Nitrogen-Boosted H₂O₂ 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 H₂O₂. 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 O₂ adsorption and activation with controlled H₂O₂ generation. The H₂O₂ 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 O₂ adsorption, facilitating electron/proton transfer, and lowering the reaction barrier for H₂O₂ synthesis. Using the genetically encoded H₂O₂ sensor HyPerion, this work validates the sustained intracellular modulation of H₂O₂ by PEAs. In a mouse model of telogen effluvium, controlled H₂O₂ delivery activates the follicular niche via Wnt/β-catenin upregulation and Ca²⁺/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 H₂O₂-based platform to harness beneficial oxidative stress for tissue renewal.