many of the metrics, it is noticeable that by week 12 the variance of scores was reduced in PCFS and FSS, although in each there was at least one subject, different in each case, who was not highly responsive to the treatment.

[0195] The cognitive function metrics showed no statistical improvement, most likely because no subjects exhibited impairment as measured by the three metrics at the baseline Week 0 tests. Hence, there was little room within any of the scales to indicate improvement. Future RCTs would need to screen subjects for mild cognitive impairment to ensure that enough such subjects are enrolled to enable detection of any possible positive effect on mild cognitive impairment.

[0196] The mechanism(s) mediated by hBM-MSC EVs possibly responsible for the observed results may be varied due to the wide array of bioactive molecules within EVs and the pleiotropic activities of an EV population.

[0197] Collectively these results suggest that a hBM-MSC EV preparation like the IMP studied here offers the potential to significantly and durably resolve symptoms of Long COVID illness. The results suggest that hBM-MSC EVs may provide a safe and effective means to ameliorateLong COVID. Response heterogeneity amongst the subjects in terms of achieving resolution of certain symptoms rapidly suggests that future studies should explore additional dose amount and frequency options to determine if heterogeneous responsiveness can be overcome. Such response heterogeneity also presents an opportunity, in larger controlled studies, to understand more about the underlying pathologies of Long COVID and how such different mechanisms might be targeted by other approaches.Conclusions

[0198] hBM-MSC EV IMP was found safe following IV infusion of two doses in Long COVID subjects. Significantly improved quality of life and decreased fatigue and pain indicate that hBM-MSC EVs can be evaluated further as a potential effective treatment for Long COVID.Example 3 - Safety and Efficacy Study I

[0199] The safety and efficacy of intravenous (IV) administration of bone marrow mesenchymal stem cell derived extracellular vesicles (EV) can be evaluated as treatment for Post-Acute COVID-19 and Chronic Post-COVID-19 syndrome using inclusion criteria, exclusion criteria, and outcome measures as described below.

[0200] Inclusion Criteria:1. Provision of signed and dated informed consent form (either by the individual or by the individual's healthcare proxy).2. Stated willingness to comply with all study procedures and availability for the duration of the study.3. Male or female aged 18-85.4. Discharged from recent hospitalization for severe COVID-19 disease requiring supplemental oxygen but not requiring mechanical ventilation or ECMO or dialysis.5. Must be between 4 to 20 weeks since onset of acute COVID-19 symptoms onset.6. No return to baseline health or hiatus between acute COVID-19 and onset of post-acute COVID-19 or chronic post-COVID-19 syndrome.7. Current SARS-CoV-2 RT PCR must be negative prior to enrollment.8. At least 2 or more persistent symptoms frequently reported for post-acute COVID-19 or chronic post-COVID-19 syndrome such as fatigue, cough, headache, body aches, fever, chills, loss of taste, loss of smell, diarrhea, congestion, dyspnea, sore throat, chest pain, abdominal pain, confusion, or vomiting must be moderate in severity based on modified CDC Symptoms Questionnaire.9. Medical Resource Council Dyspnea Score of < 3 out of 5.10. Baseline EQ-5D-5L must be higher than 21211. (EQ-5D-5L has 5 dimensions: mobility, self-care, usual activities, pain / discomfort, anxiety / depression. Each dimension is scored from 1 (full) to 5 (worst), such that a score of 11111 is reflective of full quality-of-life and a score of 55555 is reflective of worst quality-of-life.)11. Baseline 6-Minute Walk Test (6-MWT) is 500 meters or less.12. Supplemental oxygen should be <5 L CE / min.13. If the candidate is either male or female of reproductive potential, he or she must agree to use of double barrier method of highly effective birth control contraception such as condoms with oral contraceptive pill or choose to remain abstinent if already practicing abstinence during the screening period. The duration of required usage of double barrier method OR maintenance of abstinence must include the time from the beginning of the screening period until 90 days following the last dose of the study treatment.

