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Neural stem cell-derived exosomes (NSC-Exo) have recently attracted attention as mediators of intercellular communication with potential roles in tissue repair. However, how NSC-Exo promote BBB recovery after RBI remains unclear. This study explored whether NSC-Exo restore BBB function by regulating the HMGB1\/TLR signaling pathway, thereby promoting endogenous NSC differentiation toward astrocytes and enhancing mitochondrial biogenesis. A rat RBI model was established and treated with NSC-Exo. Molecular marker analysis, transcriptomic profiling, and BBB functional assessment were performed to clarify the underlying mechanisms. The results showed that NSC-Exo enhanced NSC stemness and astrocytic differentiation, improved mitochondrial function, and reduced ROS accumulation. NSC-Exo also suppressed HMGB1\/TLR2 pathway activation and promoted BBB repair. Functional experiments further indicated that HMGB1 overexpression weakened the protective effects of NSC-Exo, whereas TLR2 knockdown reversed this effect. In conclusion, NSC-Exo facilitate endogenous NSC remodeling and BBB restoration after RBI, at least partly through regulation of the HMGB1\/TLR2 axis, providing a potential strategy for RBI treatment.<\/jats:p>","DOI":"10.1038\/s41420-026-03250-4","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T04:45:30Z","timestamp":1784954730000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptomic analysis reveals that neural stem cell-derived exosomes regulate the HMGB1\/TLR2 signaling axis to promote astrocytic differentiation and mitochondrial biogenesis in the repair of radiation-induced blood-brain barrier damage"],"prefix":"10.1038","volume":"12","author":[{"given":"Fanrui","family":"Zeng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zichen","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenghao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohua","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6617-018X","authenticated-orcid":false,"given":"Rong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"3250_CR1","doi-asserted-by":"publisher","first-page":"462","DOI":"10.3390\/neurosci5040034","volume":"5","author":"L Gonz\u00e1lez-Johnson","year":"2024","unstructured":"Gonz\u00e1lez-Johnson L, Fari\u00f1a A, Far\u00edas G, Zomosa G, Pinilla-Gonz\u00e1lez V, Rojas-Sol\u00e9 C. 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