A systemically delivered X-ray-triggered nanovesicle platform for in situ activation of endogenous neural stem cells and brain circuit repair

Materials capable of non-invasively accessing deep brain tissues, responding to external stimuli with spatiotemporal precision, and initiating endogenous repair processes remain a notable gap in the treatment of brain injury. Here we engineer XSingletO, a systemically administered nanovesicle platform that integrates blood–brain barrier transport, neural stem cell (NSC)-niche targeting, matrix-metalloproteinase-2 (MMP-2)-responsive payload release, X-ray-triggered singlet-oxygen (1O2) generation, and ratiometric signal reporting within a single material system. Upon external X-ray irradiation, XSingletO generates a localized 1O2 pulse within native NSC niches, activating resident NSCs and biasing their differentiation toward glutamatergic neurons. In a controlled cortical-impact traumatic brain injury model the resulting newborn neurons migrate over millimetre-scale distances along defined anatomical routes to repopulate cortical lesions, form synaptic connections with host neurons, establish long-range axonal projections, and improve motor behaviours. Integrated single-nucleus RNA sequencing, spatial transcriptomics and proteomics identify a PPARγ-associated programme, and NSC-enriched Pparg deletion establishes PPARγ as a required mediator of the early neurogenic response. By combining systemic delivery, remote spatiotemporal control and built-in dose reporting, XSingletO establishes a materials-based strategy for transplantation-free, non-invasive structural and functional regeneration of the injured brain.