A programmable spatiotemporal bioelectrical conduit promotes peripheral nerve regeneration by suppressing ferroptosis through modulation of ER–mitochondria coupling in Schwann cells

Abstract

Following peripheral nerve injury, abnormal endoplasmic reticulum–mitochondria coupling and activation of ferroptosis in Schwann cells are important causes of impaired myelination and regenerative failure. Based on this, we developed a multiscale anisotropic electroactive nerve conduit. The outer layer consists of a BaTiO3-loaded GelMA piezoelectric hydrogel for ultrasound-triggered acoustic–electric conversion, while the inner layer is formed by rolling an aligned gelatin/PLA/G conductive fiber membrane into a tubular structure to provide directional conductive support and biomimetic topographical guidance. Together, this bilayer architecture forms a programmable spatiotemporal bioelectrical instruction system capable of generating localized, tunable, and directional bioelectrical output. The results showed that this conduit exhibited good biocompatibility and significantly promoted Schwann cell migration, polarized alignment, recovery of myelin-related phenotypes, and secretion of neurotrophic factors, while also enhancing neurite outgrowth of DRG neurons. Mechanistic studies further demonstrated that directional bioelectrical stimulation suppressed GRP75 expression, inhibited abnormal MAM formation mediated by the IP3R1–GRP75–VDAC1 complex, restored mitochondrial oxidative phosphorylation and energy metabolism, and ultimately attenuated ferroptosis in Schwann cells. In vivo experiments further showed that this conduit markedly promoted ordered nerve fiber regeneration, myelin maturation, neurovascular network reconstruction, and recovery of target muscle function, with repair outcomes approaching those of autologous nerve grafting. These findings establish a proof-of-concept engineered strategy for peripheral nerve regeneration and provide a basis for further preclinical evaluation in long-gap peripheral nerve defect models.