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A key challenge in recovery is the brain's limited capacity to regenerate neurovascular structures after injury. To address this, we developed a dual\u2010functionalized extracellular vesicle (EV) platform designed to enhance both targeting specificity and therapeutic efficacy for post\u2010stroke repair.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Neural stem cell\u2010derived EVs were bioengineered via bio\u2010click chemistry to display RGD peptides, enabling selective binding to integrin \u03b1V\u03b23, which is upregulated on activated endothelial cells in ischemic regions. EVs were concurrently loaded with vascular endothelial growth factor (VEGF), a pro\u2010angiogenic and neurogenic cytokine that also enhances \u03b1V\u03b23 expression\u2014thus creating a synergistic positive feedback mechanism to amplify targeting and tissue repair.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Engineered EVs retained normal morphology and showed a 5.2\u2010fold increase in endothelial uptake compared to na\u00efve EVs (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). In\u00a0vitro, they significantly enhanced endothelial cell migration by 2.1\u2010fold (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). In a mouse model of transient middle cerebral artery occlusion (tMCAO), intravenously delivered dual\u2010functionalized EVs preferentially accumulated in the ischemic hemisphere, reduced infarct volume by 52.4%, and improved motor coordination (rotarod latency) by 71.8% compared to PBS\u2010treated controls (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Immunostaining revealed enhanced CD31+ microvessel density and increased Nestin+ neural stem and progenitor cell presence, indicating promotion of both angiogenesis and neurogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study presents a dual\u2010functionalized EV system that combines targeted delivery with therapeutic reinforcement through VEGF loading, offering a potent and synergistic approach for ischemic stroke repair. These findings support further translational development of engineered EVs for neurovascular regeneration.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.70597","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T06:57:53Z","timestamp":1758005873000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dual\u2010Functionalized Extracellular Vesicles Promote Brain Repair and Remodeling Following Ischemic Stroke in Mice"],"prefix":"10.1111","volume":"31","author":[{"given":"Victoria","family":"Shi","sequence":"first","affiliation":[{"name":"Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Med\u2010X Research Institute and School of Biomedical Engineering Shanghai Jiao Tong University  Shanghai China"},{"name":"Department of Anatomy and Cell Biology, Medical Faculty Saarland University  Homburg\/Saar 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