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Mesenchymal stem\/stromal cells (MSCs) have been reported to exert neuroprotective effects in models of injury and disease, acting primarily through release of small extracellular vesicles (sEVs). MSC-derived sEVs (MSC-sEVs) have therefore attracted attention as a potential cell-free therapeutic approach for treating neurological conditions such as ALS. Because MSC-sEVs can cross both the nasal epithelial barrier and blood\u2013brain barrier to reach the central nervous system (CNS), intranasal administration represents an attractive approach for repeated delivery of MSC-sEVs for long-term administration. In this study, we administered bone marrow-derived MSC-sEVs or vehicle intranasally to a SOD1(G93A) transgenic mouse model of ALS; the large majority of the sEVs had surface markers for exosomes. Dosing was for three consecutive days per week beginning one day after onset of neurological symptoms and continuing until a moribund state. Neurological score and body weight were recorded daily. Although total survival time and post-onset survival duration were not significantly prolonged by MSC-sEV treatment, MSC-sEV treatment significantly delayed progression from a mild symptom phase (NeuroScore 1) to more severe symptoms (NeuroScore 2) compared with vehicle-treated controls and showed a trend toward slower weight loss. These findings indicate that intranasal administration of MSC-sEVs can delay functional deterioration and prolong the mild impairment stage in an ALS mouse model. If translatable to human patients, such preservation of neurological function could represent a clinically meaningful outcome.<\/jats:p>","DOI":"10.1186\/s13041-026-01288-0","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T04:45:39Z","timestamp":1772513139000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Intranasal administration of human mesenchymal stromal cell-derived small extracellular vesicles delays disease progression in the SOD1(G93A) mouse model"],"prefix":"10.1186","volume":"19","author":[{"given":"Ryosuke","family":"Hirota","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"Lankford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahito","family":"Nakazaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Toyoshima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery D.","family":"Kocsis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"issue":"2","key":"1288_CR1","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1056\/NEJMra1603471","volume":"377","author":"RH Brown","year":"2017","unstructured":"Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377(2):162\u201372. https:\/\/doi.org\/10.1056\/NEJMra1603471.","journal-title":"N Engl J Med"},{"issue":"4","key":"1288_CR2","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1002\/brb3.143","volume":"3","author":"S Vinsant","year":"2013","unstructured":"Vinsant S, Mansfield C, Jimenez-Moreno R, Del Gaizo Moore V, Yoshikawa M, Hampton TG, et al. Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part I, background and methods. Brain Behav. 2013;3(4):335\u201350. https:\/\/doi.org\/10.1002\/brb3.143.","journal-title":"Brain Behav"},{"issue":"3","key":"1288_CR3","doi-asserted-by":"publisher","DOI":"10.4081\/ejh.2024.4040","volume":"68","author":"E Turano","year":"2024","unstructured":"Turano E, Virla F, Scambi I, Dabrowska S, Bankole O, Mariotti R. Adipose mesenchymal stem cells-derived extracellular vesicles exert their preferential action in damaged central sites of SOD1 mice rather than peripherally. Eur J Histochem. 2024;68(3):4040. https:\/\/doi.org\/10.4081\/ejh.2024.4040.","journal-title":"Eur J Histochem"},{"issue":"10","key":"1288_CR4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21103651","volume":"21","author":"R Bonafede","year":"2020","unstructured":"Bonafede R, Turano E, Scambi I, Busato A, Bontempi P, Virla F, et al. ASC-exosomes ameliorate the disease progression in SOD1(G93A) murine model underlining their potential therapeutic use in human ALS. Int J Mol Sci. 2020;21(10):3651. https:\/\/doi.org\/10.3390\/ijms21103651.","journal-title":"Int J Mol Sci"},{"issue":"2","key":"1288_CR5","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15020548","volume":"15","author":"AM Tolomeo","year":"2023","unstructured":"Tolomeo AM, Zuccolotto G, Malvicini R, De Lazzari G, Penna A, Franco C, et al. Biodistribution of intratracheal, intranasal, and intravenous injections of human mesenchymal stromal cell-derived extracellular vesicles in a mouse model for drug delivery studies. Pharmaceutics. 2023;15(2):548. https:\/\/doi.org\/10.3390\/pharmaceutics15020548.","journal-title":"Pharmaceutics"},{"issue":"6","key":"1288_CR6","doi-asserted-by":"publisher","first-page":"3422","DOI":"10.1021\/acs.nanolett.8b04148","volume":"19","author":"N Perets","year":"2019","unstructured":"Perets N, Betzer O, Shapira R, Brenstein S, Angel A, Sadan T, et al. Golden exosomes selectively target brain pathologies in neurodegenerative and neurodevelopmental disorders. Nano Lett. 2019;19(6):3422\u201331. https:\/\/doi.org\/10.1021\/acs.nanolett.8b04148.","journal-title":"Nano Lett"},{"issue":"6","key":"1288_CR7","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1284","volume":"13","author":"M Nakazaki","year":"2023","unstructured":"Nakazaki M, Lankford KL, Yamamoto H, Mae Y, Kocsis JD. Human mesenchymal stem-derived extracellular vesicles improve body growth and motor function following severe spinal cord injury in rat. Clin Transl Med. 2023;13(6):e1284. https:\/\/doi.org\/10.1002\/ctm2.1284.","journal-title":"Clin Transl Med"},{"key":"1288_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2021.147296","volume":"1757","author":"H Magota","year":"2021","unstructured":"Magota H, Sasaki M, Kataoka-Sasaki Y, Oka S, Ukai R, Kiyose R, et al. Intravenous infusion of mesenchymal stem cells delays disease progression in the SOD1G93A transgenic amyotrophic lateral sclerosis rat model. Brain Res. 2021;1757:147296. https:\/\/doi.org\/10.1016\/j.brainres.2021.147296.","journal-title":"Brain Res"},{"issue":"1","key":"1288_CR9","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-021-00787-6","volume":"14","author":"H Magota","year":"2021","unstructured":"Magota H, Sasaki M, Kataoka-Sasaki Y, Oka S, Ukai R, Kiyose R, et al. Repeated infusion of mesenchymal stem cells maintain the condition to inhibit deteriorated motor function, leading to an extended lifespan in the SOD1G93A rat model of amyotrophic lateral sclerosis. Mol Brain. 2021;14(1):76. https:\/\/doi.org\/10.1186\/s13041-021-00787-6.","journal-title":"Mol Brain"},{"key":"1288_CR10","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.neuroscience.2013.05.034","volume":"248","author":"S Marconi","year":"2013","unstructured":"Marconi S, Bonaconsa M, Scambi I, Squintani GM, Rui W, Turano E, et al. Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model. 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Small extracellular vesicles released by infused mesenchymal stromal cells target M2 macrophages and promote TGF-\u03b2 upregulation, microvascular stabilization and functional recovery in a rodent model of severe spinal cord injury. J Extracell Vesicles. 2021;10(11):e12137. https:\/\/doi.org\/10.1002\/jev2.12137.","journal-title":"J Extracell Vesicles"},{"issue":"6","key":"1288_CR15","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22063023","volume":"22","author":"ST Ryan","year":"2021","unstructured":"Ryan ST, Hosseini-Beheshti E, Afrose D, Ding X, Xia B, Grau GE, et al. Extracellular vesicles from mesenchymal stromal cells for the treatment of inflammation-related conditions. 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