Nitrogen-Boosted H(2)O(2) Production of Arginine-Polyphenol Nanozyme Drives Oxidative Eustress for Hair Regeneration.

Reactive oxygen species (ROS)-triggered oxidative eustress can stimulate regenerative signaling, yet its therapeutic window remains narrow. Mitochondrial respiratory complexes and superoxide dismutase (SOD) are canonical enzymatic sources of intracellular H(2)O(2). Here we report a biomimetic polyphenol-amino acid nanozyme (PEAs) that couples the semiquinone radical of coenzyme Q (ubiquinone) with the Arg143 residue of Zn/Cu-SOD1. Through self-assembling epigallocatechin gallate (EGCG) and L-arginine (L-Arg), PEAs enable O(2) adsorption and activation with controlled H(2)O(2) generation. The H(2)O(2) output is finely tuned by modulating the nitrogen (N) content from L-Arg. Integrated experimental and computational analyses reveal that the N-sites introduced by L-Arg promote semiquinone electron delocalization, increase semiquinone abundance, thereby strengthening O(2) adsorption, facilitating electron/proton transfer, and lowering the reaction barrier for H(2)O(2) synthesis. Using the genetically encoded H(2)O(2) sensor HyPerion, this work validates the sustained intracellular modulation of H(2)O(2) by PEAs. In a mouse model of telogen effluvium, controlled H(2)O(2) delivery activates the follicular niche via Wnt/β-catenin upregulation and Ca(2+)/calcineurin/NFAT downregulation, resulting in robust follicle activation and a non-pharmacological approach to alopecia therapy. This polyphenol-amino acid nanozyme therefore provides a safe and effective strategy for in vivo pro-oxidative modulation, offering a tunable H(2)O(2)-based platform to harness beneficial oxidative stress for tissue renewal.