Acutely denervated muscle EVs reshape neuronal mitochondrial metabolism via retrograde signaling to rescue peripheral nerve injury.

Peripheral nerve injury causes muscle atrophy due to slow axonal regeneration, highlighting an unmet therapeutic need. Although neuromuscular interactions are classically viewed as unidirectionally nerve dominated, we show that acutely denervated muscle (adMu) regulates nerve regeneration via a retrograde signaling pathway. adMu initiates a trans-tissue regulatory mechanism through extracellular vesicles (EVs(adMu)) that orchestrate neural energy homeostasis to accelerate regeneration. Functional profiling identifies IDH2 and CS as key metabolic enzymes within EVs(adMu). Neurons treated with EVs(adMu) exhibit a 1.39-fold increase in NADPH/NADP(+) ratio via IDH2, along with a 1.18- and 1.27-fold increase in NADH/NAD(+) and FADH(2)/FAD ratios via CS, fueling the tricarboxylic acid (TCA) cycle to enhance mitochondrial bioenergetics. This restores redox balance and energy supply, driving axonal regeneration. In sciatic nerve injury models, EV(adMu)-microneedle conduits significantly promote energy metabolism and functional recovery. Together, our findings position adMu as a metabolic signaling center enabling retrograde regulation for nerve regeneration, offering potential for clinical translation.