Chiral MoS2-based nanozymes co-delivering indole-3-propionic acid synergistically inhibit ferroptosis and reprogram metabolism for enhanced peripheral nerve regeneration.

INTRODUCTION

Peripheral nerve injury (PNI) affects over one million people annually, causing profound functional deficits and substantial socioeconomic burden. The intense oxidative stress following PNI disrupts mitochondrial energy metabolism, drives excessive reactive oxygen species production, and triggers Schwann cell ferroptosis, collectively forming a major barrier to nerve regeneration.

OBJECTIVES

This study aims to develop a biomimetic chiral nanozyme system that targets the oxidative stress-mitochondrial dysfunction-ferroptosis axis to enhance nerve regeneration following PNI.

METHODS

We engineered three types of chiral MoS2 nanozymes (D, L, and RCMS) and evaluated their antioxidant activities. The L-enantiomer CMS, exhibiting superior superoxide dismutase and catalase-like activities, was embedded into polycaprolactone (PCL) and loaded with indole-3-propionic acid (IPA) to form a controlled-release system (PCL@LCMS + IPA). Multi-omics analyses were performed to elucidate the therapeutic mechanisms. In vitro effects on Schwann cell mitochondrial function and ferroptosis were assessed, while in vivo efficacy was evaluated in PNI models.

RESULTS

PCL@LCMS + IPA selectively modulated the mitochondrial tricarboxylic acid cycle while suppressing lipid peroxidation and ferroptosis-related signaling pathways. In vitro, the system enhanced mitochondrial respiratory chain function, elevated ATP and NADPH production, restored iron homeostasis, and strengthened the glutathione peroxidase system, thereby inhibiting ferroptotic death and supporting Schwann cell-mediated repair. In vivo, PCL@LCMS + IPA maintained mitochondrial metabolic stability under oxidative stress, leading to improved axonal regeneration, angiogenesis, remyelination, and motor function recovery.

CONCLUSION

The controlled-release chiral nanozyme system effectively targets the oxidative stress-ferroptosis axis, restoring mitochondrial energy metabolism and preventing Schwann cell ferroptosis, thereby promoting functional nerve regeneration.