Plant-derived extracellular vesicles restore cellular energetics for peripheral nerve regeneration through glycolysis...

Peripheral nerve injury (PNI) causes a severe energy crisis at the injury site, restricting peripheral nerve regeneration. However, effective intervention strategies are lacking to maintain energy homeostasis. Emerging research has underscored the potential of plant-derived extracellular vesicles for PNI treatment. In this study, we demonstrated that Gastrodia elata derived extracellular vesicles (GEDEVs) exhibited neuroregenerative effects. GEDEVs selectively boosted pro-regenerative phenotypes in PC12 cells. In addition, GEDEVs reprogrammed cellular metabolism in dorsal root ganglion (DRG) neurons by upregulating aerobic glycolysis and downregulating oxidative phosphorylation. This reprogramming preserved adenosine triphosphate (ATP) availability for DRG neurons while suppressing reactive oxygen species (ROS) production. The results of RNA sequencing indicated that key glycolytic enzymes, such as PKM2 and LDHA, were significantly upregulated and may contribute to this metabolic shift. In vivo, GEDEVs promoted nerve regeneration and functional recovery. GEDEVs demonstrated a favorable safety profile, with no significant toxicity observed in vitro or in vivo assessments. In conclusion, this study demonstrates that GEDEVs represent a promising nanotherapeutic approach for enhancing nerve regeneration in PNI.