Preclinical Evidence of Extracellular Vesicle-derived MicroRNAs in Relieving Diabetic Peripheral Neuropathy: A...

Diabetic peripheral neuropathy (DPN) provokes axonal degeneration and impairs nerve repair. Preclinical studies suggest that extracellular vesicles (EVs) exert neuroregenerative effects. As miRNAs are key, transferable bioactive cargoes that mediate the majority of observed EV functions in cell-to-cell communication, this systematic review specifically evaluated animal model evidence on the therapeutic potential of EV-derived miRNAs in alleviating DPN. A comprehensive search of MEDLINE, Embase, and ISI Web of Science was conducted on March 21, 2025 following PRISMA 2020 (PROSPERO registration ID: CRD420251130044). This review included studies that utilized in vivo models of DPN and in vitro hyperglycemic models only when corroborated by in vivo validation within the same study. Functional, electrophysiological, and histological assessments of nerve regeneration constituted the outcomes. Data were qualitatively synthesized and their quality was assessed using SYRCLE's Risk of Bias Tool. Nine studies met the inclusion criteria. The synthesis revealed a bidirectional regulatory role for EV miRNAs in DPN pathophysiology, dependent on both the miRNA species and the pathophysiological state of the EV source cell. Neuroprotective miRNAs (e.g., miR-21, -146a, let-7a, -20b-3p) from healthy or stem cell sources enhanced myelin integrity, nerve conduction, and neurovascularization, while mitigating neuroinflammation. Conversely, pathological hyperglycemia could reprogram EV cargo, leading to the enrichment of neurodegenerative miRNAs (e.g., miR-28, -31a, -221) that exacerbated neuropathic features. EV miRNAs exhibit significant improvement in peripheral nerve function, alleviating neuropathic pain, or promoting nerve regeneration under hyperglycemia. Nevertheless, preclinical research with more homogenous methods is necessary to advance clinical translation.