{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:49:35Z","timestamp":1790801375575,"version":"4.1.0"},"reference-count":103,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Italiana Sclerosi Multipla (FIMS)","award":["2022\/PR-Single\/004"],"award-info":[{"award-number":["2022\/PR-Single\/004"]}]},{"name":"Fondazione Italiana Sclerosi Multipla (FIMS)","award":["DN. 1553 11.10.2022"],"award-info":[{"award-number":["DN. 1553 11.10.2022"]}]},{"name":"Fondazione Italiana Sclerosi Multipla (FIMS)","award":["B53D23028400001"],"award-info":[{"award-number":["B53D23028400001"]}]},{"name":"National Recovery and Resilience Plan (NRRP)","award":["2022\/PR-Single\/004"],"award-info":[{"award-number":["2022\/PR-Single\/004"]}]},{"name":"National Recovery and Resilience Plan (NRRP)","award":["DN. 1553 11.10.2022"],"award-info":[{"award-number":["DN. 1553 11.10.2022"]}]},{"name":"National Recovery and Resilience Plan (NRRP)","award":["B53D23028400001"],"award-info":[{"award-number":["B53D23028400001"]}]},{"name":"European Union\u2014NextGenerationEU\u2014CUP","award":["2022\/PR-Single\/004"],"award-info":[{"award-number":["2022\/PR-Single\/004"]}]},{"name":"European Union\u2014NextGenerationEU\u2014CUP","award":["DN. 1553 11.10.2022"],"award-info":[{"award-number":["DN. 1553 11.10.2022"]}]},{"name":"European Union\u2014NextGenerationEU\u2014CUP","award":["B53D23028400001"],"award-info":[{"award-number":["B53D23028400001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Adipose stem cells (ASCs) are a subset of mesenchymal stem cells with validated immunomodulatory and regenerative capabilities that make them attractive tools for treating neurodegenerative disorders, such as multiple sclerosis (MS). Several studies conducted on experimental autoimmune encephalomyelitis (EAE), the animal model of MS, have clearly shown a therapeutic effect of ASCs. However, controversial data on their efficacy were obtained from I- and II-phase clinical trials in MS patients, highlighting standardization issues and limited data on long-term safety. In this context, ASC-derived extracellular vesicles from (ASC-EVs) represent a safer, more reproducible alternative for EAE and MS treatment. Moreover, their physical characteristics lend themselves to a non-invasive, efficient, and easy handling of intranasal delivery. Using an in vitro setting, we first verified ASC-EVs\u2019 ability to cross the human nasal epithelium under an inflammatory milieu. Magnetic resonance corroborated these data in vivo in intranasally treated MOG35-55-induced EAE mice, showing a preferential accumulation of ASC-EVs in brain-inflamed lesions compared to a stochastic distribution in healthy control mice. Moreover, intranasal treatment of ASC-EVs at the EAE onset led to a long-term therapeutic effect using two different experimental protocols. A marked reduction in T cell infiltration, demyelination, axonal damage, and cytokine production were correlated to EAE amelioration in ASC-EV-treated mice compared to control mice, highlighting the immunomodulatory and neuroprotective roles exerted by ASC-EVs during EAE progression. Overall, our study paves the way for promising clinical applications of self-administered ASC-EV intranasal treatment in CNS disorders, including MS.<\/jats:p>","DOI":"10.3390\/cells14151172","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T07:37:23Z","timestamp":1753861043000},"page":"1172","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Intranasal Administration of Extracellular Vesicles Derived from Adipose Mesenchymal Stem Cells Has Therapeutic Effect in Experimental Autoimmune Encephalomyelitis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4711-1528","authenticated-orcid":false,"given":"Barbara","family":"Rossi","sequence":"first","affiliation":[{"name":"Division of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7346-9139","authenticated-orcid":false,"given":"Federica","family":"Virla","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Angelini","sequence":"additional","affiliation":[{"name":"Division of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7678-6359","authenticated-orcid":false,"given":"Ilaria","family":"Scambi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Bani","sequence":"additional","affiliation":[{"name":"Division of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Marostica","sequence":"additional","affiliation":[{"name":"Clinical Neuroimmunology Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Caprioli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Anni","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7376-9425","authenticated-orcid":false,"given":"Roberto","family":"Furlan","sequence":"additional","affiliation":[{"name":"Clinical