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.

Radiation-induced brain injury (RBI) is frequently associated with blood-brain barrier (BBB) disruption, which contributes to poor prognosis. 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. Schematic illustration of the molecular mechanism by which NSC-Exo ameliorates RBI through inhibition of the HMGB1/TLR2 signaling pathway.