Poly(Citric Acid) Bidirectional Regulator: Coordinating Iron Homeostasis to Suppress Stress Responses and Boosting Mitochondrial Bioenergetics for Enhanced Nerve Repair

Abstract

ABSTRACT Due to the complex regenerative microenvironment, peripheral nerve repair poses significant challenges in clinical treatment. Severe injuries can lead to dysregulated iron homeostasis, and excessive iron produces reactive oxygen species (ROS) through the Fenton reaction. The subsequent oxidative stress further leads to mitochondrial and endoplasmic reticulum (ER) stress, which impedes nerve regeneration. In addition, insufficient vascular remodeling also limits the repair of damaged nerves. Herein, a poly(citric acid) (PCA)‐loaded gelatin‐lipoic acid (Gel‐LA) microgel hydrogel‐filled oriented electrospun fiber conduit was developed, which guides axonal alignment by topographical cues, promotes cellular infiltration and nutrient transport through a microgel cascade pore structure, and regulates the regenerative microenvironment via the ferrous ion (Fe 2+ ) chelation effect of PCA. The results demonstrate that this conduit effectively reduces the levels of Fe 2+ at the injury site, thereby alleviating mitochondrial and ER stress while promoting energy metabolism, vascular reconstruction, and nerve regeneration. This study highlights the potential of PCA in modulating the microenvironment of nerve injuries and provides new insights for developing tissue‐engineered scaffolds.