Athlete-derived extracellular vesicles protect against spinal cord injury via inhibition of neuronal ferroptosis

Spinal cord injury (SCI) causes high morbidity, disability, and mortality, while current surgical and pharmacological treatments provide limited benefit. Ferroptosis, a newly recognized form of regulated cell death, contributes critically to SCI pathology, and targeting this process may enhance neuronal survival. Extracellular vesicles, key mediators of intercellular communication, are emerging as promising therapeutic agents for central nervous system injury. Here, we examined the role of athlete-derived plasma extracellular vesicles (AEVs) in neuronal ferroptosis and motor function recovery after SCI. In a murine model, AEVs markedly inhibited ferroptosis and improved motor outcomes. Mechanistically, AEVs delivered RNF216, which promoted ubiquitination and degradation of NOX1, thereby reducing ferroptotic damage and facilitating recovery. Moreover, RNF216-enriched vesicles enhanced synaptic plasticity, supporting neuronal regeneration and network reestablishment. These findings reveal a previously unrecognized RNF216-NOX1 axis in SCI and highlight AEVs as a previously unidentified therapeutic strategy.