[0201] Exclusion Criteria:1. Vulnerable populations such as pregnant patients, children, individuals with severe physical or mental disabilities who cannot provide meaningful consent.2. Active malignancy requiring treatment within the last five years.3. Major physical trauma in the last 3 months, including motor vehicle accidents, assaults, mechanical falls with sequelae of significant bleeding or craniofacial bruising, and surgeries.4. Patients with persistent symptoms due to any of the following chronic comorbidities such as active tuberculosis or cystic fibrosis, chronic respiratory disease including chronic obstructive pulmonary disease or pulmonary fibrosis requiring baseline home oxygen > 5 L CE / min, history of unstable angina or a heart attack during the last 12 months, pulmonary hypertension, hepatic impairment, chronic kidney disease, uncontrolled diabetes, substance abuse, severe osteoarthritis, HIV, migraine disorder, fibromyalgia, dementia, connective tissue disorders, and endocrine disorders.5. Depression as screened by positive Patient Health Questionnaire (PHQ2) and confirmed as moderate or higher severity on PHQ9. Of note, subjects found to have moderate or higher on PHQ-9 will be referred for appropriate outpatient psychiatric evaluation and intervention for their depression.6. Vital sign abnormalities: temperature > 38 °C, temperature < 35 °C; systolic blood pressure (SBP) < 90 mmHg, SBP > 170 mmHg; diastolic blood pressure (DBP) ≤ 50 mmHg, DBP ≥ 100 mmHg; heart rate (HR) < 50 beats per minute (BPM), HR > 120 BPM.7. Lab abnormalities: WBC ≥ 12,000 / μL, Creatinine ≥ 1.5 mg / dL, AST > 100 IU / 1, and / or ALT ≥ 100 IU / 18. Patients who require rolling walker or wheelchair or higher level of assistance for ambulation.Table 4. Study designTable 5, Primary outcome measuresTable 6. Secondary outcome measuresTable 7. Other outcome measuresTable 8: Classes of factors contained in the therapeutic product

[0202] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating fatigue in a subject previously infected with SARS-CoV-2, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa- miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof.

2. A method of treating fatigue in a subject previously infected with SARS-CoV-2, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein at least 80% of the EVs are CD63+, CD9-, CD81-.

3. A method of treating fatigue in a subject previously infected with SARS-CoV-2, the method comprising administering to the subject a composition comprising Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-0- sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gammaglutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TEMP -2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

4. The method of any one of claims 1-3, wherein the subject is negative for SARS-CoV-2 for at least four weeks prior to the administering.

5. The method of claim 4, wherein the subject is SARS-CoV-2 negative if a first biological sample from the subject is negative for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR).

6. The method of any one of claims 1-5, wherein the subject was previously infected with SARS-CoV-2 if a second biological sample from the subject was positive for SARS- CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR).

7. The method of any one of claims 1-6, wherein treating fatigue in the subject comprises a reduction in a Fatigue Severity Scale (FSS) score after the administering as compared to the FSS score prior the administering.

8. The method of claim 7, wherein after the administering, the subject’s FSS score is three or less.

9. The method of claim 7 or claim 8, wherein prior to the administering, the subject’s FSS score is four or greater.

10. The method of any one of claims 1-9, wherein the fatigue is chronic fatigue.

11. The method of claim 10, wherein the subject experienced chronic fatigue for at least six months prior to the administering.

12. The method of any one of claims 1-11, wherein treating the fatigue comprises reducing the post-COVID-19 Functional Status (PCFS) score of the subject after the administering as compared to prior the administering.

13. The method of claim 1, wherein the one or more EVs comprise hsa-miR-125b-5p, hsa- miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa- miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa- miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa- miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof.

14. The method of claim 1 or claim 2, wherein the composition comprises Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-0- sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factorbinding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gammaglutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP -2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

15. A method of treating pain in a subject previously infected with SARS-CoV-2, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein at least 80% of the EVs are CD63+, CD9-, CD81-.

16. A method of treating pain in a subject previously infected with SARS-CoV-2, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein the one or more EVs comprise hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa- miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof.

17. A method of treating pain in a subject previously infected with SARS-CoV-2, the method comprising administering to the subject a composition comprising Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-0- sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factorreceptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gammaglutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP -2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

18. The method of any one of claims 15-17, wherein the subject is negative for SARS-CoV- 2 for at least four weeks prior to the administering.

19. The method of claim 18, wherein the subject is SARS-CoV-2 negative if a first biological sample from the subject is negative for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR).

