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We previously showed that astrocyte\u2010derived EVs modulate neuronal mitochondria in\u00a0vitro. Whether endogenous astrocytic EVs associate with neuronal mitochondria in\u00a0vivo remained unknown. To address this, we generated an EV reporter mouse, Aldh1l1\u2010Cre; CD9\u2010tGFP\n                    <jats:sup>fl\/fl<\/jats:sup>\n                    , which resulted in fluorescent labeling of astrocyte\u2010derived CD9\u2010positive EVs. Astrocyte\u2010specific expression of CD9\u2010tGFP was verified in brain tissue, where CD9\u2010tGFP\u2010positive particles comprised 13.2%\u2009\u00b1\u20091.6% of total isolated EVs. In primary glial cultures, CD9\u2010tGFP was restricted to astrocytes, localizing to vesicular compartments and cell protrusions (filopodia and cilia); 89.3%\u2009\u00b1\u20092.2% of astrocyte\u2010derived EVs were CD9\u2010tGFP positive. In cortex, hippocampus, and cerebellum, CD9\u2010tGFP was predominantly detected in astrocytic processes co\u2010labeled with glutamate aspartate transporter 1 (GLAST1) and glial fibrillary acidic protein (GFAP), forming contacts with laminin\u2010positive capillaries and parvalbumin\u2010positive neurons. CD9\u2010tGFP\u2010labeled EVs were detected at capillaries and inside neurons, and STED microscopy revealed partial co\u2010localization with neuronal mitochondria. Live\u2010cell spinning disk confocal imaging and AI\u2010assisted proximity analysis confirmed uptake of CD9\u2010tGFP EVs by neuronal cells and cargo enrichment at mitochondria in\u00a0vitro. Immunoblotting and imaging of isolated mitochondria established physical association with EV\u2010derived CD9\u2010tGFP in\u00a0vivo, with 3\u2010fold higher CD9\u2010tGFP puncta density on synaptic mitochondria. Together, these findings validate the Aldh1l1\u2010Cre; CD9\u2010tGFP\n                    <jats:sup>fl\/fl<\/jats:sup>\n                    reporter mouse as a tool for tracking astrocyte\u2010derived EVs in\u00a0vivo and provide evidence of preferential cargo enrichment at synaptic mitochondria.\n                  <\/jats:p>","DOI":"10.1096\/fj.202602265r","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T11:16:28Z","timestamp":1789125388000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Reporter Mouse for Astrocyte\u2010Derived Extracellular Vesicles Reveals Enrichment of Cargo at Neuronal Mitochondria"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7741-133X","authenticated-orcid":false,"given":"Xiaojia","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Medicine University of 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