Injury-responsive p75 neurotrophin receptor-targeted schwann cell-derived extracellular vesicles promote neurovascular remodeling and functional improvement after sciatic nerve injury

Sciatic nerve injury (SNI) often results in incomplete functional recovery because therapeutic signals are not efficiently delivered to the evolving injury microenvironment. We developed an injury-responsive, cell-free tissue-engineering strategy using Schwann cell-derived extracellular vesicles (sc-EVs) functionalized with a p75 neurotrophin receptor (p75 ^NTR )-targeting aptamer. Following systemic administration, p75 ^NTR -targeted sc-EVs preferentially accumulated in injured sciatic nerves and promoted myelin debris clearance, neurite outgrowth, neurovascular remodeling, and long-term functional improvement in mice. Integrated transcriptomic and proteomic analyses identified prosaposin (PSAP) and aldolase A (ALDOA) as candidate regenerative cargo molecules. Recombinant PSAP and ALDOA partially restored neurite growth under inflammatory conditions, supporting a potential metabolic–neurotrophic coupling mechanism in EV-mediated repair. These findings indicate that injury-responsive sc-EVs can modulate the regenerative microenvironment and provide a targeted, cell-free approach for peripheral nerve tissue engineering.