Reactive Oxygen Species‐Responsive Composite Fibers Regulate Oxidative Metabolism through Internal and External Factors to Promote the Recovery of Nerve Function

Abstract It is challenging to sufficiently regulate endogenous neuronal reactive oxygen species (ROS) production, reduce neuronal apoptosis, and reconstruct neural networks under spinal cord injury conditions. Here, hydrogel surface grafting and microsol electrospinning are used to construct a composite biomimetic scaffold with “external‐endogenous” dual regulation of ROS. The outer hydrogel enhances local autophagy through responsive degradation and rapid release of rapamycin (≈80% within a week), neutralizing extracellular ROS and inhibiting endogenous ROS production, further reducing neuronal apoptosis. The inner directional fibers continuously supply brain‐derived neurotrophic factors to guide axonal growth. The results of in vitro co‐culturing show that the dual regulation of oxidative metabolism by the composite scaffold approximately doubles the neuronal autophagy level, reduces 60% of the apoptosis induced by oxidative stress, and increases the differentiation of neural stem cells into neuron‐like cells by ≈2.5 times. The in vivo results show that the composite fibers reduce the ROS levels by ≈80% and decrease the formation of scar tissue. RNA sequencing results show that composite scaffolds upregulate autophagy‐associated proteins, antioxidase genes, and axonal growth proteins. The developed composite biomimetic scaffold represents a therapeutic strategy to achieve neurofunctional recovery through programmed and accurate bidirectional regulation of the ROS cascade response.