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Chiral MoS2-based nanozymes co-delivering indole-3-propionic acid synergistically inhibit ferroptosis and reprogram
Linbin Xu1, Xinghao Yin1, Xin Wang2
1Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Center for Orthopaedics, Shanghai, China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, China.
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.
