Bifunctional Artificial Enzymes‐Loaded Microgels With LOX‐ and CAT‐Like Activities for Metabolic Reprogramming and Scarless Wound Repair

ABSTRACT Lactate plays a central role in regulating wound metabolism and has been implicated in fibrosis through mechanisms such as histone lactylation and endothelial‐to‐mesenchymal transition. However, strategies to modulate lactate‐driven metabolic imbalance and oxidative stress remain limited. Herein, a metabolism‐regulating and inflammation‐modulatory artificial enzyme, Metazyme, was developed, which exhibited dual lactate oxidase (LOX)‐like and catalase (CAT)‐like activities to oxidize lactate and decompose hydrogen peroxide (H 2 O 2 ), enabling efficient oxygen recycling. Embedding Metazyme into a rod‐shaped microgel matrix yielded MetaRgel, a localized and sustained catalytic platform for wound microenvironment modulation. The MetaRgel reduced lactate and reactive oxygen species (ROS) levels, relieved hypoxia, and downregulated glycolysis‐related enzymes such as pyruvate kinase (PKM2) and pyruvate dehydrogenase kinase isoform 1 (PDK1) in vitro and thereby suppressed the pro‐inflammatory cytokine interleukin‐6 (IL‐6) and the fibrotic mediator transforming growth factor‐β1 (TGF‐β1). In a rat full‐thickness wound model in vivo, the MetaRgel significantly accelerated healing, enhanced granulation and collagen organization, and notably reduced glycolytic enzyme activity as well as the fibrotic marker α‐smooth muscle actin (α‐SMA) and hypoxia‐inducible factor 1α (HIF‐1α). The targeting of lactate‐centered metabolic dysregulation with cascade artificial enzymes offers a promising approach to interrupt inflammation‐metabolism‐fibrosis crosstalk and promote scarless skin regeneration.