Neuroimmunology Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6936-8901","authenticated-orcid":false,"given":"Pasquina","family":"Marzola","sequence":"additional","affiliation":[{"name":"Department of Engineering for Innovation Medicine, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Mariotti","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8978-3539","authenticated-orcid":false,"given":"Gabriela","family":"Constantin","sequence":"additional","affiliation":[{"name":"Division of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Bonetti","sequence":"additional","affiliation":[{"name":"Neurology Unit, Azienda Ospedaliera Universitaria Integrata Verona, 37126 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0760-1787","authenticated-orcid":false,"given":"Ermanna","family":"Turano","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1186\/s13287-024-03885-z","article-title":"Translational potential of mesenchymal stem cells in regenerative therapies for human diseases: Challenges and opportunities","volume":"15","author":"Song","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1002\/stem.2779","article-title":"Immunomodulation By Therapeutic Mesenchymal Stromal Cells (MSC) Is Triggered Through Phagocytosis of MSC By Monocytic Cells","volume":"36","author":"Luk","year":"2018","journal-title":"Stem Cells"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"eaam7828","DOI":"10.1126\/scitranslmed.aam7828","article-title":"Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation","volume":"9","author":"Galleu","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_4","first-page":"120","article-title":"Mesenchymal stem cells: From biology to clinical use","volume":"5","author":"Krampera","year":"2007","journal-title":"Blood Transfus."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1182\/blood-2005-04-1496","article-title":"Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy","volume":"106","author":"Zappia","year":"2005","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/S1474-4422(11)70305-2","article-title":"Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: An open-label phase 2a proof-of-concept study","volume":"11","author":"Connick","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1177\/1352458509359727","article-title":"The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: Consensus report of the International MSCT Study Group","volume":"16","author":"Freedman","year":"2010","journal-title":"Mult. Scler. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"75","DOI":"10.4103\/1673-5374.264455","article-title":"Mesenchymal stem cells secretome: Current trends and future challenges","volume":"15","author":"Teixeira","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3574","DOI":"10.1093\/brain\/awaa333","article-title":"Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis","volume":"143","author":"Petrou","year":"2020","journal-title":"Brain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/S1474-4422(21)00301-X","article-title":"Safety, tolerability, and activity of mesenchymal stem cells versus placebo in multiple sclerosis (MESEMS): A phase 2, randomised, double-blind crossover trial","volume":"20","author":"Uccelli","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1186\/s13063-019-3346-z","article-title":"MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): A randomized, double blind, cross-over phase I\/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis","volume":"20","author":"Uccelli","year":"2019","journal-title":"Trials"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S1474-4422(21)00324-0","article-title":"Mesenchymal stem cells for multiple sclerosis: Hype or hope?","volume":"20","author":"Hohlfeld","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eaba6884","DOI":"10.1126\/sciadv.aba6884","article-title":"Shattering barriers toward clinically meaningful MSC therapies","volume":"6","author":"Levy","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/s41419-022-05034-x","article-title":"Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: A next generation therapeutic tool?","volume":"13","author":"Kou","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"963689720908500","DOI":"10.1177\/0963689720908500","article-title":"Mesenchymal Stem Cell-Derived Extracellular Vesicles in Tissue Regeneration","volume":"29","author":"Zhang","year":"2020","journal-title":"Cell Transplant."