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Here, we investigated alterations in EV RNA cargoes extracted from rat brain and plasma before and after stroke induction via middle cerebral artery occlusion and subsequent human neural stem cells (hNSCs) transplantation. EV RNA coexpression profiles were assessed, and digital source tracking was used to determine EV origin. The therapeutic effects of intra\u2010arterial delivery of hNSCs on ischemic rat brains were quantified, focusing on functional recovery, resolution of ischemic lesions, and the microenvironment. Stroke induced distinct EV secretion patterns, with a notable increase in EV secretion from non\u2010neuronal cells. hNSCs transplantation caused minimal immune rejection and transplanted cells survived in the brain for over a week. Stem cell\u2010derived EVs were detected in peripheral blood, indicating prolonged systemic distribution after transplantation. Gene regulatory network analyses identified specific EV miRNAs that play crucial roles in neurogenesis, wound healing, angiogenesis, and blood\u2013brain barrier integrity. An integrated analysis of EV RNAs in brain and plasma samples revealed that stroke increased correlations in RNA expression between brain and plasma and that hNSCs transplantation reversed the effect. Brain\u2010 and plasma\u2010derived EVs carry similar molecular information after stroke, suggesting that plasma\u2010derived EV RNAs reflect stroke pathophysiology. Intra\u2010arterial transplantation of hNSCs improved outcomes after stroke in rats, by promoting endogenous neurogenesis and maintaining blood\u2013brain barrier integrity. The identified EV miRNAs provided a new mechanism by which hNSCs transplantation regulates neural regeneration through the miR\u2010204\u20105p\/EFNB3 axis.<\/jats:p>","DOI":"10.1002\/mco2.70400","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T13:50:52Z","timestamp":1761659452000},"source":"Crossref","is-referenced-by-count":6,"title":["Molecular Encoding of Ischemic Stroke and its Resolution after Human Neural Stem Cell Therapy by Extracellular Vesicles"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5012-3541","authenticated-orcid":false,"given":"Chuheng","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Peking Union Medical College Hospital Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"},{"name":"Department of Radiation Oncology National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"},{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9883-8474","authenticated-orcid":false,"given":"Yiqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Peking Union Medical College Hospital Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"},{"name":"Department of Neurosurgery Xuanwu Hospital China International Neuroscience Institute Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohang","family":"Liang","sequence":"additional","affiliation":[{"name":"Center For MRI Research Academy For Advanced Interdisciplinary Studies Peking University  Beijing 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