Mitochondrial remodeling by extracellular vesicles co-delivering functional mitochondria and a mitophagy inducer for neuropathic pain relief.

Neuropathic pain remains a major clinical challenge due to limited efficacy and tolerability of current treatments. Mitochondrial dysfunction in dorsal root ganglion (DRG) cells is recognized as a key pathogenic mechanism, but effective strategies to restore mitochondrial homeostasis are lacking. Here, we first identified profound deficits in mitochondrial quantity and quality in DRG neurons and satellite glial cells (SGCs) from a chemotherapy-induced peripheral neuropathy (CIPN) model. To address this, we developed an extracellular vesicle-based nanoplatform (EVs@Mi/UR) loaded with a mitophagy inducer, which integrates exogenous mitochondrial transplantation with mitophagy induction. EVs@Mi/UR not only increased mitochondrial mass in DRG neurons and SGCs through efficient mitochondrial transplantation, but also improved mitochondrial quality by eliminating damaged organelles, thereby enhancing mitochondrial respiration and metabolic function. In both CIPN and spared nerve injury (SNI) mouse models, EVs@Mi/UR significantly alleviated mechanical allodynia, thermal hyperalgesia, and cold hypersensitivity with superior efficacy. Notably, even in SNI models that did not exhibit baseline mitochondrial deficits, EVs@Mi/UR still produced analgesic effects by improving mitochondrial quality. This work establishes mitochondrial remodeling as a promising strategy for neuropathic pain and provides a translatable EV-based nanoplatform for dual-modality mitochondrial intervention.