Fuel-maintenance coupling reprograms mitochondrial homeostasis to enable peripheral nerve regeneration

Peripheral nerve regeneration is frequently stalled by a "metabolic bottleneck" characterized by mitochondrial dysfunction and bioenergetic exhaustion. Although nerve guidance conduits (NGCs) provide structural support, most remain metabolically inactive and fail to address this energetic deficit. Here, we developed a fuel-maintenance coupling metabolic reprogramming strategy to support peripheral nerve repair. A biomimetic NGC was engineered with an aligned electrospun polycaprolactone (PCL) sheath filled with an injectable, in situ photocrosslinkable Magnolol-loaded chitosan-lipoic acid hydrogel (LA-CS@Mag). In this synergistic system, α-lipoic acid serves as the metabolic fuel to restore ATP production, while Mag functions as a mitochondrial quality controller to promote mitophagy-associated mitochondrial clearance. In vitro, LA-CS@Mag protected rat Schwann cells (RSCs) from oxidative stress, restored mitochondrial membrane potential, reduced ROS accumulation, and improved ATP production, accompanied by activation of BNIP3/Parkin-related mitophagy. Moreover, conditioned medium from LA-CS@Mag-treated RSCs reduced M1-like macrophage polarization and promoted an M2-like reparative phenotype, suggesting Schwann cell-mediated immunomodulatory effects. In vivo, implantation of the LA-CS@Mag/PCL conduit modulated macrophage polarization, suppressed excessive early inflammatory responses, and promoted a reparative immune microenvironment. In a rat sciatic nerve defect model, the bioactive conduit significantly accelerated axonal regeneration and remyelination, prevented target muscle atrophy, and achieved functional recovery comparable to autografts. Collectively, this study identifies mitochondrial homeostasis as a therapeutic target and provides a metabolically instructive strategy for next-generation nerve guidance conduits.