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1146\/annurev-pharmtox-061616-030146","article-title":"Stem Cell Extracellular Vesicles: Extended Messages of Regeneration","volume":"57","author":"Riazifar","year":"2017","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101978","DOI":"10.1016\/j.scr.2020.101978","article-title":"Strategies for scalable manufacturing and translation of MSC-derived extracellular vesicles","volume":"48","author":"Adlerz","year":"2020","journal-title":"Stem Cell Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1002\/stem.2575","article-title":"Concise Review: MSC-Derived Exosomes for Cell-Free Therapy","volume":"35","author":"Phinney","year":"2017","journal-title":"Stem Cells"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.yexcr.2015.12.009","article-title":"Exosome derived from murine adipose-derived stromal cells: Neuroprotective effect on in vitro model of amyotrophic lateral sclerosis","volume":"340","author":"Bonafede","year":"2016","journal-title":"Exp. Cell Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Farinazzo, A., Angiari, S., Turano, E., Bistaffa, E., Dusi, S., Ruggieri, S., Bonafede, R., Mariotti, R., Constantin, G., and Bonetti, B. (2018). Nanovesicles from adipose-derived mesenchymal stem cells inhibit T lymphocyte trafficking and ameliorate chronic experimental autoimmune encephalomyelitis. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-25676-2"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.jcyt.2015.01.005","article-title":"Murine adipose-derived mesenchymal stromal cell vesicles: In vitro clues for neuroprotective and neuroregenerative approaches","volume":"17","author":"Farinazzo","year":"2015","journal-title":"Cytotherapy"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3494","DOI":"10.1007\/s12035-021-02324-x","article-title":"Stem Cell-Derived Exosomes: A New Strategy of Neurodegenerative Disease Treatment","volume":"58","author":"Fayazi","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1089\/neu.2018.5835","article-title":"Exosomes Derived from Bone Mesenchymal Stem Cells Repair Traumatic Spinal Cord Injury by Suppressing the Activation of A1 Neurotoxic Reactive Astrocytes","volume":"36","author":"Liu","year":"2019","journal-title":"J. Neurotrauma"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"68","DOI":"10.15283\/ijsc17052","article-title":"Therapeutic Efficacy of Mesenchymal Stem Cells and Mesenchymal Stem Cells-derived Neural Progenitors in Experimental Autoimmune Encephalomyelitis","volume":"11","author":"Nasri","year":"2018","journal-title":"Int. J. Stem Cells"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.jcyt.2023.12.007","article-title":"Extracellular vesicles from adipose mesenchymal stem cells target inflamed lymph nodes in experimental autoimmune encephalomyelitis","volume":"26","author":"Turano","year":"2024","journal-title":"Cytotherapy"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"703","DOI":"10.15252\/emmm.201606666","article-title":"An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice","volume":"9","author":"Cheng","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_27","first-page":"4440","article-title":"Intranasal administration of CNS therapeutics to awake mice","volume":"74","author":"Hanson","year":"2013","journal-title":"J. Vis. Exp."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Pires, P.C., Rodrigues, M., Alves, G., and Santos, A.O. (2022). Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14030588"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1002\/stem.194","article-title":"Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis","volume":"27","author":"Constantin","year":"2009","journal-title":"Stem Cells"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.neuroscience.2013.05.034","article-title":"Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model","volume":"248","author":"Marconi","year":"2013","journal-title":"Neuroscience"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e12162","DOI":"10.1002\/jev2.12162","article-title":"The impact of storage on extracellular vesicles: A systematic study","volume":"11","author":"Gelibter","year":"2022","journal-title":"J. Extracell. Vesicles"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1074\/jbc.M116.747618","article-title":"Secreted Glioblastoma Nanovesicles Contain Intracellular Signaling Proteins and Active Ras Incorporated in a Farnesylation-dependent Manner","volume":"292","author":"Luhtala","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Bonafede, R., Turano, E., Scambi, I., Busato, A., Bontempi, P., Virla, F., Schiaffino, L., Marzola, P., Bonetti, B., and Mariotti, R. (2020). ASC-Exosomes Ameliorate the Disease Progression in SOD1(G93A) Murine Model Underlining Their Potential Therapeutic Use in Human ALS. