A H₂S‐Evolving Alternately‐Catalytic Enzyme Bio‐Heterojunction with Antibacterial and Macrophage‐Reprogramming Activity for All‐Stage Infectious Wound Regeneration

Abstract The disorder of the macrophage phenotype and the hostile by‐product of lactate evoked by pathogenic infection in hypoxic deep wound inevitably lead to the stagnant skin regeneration. In this study, hydrogen sulfide (H₂S)‐evolving alternately catalytic bio‐heterojunction enzyme (AC‐BioHJzyme) consisting of CuFe₂S₃ and lactate oxidase (LOD) named as CuFe₂S₃@LOD is developed. AC‐BioHJzyme exhibits circular enzyme‐mimetic antibacterial (EMA) activity and macrophage re‐rousing capability, which can be activated by near‐infrared‐II (NIR‐II) light. In this system, LOD exhausts lactate derived from bacterial anaerobic respiration and generated hydrogen peroxide (H₂O₂), which provides an abundant stock for the peroxidase‐mimetic activity to convert the produced H₂O₂ into germicidal •OH. The GPx‐mimetic activity endows AC‐BioHJzyme with a glutathione consumption property to block the antioxidant systems in bacterial metabolism, while the O₂ provided by the CAT‐mimetic activity can generate ¹O₂ under the NIR‐II irradiation. Synchronously, the H₂S gas liberated from CuFe₂S₃@LOD under the infectious micromilieu allows the reduction of Fe(III)/Cu(II) to Fe(II)/Cu(І), resulting in sustained circular EMA activity. In vitro and in vivo assays indicate that the CuFe₂S₃@LOD AC‐BioHJzyme significantly facilitates the infectious cutaneous regeneration by killing bacteria, facilitating epithelialization/collagen deposition, promoting angiogenesis, and reprogramming macrophages. This study provides a countermeasure for deep infectious wound healing via circular enzyme‐mimetic antibiosis and macrophage re‐rousing.