Infection-adaptive regenerative wound healing through rationally engineered copper-polyphenol artificial enzymes enabling quadruple-modal ROS cascade modulation in pathological microenvironments

Volume 275, February 2026, 113132

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Synthetic polyphenols with multiple coordination centers was prepared.

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PRSA-Cu with mixed-valence Cu2+/Cu+ centers enables quadruple-mode catalysis.

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PRSA-Cu exerted Type I PDT generates water-derived •OH overcoming hypoxia limitations.

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The hyperthermia cycle of PRSA-Cu liberates Cu+/Cu2+, activates H2O2, depletes GSH.

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PRSA-Cu eradicates pathogens and promotes wound regeneration.

Abstract

While artificial enzyme-based catalytic therapies offer promise for bacterial infection treatment through cost-effectiveness and substrate specificity, conventional systems remain hampered by monofunctionality and inadequate catalytic efficiency. Here, we developed PRSA-Cu, a copper-phenolic coordination polymer artificial enzyme with multi‑copper centers and mixed-valence states (Cu2+ and Cu+) enabling synergistic antibacterial mechanisms. Initially, this multimodal system amplifies oxidative stress by imitating enzyme processes to generate hydroxyl radicals (•OH) through Cu2+/Cu+-mediated peroxidase-like (POD-like) reactions. Subsequently, it depletes glutathione (GSH) to neutralize bacterial antioxidant defenses via glutathione peroxidase-like (GPx-like) catalysis. Thirdly, the system enhances catalytic efficiency through photothermal effects that optimize enzymatic kinetics. Finally, it enables oxygen-independent Type I photodynamic activity, producing water-derived •OH even in hypoxic conditions. This self-amplifying cycle emerges from synergistic heat-radical-redox interplay, wherein localized hyperthermia elevates membrane permeability to enable Cu2+/Cu+ liberation and H2O2 activation via ligand-metal charge transfer (LMCT), while concurrent glutathione (GSH) exhaustion suppresses ROS scavenging. In vitro studies confirmed periplasmic membrane disintegration in both S. aureus and E. coli through cytoplasmic component leakage. In vivo evaluations demonstrated near-complete wound closure within 9 days through concurrent biofilm eradication and angiogenesis stimulation. This platform establishes a paradigm shift from single-pathway antimicrobials to spatiotemporally coordinated artificial enzymes, unifying photothermal-photodynamic-multienzyme catalysis for clinical translation.

Graphical abstractEngineered Copper-Polyphenol Artificial Enzymes Enabling Quadruple-Modal ROS Cascade Modulation in Pathological Microenvironments. Unlabelled Image