Nitrogen‐Boosted H2O2 Production of Arginine‐Polyphenol Nanozyme Drives Oxidative Eustress for Hair Regeneration

PEA nanoenzymes are assembled from L‐arginine and EGCG. The nitrogen element in arginine enhances the thermodynamic feasibility of H2O2 production through PEA's oxygen reduction catalysis, enabling nitrogen‐dependent H2O2 release. Intradermal delivery of PEA via microneedles promotes efficient H2O2 synthesis, thereby stimulating regrowth in telogen effluvium model. Abstract 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. PEA nanoenzymes are assembled from L-arginine and EGCG. The nitrogen element in arginine enhances the thermodynamic feasibility of H 2 O 2 production through PEA's oxygen reduction catalysis, enabling nitrogen-dependent H 2 O 2 release. Intradermal delivery of PEA via microneedles promotes efficient H 2 O 2 synthesis, thereby stimulating regrowth in telogen effluvium model. Abstract 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. Advanced Science, EarlyView.