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103651"},{"key":"ref_35","first-page":"2481","article-title":"Magnetic resonance imaging of ultrasmall superparamagnetic iron oxide-labeled exosomes from stem cells: A new method to obtain labeled exosomes","volume":"11","author":"Busato","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3.44.1","DOI":"10.1002\/cpcb.23","article-title":"Labeling and Magnetic Resonance Imaging of Exosomes Isolated from Adipose Stem Cells","volume":"75","author":"Busato","year":"2017","journal-title":"Curr. Protoc. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1007\/s13346-023-01474-w","article-title":"Characterization of critical parameters using an air\u2013liquid interface model with RPMI 2650 cells for permeability studies of small molecules","volume":"14","author":"Barlang","year":"2024","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.ejpb.2016.07.010","article-title":"Application of RPMI 2650 nasal cell model to a 3D printed apparatus for the testing of drug deposition and permeation of nasal products","volume":"107","author":"Pozzoli","year":"2016","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Dusi, S., Angiari, S., Pietronigro, E.C., Lopez, N., Angelini, G., Zenaro, E., Della Bianca, V., Tosadori, G., Paris, F., and Amoruso, A. (2019). LFA-1 Controls Th1 and Th17 Motility Behavior in the Inflamed Central Nervous System. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02436"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ymeth.2015.03.002","article-title":"Engineering mesenchymal stem cells for regenerative medicine and drug delivery","volume":"84","author":"Park","year":"2015","journal-title":"Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1634\/stemcells.2006-0164","article-title":"Multipotential mesenchymal stem cells are mobilized into peripheral blood by hypoxia","volume":"24","author":"Rochefort","year":"2006","journal-title":"Stem Cells"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1016\/j.immuni.2023.04.013","article-title":"Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis","volume":"56","author":"Kiss","year":"2023","journal-title":"Immunity"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Mayrhofer, F., Dariychuk, Z., Zhen, A., Daugherty, D.J., Bannerman, P., Hanson, A.M., Pleasure, D., Soulika, A., Deng, W., and Chechneva, O.V. (2021). Reduction in CD11c(+) microglia correlates with clinical progression in chronic experimental autoimmune demyelination. Neurobiol. Dis., 161.","DOI":"10.1016\/j.nbd.2021.105556"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41392-023-01486-5","article-title":"Role of neuroinflammation in neurodegeneration development","volume":"8","author":"Zhang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Wang, Y., and Xia, X. (2022). Editorial: The role of exosomes in neuroinflammation and neurodegeneration. Front. Cell. Neurosci., 16.","DOI":"10.3389\/fncel.2022.1109885"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.5966\/sctm.2015-0078","article-title":"Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression","volume":"4","author":"Doeppner","year":"2015","journal-title":"Stem Cells Transl. Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Otero-Ortega, L., Laso-Garc\u00eda, F., G\u00f3mez-de Frutos, M.D., Rodr\u00edguez-Frutos, B., Pascual-Guerra, J., Fuentes, B., D\u00edez-Tejedor, E., and Guti\u00e9rrez-Fern\u00e1ndez, M. (2017). White Matter Repair After Extracellular Vesicles Administration in an Experimental Animal Model of Subcortical Stroke. Sci. Rep., 7.","DOI":"10.1038\/srep44433"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1038\/jcbfm.2013.152","article-title":"Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats","volume":"33","author":"Xin","year":"2013","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1161\/STROKEAHA.119.028012","article-title":"Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles Induce Ischemic Neuroprotection by Modulating Leukocytes and Specifically Neutrophils","volume":"51","author":"Wang","year":"2020","journal-title":"Stroke"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1074\/jbc.M117.807180","article-title":"Mesenchymal stem cells and cell-derived extracellular vesicles protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-\u03b2 oligomers","volume":"293","author":"Saraiva","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.4103\/1673-5374.255978","article-title":"Mesenchymal stem cell-derived exosomes promote neurogenesis and cognitive function recovery in a mouse model of Alzheimer\u2019s disease","volume":"14","year":"2019","journal-title":"Neural Regen. Res."