Preclinical efficacy of extracellular vesicle therapy in peripheral nerve injury: a comprehensive systematic review and network meta-analysis

Peripheral nerve injuries (PNIs) result in significant motor and sensory deficits, with autologous nerve grafting as the gold standard but limited by donor morbidity and incomplete recovery. Extracellular vesicles (EVs) have emerged as a promising cell-free therapy, offering potent paracrine signaling, safety, and immunological compatibility. This study systematically evaluated the preclinical efficacy of EV-based therapies for PNI. A systematic review and network meta-analysis were conducted according to PRISMA guidelines, searching PubMed, Scopus, and Web of Science to July 1, 2025. Eligible in vivo studies investigated EVs from any cell source in animal PNI models, compared with controls, and reported functional, structural, electrophysiological, or sensory outcomes. Risk of bias was assessed using the CAMARADES checklist. Three hierarchical meta-analyses compared EVs, structural grafts, cellular therapies, and combination strategies. The primary endpoint was sciatic functional index (SFI), and secondary outcomes included muscle preservation, sensory recovery, and electrophysiology. Thirty-five studies met inclusion, with 32 included in quantitative synthesis. EV therapy significantly improved SFI versus control (MD: 21.80; 95% CI 7.20–36.39; p = 0.0034), with greater effects in crush injuries and when combined with scaffolds, conduits, or autografts (up to MD: 54.41). Secondary outcomes showed improved gastrocnemius weight, muscle fiber area, nerve conduction velocity, and mechanical withdrawal thresholds. MSC-derived EVs, particularly scaffold-delivered, yielded the most consistent gains, while Schwann cell-derived EVs were effective as monotherapy. Mechanistically, EVs enhanced axonal growth, remyelination, angiogenesis, and M2 macrophage polarization while reducing inflammation. EV-based therapies significantly enhance functional, structural, and electrophysiological recovery in preclinical PNI models, with synergistic benefits when combined with structural supports. Standardization of EV production and delivery, and validation in clinically relevant models, are essential for translation into human therapy.