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

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 (H₂O₂), 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.