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Elia, C.A., Tamborini, M., Rasile, M., Desiato, G., Marchetti, S., Swuec, P., Mazzitelli, S., Clemente, F., Anselmo, A., and Matteoli, M. (2019). Intracerebral Injection of Extracellular Vesicles from Mesenchymal Stem Cells Exerts Reduced Abeta Plaque Burden in Early Stages of a Preclinical Model of Alzheimer\u2019s Disease. Cells, 8.","DOI":"10.3390\/cells8091059"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Mendes-Pinheiro, B., Anjo, S.I., Manadas, B., Da Silva, J.D., Marote, A., Behie, L.A., Teixeira, F.G., and Salgado, A.J. (2019). Bone Marrow Mesenchymal Stem Cells\u2019 Secretome Exerts Neuroprotective Effects in a Parkinson\u2019s Disease Rat Model. Front. Bioeng. Biotechnol., 7.","DOI":"10.3389\/fbioe.2019.00294"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"949","DOI":"10.5966\/sctm.2016-0111","article-title":"The Cleavage Effect of Mesenchymal Stem Cell and Its Derived Matrix Metalloproteinase-2 on Extracellular \u03b1-Synuclein Aggregates in Parkinsonian Models","volume":"6","author":"Oh","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"634","DOI":"10.5966\/sctm.2016-0071","article-title":"Impact of the Secretome of Human Mesenchymal Stem Cells on Brain Structure and Animal Behavior in a Rat Model of Parkinson\u2019s Disease","volume":"6","author":"Teixeira","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41583-024-00823-z","article-title":"The neuropathobiology of multiple sclerosis","volume":"25","author":"Woo","year":"2024","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1002\/jnr.24224","article-title":"Animal models of multiple sclerosis: Focus on experimental autoimmune encephalomyelitis","volume":"96","author":"Bjelobaba","year":"2018","journal-title":"J. Neurosci. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"8779","DOI":"10.1002\/jcp.29721","article-title":"Therapeutic effects of extracellular vesicles from human adipose-derived mesenchymal stem cells on chronic experimental autoimmune encephalomyelitis","volume":"235","author":"Jafarinia","year":"2020","journal-title":"J. Cell. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6670","DOI":"10.1021\/acsnano.9b01004","article-title":"Stem Cell-Derived Exosomes as Nanotherapeutics for Autoimmune and Neurodegenerative Disorders","volume":"13","author":"Riazifar","year":"2019","journal-title":"ACS Nano"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.imlet.2012.06.001","article-title":"Microvesicles derived from mesenchymal stem cells: Potent organelles for induction of tolerogenic signaling","volume":"147","author":"Mokarizadeh","year":"2012","journal-title":"Immunol. Lett."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Laso-Garcia, F., Ramos-Cejudo, J., Carrillo-Salinas, F.J., Otero-Ortega, L., Feliu, A., Gomez-de Frutos, M., Mecha, M., Diez-Tejedor, E., Guaza, C., and Gutierrez-Fernandez, M. (2018). Therapeutic potential of extracellular vesicles derived from human mesenchymal stem cells in a model of progressive multiple sclerosis. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0202590"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1002\/iub.1469","article-title":"Adipose-derived mesenchymal stem cells modulate the immune response in chronic experimental autoimmune encephalomyelitis model","volume":"68","author":"Shalaby","year":"2016","journal-title":"IUBMB Life"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1016\/j.xphs.2017.02.030","article-title":"Pharmacokinetics of Exosomes-An Important Factor for Elucidating the Biological Roles of Exosomes and for the Development of Exosome-Based Therapeutics","volume":"106","author":"Morishita","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"26316","DOI":"10.3402\/jev.v4.26316","article-title":"Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting","volume":"4","author":"Wiklander","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.jconrel.2014.12.013","article-title":"Biodistribution and delivery efficiency of unmodified tumor-derived exosomes","volume":"199","author":"Smyth","year":"2015","journal-title":"J. Control Release"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nature15756","article-title":"Tumour exosome integrins determine organotropic metastasis","volume":"527","author":"Hoshino","year":"2015","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1161\/CIRCULATIONAHA.112.114173","article-title":"Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension","volume":"126","author":"Lee","year":"2012","journal-title":"Circulation"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.canlet.2015.10.020","article-title":"Bovine milk-derived exosomes for drug delivery","volume":"371","author":"Munagala","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.biomaterials.2016.07.003","article-title":"Efficient production and enhanced tumor delivery of engineered extracellular vesicles","volume":"105","author":"Watson","year":"2016","journal-title":"Biomaterials"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1182\/blood-2013-03-489732","article-title":"CD169 mediates the capture of exosomes in spleen and lymph node","volume":"123","author":"Saunderson","year":"2014","journal-title":"Blood"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s12195-016-0458-3","article-title":"Elucidation of Exosome Migration across the Blood-Brain Barrier Model In Vitro","volume":"9","author":"Chen","year":"2016","journal-title":"Cell Mol. Bioeng."