Agrin‐Enriched Neonatal Spinal Cord‐Derived Extracellular Vesicles Bypass Age Barriers to Organize Spinal Cord Repair

ABSTRACT Spinal cord injury (SCI) poses a formidable challenge in regenerative medicine, with current therapeutic strategies proving largely unsuccessful in achieving functional repair. Notably, paediatric patients and neonatal mice exhibit spontaneous and efficient regeneration after SCI, while the mechanisms remain elusive. Through integrated multi‐omics analysis in neonatal, adult and aged mice with SCI, we discovered that the regeneration time window, inflammatory response, and intercellular communication are all age‐dependent. Neonatal spinal cord‐derived extracellular vesicles (nSC‐EVs) were identified carrying a regenerative protein signature and were critical mediators in restoring SCI repair in neonatal mice. Functionally, nSC‐EVs promote neurogenesis via the Wnt/β‐catenin pathway and mediate axonal growth through the core effector Agrin (encoded by Agrn ), which was found to be predominantly expressed in endothelial cells. We further developed a targeted delivery system for nSC‐EVs, which significantly enhanced functional recovery, including motor and bladder control, in adult SCI mice. This work elucidates the mechanistic basis of age‐dependent repair processes and proposes a novel EV‐based therapy for SCI.