Extracellular Vesicles in Peripheral Nerve Regeneration: From Biology to Therapeutic Engineering.

Peripheral nerve injuries (PNIs) pose a significant clinical challenge, often resulting in irreversible functional deficits due to limited spontaneous regeneration. While current therapeutic approaches offer partial solutions, their efficacy remains suboptimal. In recent years, extracellular vesicles (EVs) have emerged as bioactive carriers capable of orchestrating complex regenerative processes without the risks associated with live-cell transplantation. Derived from sources, EVs deliver a repertoire of functional cargos that modulate immune responses, promote axonal regrowth, enhance remyelination, and stimulate angiogenesis. Furthermore, bioengineering strategies enable EVs to be loaded with therapeutic molecules, surface-modified for targeted delivery, and incorporated into stimuli-responsive scaffolds for controlled release. When integrated with biomaterials, EVs demonstrate synergistic effects that enhance spatial guidance, immune modulation, and neurovascular remodeling in preclinical models. However, significant challenges remain, including large-scale EV production, standardization of isolation methods, and meeting regulatory requirements for clinical translation. In this review, we provide a comprehensive overview of the biological roles of native and engineered EVs in peripheral nerve regeneration, highlights advances in EV-functionalized scaffolds, and discusses translational challenges and future directions for clinical implementation.