Walnut-Derived Extracellular Vesicles Orchestrate a Pre-Regenerative Niche via c-Myc Mediated Metabolic Reprogramming.

Peripheral nerve injury (PNI) remains a major regenerative challenge, in part because the post-injury microenvironment can disrupt Schwann cell (SCs) homeostasis. Walnuts (Juglans regia) have long been used in ethnomedicine for perceived neurotrophic or neuroprotective benefits, a view historically linked to their resemblance to the brain. To examine whether this traditional concept can be leveraged as a nanotherapeutic approach, we isolated walnut-derived extracellular vesicles (WEVs) and evaluated their effects on peripheral nerve repair. We found that WEVs are readily internalized by SCs and can help establish a "pre-regenerative niche," defined here as a permissive metabolic microenvironment that supports repair. Mechanistically, WEVs appear to engage a c-Myc-mediated transcriptional program that shifts SC metabolism toward aerobic glycolysis and increases lactate export, consistent with activation of a glia-to-neuron lactate shuttle. In parallel, WEVs may stabilize the glial bioenergetic hub by limiting stress-induced mitophagy. In a rat sciatic nerve compression model, these changes were associated with preserved mitochondrial ultrastructure in the acute phase, followed by enhanced remyelination, improved motor and sensory outcomes, and attenuated muscle atrophy. Collectively, our findings suggest a mechanistic basis for the reported neuroprotective value of walnuts and identify WEVs as a niche-modulating nanotherapeutic candidate that may promote regeneration by aligning glial metabolic plasticity with neuronal energy demands.