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12 reviewsSUMMARYOxidative damage and neuroinflammation are the key features of central nervous system (CNS) injury.Inspired by the neuroprotective properties of neural stem cell-derived exosomes (NExo) and the reactive oxygen species (ROS) scavenging ability of selenium, we develop an advanced NExo bearing ultrasmall nanoselenium (∼3.5 nm) via lipid-mediated nucleation (SeNExo). In addition to maintaining the biological components of NExo, the resulting SeNExo exhibits a Se–O bond that dramatically enhances its ROS-scavengingperformance. SeNExo penetrates the blood-brain barrier (BBB) via the apolipoprotein E and prolow-densitylipoprotein receptor-related protein 1 (APOE_LRP-1) interaction. Through proteomics, microRNA (miRNA)omics, and single-nucleus RNA sequencing, we find that SeNExo can alleviate neuronal apoptosis, restoreglia homeostasis, and remodel glia-neuron networks. Therefore, SeNExo confers potent therapeutic benefits,significantly reducing cerebral lesions in a murine traumatic brain injury model. Even extending to a murinespinal cord injury model, SeNExo promotes locomotory recovery, further supporting SeNExo as a neotypeand a promising therapeutic agent for treating traumatic CNS injury.