20. The method of any one of claims 15-19, wherein the subject was previously infected with SARS-CoV-2 if a second biological sample from the subject was positive for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR).

21. The method of any one of claims 15-20, wherein treating the pain comprises reducing the post-COVID-19 Functional Status (PCFS) score of the subject after the administering as compared to prior the administering.

22. The method of any one of claims 15-21, wherein treating pain comprises reducing the pain in the subject after the administering as compared to prior the administering.

23. The method of claim 15, wherein the one or more EVs comprise hsa-miR-125b-5p, hsa- miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa- miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa- miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa- miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof.

24. The method of claim 15 or claim 16, wherein the composition comprises Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-0- sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogenactivator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gammaglutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP -2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

25. A method of treating Long COVED in a subject previously infected with SARS-CoV-2, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein at least 80% of the EVs are CD63+, CD9-, CD81-.

26. A method of treating Long COVED in a subject previously infected with SARS-CoV-2, the method comprising administering to the subject a composition comprising one or more extracellular vesicles (EVs); wherein the one or more EVs comprise hsa-miR- 125b-5p, hsa-miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR- 221-3p, hsa-miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR- 27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR- 320a, hsa-miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof.

27. A method of treating Long COVED in a subject previously infected with SARS-CoV-2, the method comprising administering to the subject a composition comprising Ferritin, 1GFBP-4 (Insulin-like growth factor binding protein-4), EL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), blG-EE3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupled receptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), 1GFBP-6 (Insulin-like growth factor binding protein-6), EES3ST4 (Heparan sulfate glucosamine 3-0- sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, SerpinB6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gammaglutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP -2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

28. The method of any one of claims 25-27, wherein the subject is negative for SARS-CoV- 2 for at least four weeks prior to the administering.

29. The method of claim 28, wherein the subject is SARS-CoV-2 negative if a first biological sample from the subject is negative for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR).

30. The method of any one of claims 25-29, wherein the subject was previously infected with SARS-CoV-2 if a second biological sample from the subject was positive for SARS-CoV-2 as detected via reverse transcription polymerase chain reaction (RT-PCR).

31. The method of any one of claims 25-30, wherein treating the Long COVID comprises reducing the post-COVID-19 Functional Status (PCFS) score of the subject after the administering as compared to prior the administering.

32. The method of any one of claims 25-31, wherein treating the LONG COVED comprises reducing the pain in the subject after the administering as compared to prior the administering.

33. The method of claim 25, wherein the one or more EVs comprise hsa-miR-125b-5p, hsa- miR-145-5p, hsa-miR-191-5p, hsa-miR-199a-3p, hsa-miR-21-5p, hsa-miR-221-3p, hsa- miR-222-3p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-27a-3p, hsa- miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-31-5p, hsa-miR-320a, hsa- miR-34a-5p, hsa-miR-423-3p, hsa-miR-424-5p, or hsa-miR-940, or a combination of two or more thereof.

34. The method of claim 25 or claim 26, wherein the composition comprises Ferritin, IGFBP-4 (Insulin-like growth factor binding protein-4), IL-1 R6 (Interleukin 1 Receptor 6), LAMP2 (Lysosome-associated membrane glycoprotein 2), bIG-H3 (Transforming growth factor-beta-induced protein ig-h3), GPR115 (Adhesion G protein-coupledreceptor F4), CD63 antigen, CD 109 antigen, Serpin Fl (Pigment epithelium-derived factor), IGFBP-6 (Insulin-like growth factor binding protein-6), HS3ST4 (Heparan sulfate glucosamine 3-0- sulfotransferase 4), OPN (Osteopontin), PAI-1 (Plasminogen activator inhibitor-1 or SERPINE 1), Cathepsin B, IGFBP-2 (Insulin-like growth factor binding protein-2), Semaphorin 6C, IGF-2 (Insulin-like growth factor-2), Sortilin, Serpin B6, Dkk-3 (Dickkopf-related protein 3), CNTF (Ciliary neurotrophic factor), TSP-1 (Thrombospondin 1), GM-CSF Ra (Granulocyte-macrophage colony-stimulating factor receptor subunit alpha), Thrombomodulin, Endoglycan, (podocalyxin-like protein 2) IGFBP-3 (Insulin-like binding protein-3), RGM-C (Hemojuvelin), PF4 (Platelet Factor 4), MIF (Macrophage migration inhibitory factor), TGM4 (Protein-glutamine gammaglutamyltransferase 4), Periostin, Furin, TIMP-1 (Tissue inhibitor of MMPs 1), Decorin, PCK1 (Phosphoenol pyruvate carboxykinase, cytosolic), CD9 antigen, CD99 antigen, CA2 (Carbonic anhydrase 2), PRDX4 (Peroxidredoxin-4), Transferrin, DcR3 (Tumor necrosis factor receptor superfamily member 6B), GP73 (Golgi membrane protein 1), CD81 antigen, Lumican, or TIMP -2 (Tissue Inhibitor of MMPs 2), or a combination of two or more thereof.