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.4103\/1673-5374.385875","article-title":"Intranasal administration of stem cell-derived exosomes for central nervous system diseases","volume":"19","author":"Gotoh","year":"2024","journal-title":"Neural Regen. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1002\/stem.3456","article-title":"Intranasal delivery of mesenchymal stem cells-derived extracellular vesicles for the treatment of neurological diseases","volume":"39","author":"Herman","year":"2021","journal-title":"Stem Cells"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"E3536","DOI":"10.1073\/pnas.1703920114","article-title":"Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus","volume":"114","author":"Long","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3422","DOI":"10.1021\/acs.nanolett.8b04148","article-title":"Golden Exosomes Selectively Target Brain Pathologies in Neurodegenerative and Neurodevelopmental Disorders","volume":"19","author":"Perets","year":"2019","journal-title":"Nano Lett."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1038\/mt.2011.164","article-title":"Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain","volume":"19","author":"Zhuang","year":"2011","journal-title":"Mol. Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1002\/jps.21031","article-title":"Evaluation of human nasal RPMI 2650 cells grown at an air-liquid interface as a model for nasal drug transport studies","volume":"97","author":"Bai","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2246","DOI":"10.1021\/acs.molpharmaceut.8b00087","article-title":"Pharmacological Characterization of the RPMI 2650 Model as a Relevant Tool for Assessing the Permeability of Intranasal Drugs","volume":"15","author":"Mercier","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3200","DOI":"10.1038\/s41419-017-0041-4","article-title":"Extracellular vesicles from human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs) protect against renal ischemia\/reperfusion injury via delivering specificity protein (SP1) and transcriptional activating of sphingosine kinase 1 and inhibiting necroptosis","volume":"8","author":"Yuan","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13041-024-01077-7","article-title":"The brain cytokine orchestra in multiple sclerosis: From neuroinflammation to synaptopathology","volume":"17","author":"Amoriello","year":"2024","journal-title":"Mol. Brain"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/s12974-024-03120-9","article-title":"Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis","volume":"21","author":"Guadalupi","year":"2024","journal-title":"J. Neuroinflamm."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/nrn2255","article-title":"Chemokines: A new class of neuromodulator?","volume":"8","author":"Kitabgi","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jneuroim.2008.04.022","article-title":"Chemokines and neuromodulation","volume":"198","year":"2008","journal-title":"J. Neuroimmunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1093\/jmcb\/mjt028","article-title":"A deficiency in CCR2+ monocytes: The hidden side of Alzheimer\u2019s disease","volume":"5","author":"Naert","year":"2013","journal-title":"J. Mol. Cell Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1186\/s12974-021-02371-0","article-title":"Astrocytic C\u2013X\u2013C motif chemokine ligand-1 mediates \u03b2-amyloid-induced synaptotoxicity","volume":"18","author":"Johnson","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1634\/stemcells.22-1-109","article-title":"Chemokines promote quiescence and survival of human neural progenitor cells","volume":"22","author":"Krathwohl","year":"2004","journal-title":"Stem Cells"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2274","DOI":"10.1002\/glia.22892","article-title":"CCL11 enhances excitotoxic neuronal death by producing reactive oxygen species in microglia","volume":"63","author":"Parajuli","year":"2015","journal-title":"Glia"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3233\/JAD-150041","article-title":"CXCL1 