Brain-Penetrant Dual-Action AIE Probes for Extracellular Vesicle Tracking and Enhancing Neuronal Protection in Traumatic Brain Injury.

Traumatic brain injury (TBI) remains a leading cause of death and disability, with current treatments showing limited efficacy. Recently, extracellular vesicles (EVs) have emerged as a promising therapeutic avenue. However, challenges persist in their clinical application owing to inadequate blood-brain barrier permeability and inefficient delivery to key brain cells. In this study, we developed a near-infrared aggregation-induced emission probe (P2T) that enhances the optical tracking of EVs. P2T-labeled EVs demonstrated improved blood-brain barrier permeability and increased neuronal uptake, thereby enhancing their therapeutic efficacy. Using P2T to track endothelial cell-derived EVs (EC-EVs) in a TBI mouse model, we employed single-nucleus RNA sequencing and functional studies, which revealed that EC-EVs facilitate neurological recovery by inhibiting neuronal apoptosis via the mGluR1/PLC signaling pathway. This research not only establishes a valuable tool for studying EV biology in the brain, but also advances the targeted delivery of EVs, promoting their clinical use in diagnosing and treating neurological disorders. Moreover, we identified specific brain cell targets and molecular mechanisms through which EC-EVs exert neuroprotective effects following TBI, providing a solid theoretical foundation for their clinical application.