35. The method of any one of claims 25-34, wherein the Long COVED is chronic COVED, post-acute sequelae of COVED-19 (PASC), post-acute COVED-19 syndrome, chronic post-COVED-19 syndrome, post-COVED conditions (PCC), long-haul COVED, postacute COVED-19, long-term effects of COVED, or a combination thereof.

36. The method of any one of claims 1-35, wherein the treating comprises improving the quality of life (QoL) of the subject, increasing cognitive functioning of the subject, decreasing fatigue in the subject, or decreasing pain in the subject, or a combination of two or more thereof.

37. The method of any one of claims 1-36, wherein the subject is suffering from or suffered from: post exertional malaise, fatigue, brain fog, cough, headache, body aches, fever, chills, dizziness, gastrointestinal symptoms, palpitations, dementia, hair loss, diarrhea, congestion, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, changes in sexual desire or capacity, loss of or change in smell, loss of or change in taste, thirst, chronic cough, chest pain, neuropsychiatric abnormalities, pulmonary abnormalities, cardiovascular abnormalities, abnormal movements, sore throat, abdominal pain, overreactive immune response, highly dysregulated innate immune system, highly dysregulated adaptive immune system, confusion, or vomiting, or a combination of two or more thereof.

38. The method of any one of claims 1-37, wherein after the administering the subject experiences an improvement in a Patient-Reported Outcome Measure (PROM), optionally wherein the subject shows statistically significant improvement in the PROM after treatment.

39. The method of any one of claims 1-38, wherein after the administering the subject experiences improvement in one or more of the following: Euro quality of life (QoL) 5 Dimension 5 Level (EQ-5D-5L), Impact of Event Scale - Revised (IES-R), Post-COVID- 19 Functional Status Scale (PCFS), Fatigue Severity Scale (FSS), 36-Item Short Form Health Survey (SF-36), a brief cognitive screening test (Mini-Cog), Mini -Mental State Examination (MMSE), or Montreal Cognitive Assessment (MOCA), or a combination of two or more thereof.

40. The method of any one of claims 1-39, wherein administering reduces the level of one or more acute phase biomarkers in a sample from the subject.

41. The method of claim 40, wherein the one or more acute phase biomarkers comprise C- Reactive Protein (CRP), ferritin, D-dimer, neutrophils, or combinations of two or more thereof.

42. The method of any one of claims 1-41, wherein administering comprises intravenous administration.

43. The method of any one of claims 1-42, wherein the composition is prepared by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition.

44. The method of any one of claims 1-43, the method comprising preparing the composition prior to the administering, wherein preparing the composition occurs by a process comprising: (a) culturing bone marrow mesenchymal stem cells (BM-MSCs) under the following conditions to produce an MSC conditioned media: (i) oxygen tension below 5%; and (ii) culture media having a pH below 7; (b) harvesting the MSC conditioned media; and (c) formulating the MSC conditioned media to produce the composition.

45. The method of claim 43 or claim 44, wherein the culture media is serum-free.

46. The method of any one of claims 43-45, wherein the culture media has a glucose concentration below 4.5 g / L.

47. The method of any one of claims 43-46, wherein formulating the MSC conditioned media comprises exchanging the conditioned media for a pharmaceutically acceptable formulation.

48. The method of claim 47, wherein the pharmaceutically acceptable formulation comprises saline.

49. The method of any one of claims 1, 2, 13, 15, 16, 23, 25, 26, 33, wherein the composition comprises at least 6xlO10to 8xlO10extracellular vesicles per ml and is administered at a dose of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ml.

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