Triggers Caspase-3 Dependent Tau Cleavage in Long-Term Neuronal Cultures and in the Hippocampus of Aged Mice: Implications in Alzheimer\u2019s Disease","volume":"48","author":"Zhang","year":"2015","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.jconrel.2019.07.022","article-title":"Mesenchymal stem\/stromal cell secretome for lung regeneration: The long way through \u201cpharmaceuticalization\u201d for the best formulation","volume":"309","author":"Bari","year":"2019","journal-title":"J. Control Release"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"113961","DOI":"10.1016\/j.addr.2021.113961","article-title":"Dosing extracellular vesicles","volume":"178","author":"Gupta","year":"2021","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Shen, W., You, T., Xu, W., Xie, Y., Wang, Y., and Cui, M. (2023). Rapid and Widespread Distribution of Intranasal Small Extracellular Vesicles Derived from Mesenchymal Stem Cells throughout the Brain Potentially via the Perivascular Pathway. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15112578"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1001\/jamaneurol.2020.1840","article-title":"Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial","volume":"77","author":"Craft","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e101143","DOI":"10.1136\/gpsych-2023-101143","article-title":"Clinical safety and efficacy of allogenic human adipose mesenchymal stromal cells-derived exosomes in patients with mild to moderate Alzheimer\u2019s disease: A phase I\/II clinical trial","volume":"36","author":"Xie","year":"2023","journal-title":"Gen. Psychiatr."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Turano, E., Scambi, I., Virla, F., Bonetti, B., and Mariotti, R. (2023). Extracellular Vesicles from Mesenchymal Stem Cells: Towards Novel Therapeutic Strategies for Neurodegenerative Diseases. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032917"},{"key":"ref_95","first-page":"394917","article-title":"Immunoregulation by mesenchymal stem cells: Biological aspects and clinical applications","volume":"2015","author":"Montesinos","year":"2015","journal-title":"J. Immunol. Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/5584_2017_131","article-title":"The Robust Potential of Mesenchymal Stem Cell-Loaded Constructs for Hard Tissue Regeneration After Cancer Removal","volume":"1084","author":"Hosseini","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1146\/annurev-physiol-021014-071641","article-title":"Exosomes: Vehicles of intercellular signaling, biomarkers, and vectors of cell therapy","volume":"77","author":"Kourembanas","year":"2015","journal-title":"Annu. Rev. Physiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1007\/s00018-017-2473-5","article-title":"Interactions between mesenchymal stem cells and the immune system","volume":"74","author":"Li","year":"2017","journal-title":"Cell Mol. Life Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1007\/s12035-013-8544-1","article-title":"Exosomes: Mediators of neurodegeneration, neuroprotection and therapeutics","volume":"49","author":"Kalani","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1080\/08820139.2020.1712416","article-title":"Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Novel Cell-Free Therapy","volume":"49","author":"Jafarinia","year":"2020","journal-title":"Immunol. Investig."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.3727\/096368913X667709","article-title":"Paracrine mechanisms of mesenchymal stem cell-based therapy: Current status and perspectives","volume":"23","author":"Liang","year":"2014","journal-title":"Cell Transplant."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Maumus, M., Rozier, P., Boulestreau, J., Jorgensen, C., and No\u00ebl, D. (2020). Mesenchymal Stem Cell-Derived Extracellular Vesicles: Opportunities and Challenges for Clinical Translation. Front. Bioeng. Biotechnol., 8.","DOI":"10.3389\/fbioe.2020.00997"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e12416","DOI":"10.1002\/jev2.12416","article-title":"MISEV2023: An updated guide to EV research and applications","volume":"13","author":"Welsh","year":"2024","journal-title":"J. Extracell. Vesicles"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/15\/1172\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:18:35Z","timestamp":1760033915000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/15\/1172"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,30]]},"references-count":103,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["cells14151172"],"URL":"https:\/\/doi.org\/10.3390\/cells14151172","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,30]]}}}