Stage‐Specific Molecular Cargo of Schwann Cell–Derived Extracellular Vesicles is Associated With Peripheral Nerve Repair

Schwann cells (SCs) play a critical role in peripheral nerve regeneration, undergoing dynamic phenotype transitions from myelinating to repair stages following injury. While SC-derived extracellular vesicles (SC-EVs) have emerged as key mediators of intercellular communication during nerve repair, their stage-specific molecular cargo and functional roles remained incompletely understood. Here, we delineate protein, microRNA and long non-coding RNA (lncRNA) landscapes of SC-EVs across distinct differentiation stages, including immature, myelinating, and repair phenotypes, using an in vitro model of primary rat SCs. We show that repair SC-EVs carry distinct microRNAs predicted to modulate genes involved in myelin ensheathment, neuronal differentiation, and neurogenesis. Treatment of immature Schwann cells with repair SC-EVs increased SOX2 expression, suggesting activation of repair-associated Schwann cell responses. Furthermore, modulation of miR-330-5p, miRNA identified in repair SC-EVs, altered SOX2 expression, Schwann cell proliferation, and migration. Repair SC-EVs also contain lncRNAs that may bind and sequester miRNAs, potentially relieving repression of pro-regenerative genes. These findings suggest possible mechanisms by which SC-EVs may regulate Schwann cell repair functions and provide a molecular framework for mechanistic studies.