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Netrin-1 is a multifunctional guidance molecule with neuroprotective properties, and chemically modified mRNA (modRNA) offers a promising platform for transient therapeutic protein expression. However, safe and efficient delivery of modRNA to the ischemic brain remains a major barrier to clinical translation. Here, we engineered Netrin-1 modRNA-loaded extracellular vesicles (EV@mNetrin-1) derived from human umbilical cord mesenchymal stem cells (hUMSCs) and administered them via a noninvasive intranasal route. EV-mediated delivery enabled intracellular translation of Netrin-1 modRNA into protein in neurons and increased Netrin-1 expression in ischemic brain tissue. In\u00a0vitro, EV@mNetrin-1 significantly reduced neuronal apoptosis and improved neuronal survival following oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R). In\u00a0vivo, intranasal administration of EV@mNetrin-1 enhanced brain Netrin-1 expression, reduced infarct volume, improved neurological outcomes, and attenuated neuronal apoptosis in transient middle cerebral artery occlusion (tMCAO) mice. Mechanistically, the neuroprotective effects of EV@mNetrin-1 were associated with DCC-dependent activation of PI3K\/AKT signaling. Collectively, these findings demonstrate the therapeutic potential of intranasal EV-mediated Netrin-1 modRNA delivery for ischemic stroke and support the development of RNA therapeutics for central nervous system disorders.<\/jats:p>","DOI":"10.34133\/bmr.0423","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T17:59:58Z","timestamp":1789495198000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":0,"title":["Intranasal Netrin-1 modRNA-Loaded Extracellular Vesicles Reduce Neuronal Apoptosis after Ischemic Stroke"],"prefix":"10.34133","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1430-7845","authenticated-orcid":false,"given":"Shanshan","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Neurology, Gongli Hospital of Shanghai Pudong New Area","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7551-1698","authenticated-orcid":false,"given":"Anmin","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai General Hospital, \rShanghai Jiao Tong University of Medicine, Shanghai 200080, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7969-1534","authenticated-orcid":false,"given":"Yanqin","family":"Geng","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, \rShanghai Jiao Tong University, Shanghai 200030, China."},{"name":"Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, \rTianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin 300350, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanlai","family":"Li","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, \rShanghai Jiao Tong University, Shanghai 200030, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yandi","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Gongli Hospital of Shanghai Pudong New Area","place":["China"]},{"name":"School of Gongli Hospital Medical Technology, \rUniversity of Shanghai for Science and Technology, Shanghai 200093, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangjie","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Gongli Hospital of Shanghai Pudong New Area","place":["China"]},{"name":"School of Gongli Hospital Medical Technology, \rUniversity of Shanghai for Science and Technology, Shanghai 200093, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaohui","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, \rShanghai Jiao Tong University, Shanghai 200030, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[{"name":"Anti-Aging Center, Gongli Hospital of Shanghai Pudong New Area","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1350-4008","authenticated-orcid":true,"given":"Qiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Gongli Hospital of Shanghai Pudong New Area","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)00642-1"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(25)00356-4"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.4103\/NRR.NRR-D-24-01324"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X20666220302150723"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2013.150"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1291-5"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.118.024631"},{"issue":"1","key":"e_1_3_4_9_2","first-page":"118","article-title":"The mRNA-based innovative strategy: Progress and challenges","volume":"18","author":"Zhou H","year":"2026","unstructured":"Zhou H, Wei D, Chen Z, Chen H, Dong C, Yao W, Wang J, Liu X, Li Y, Yang Y, et al. 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