A self-assembled dual-component hydrogel with Ce(III)/Ce(IV)-tuned cascade nanozyme and coordinated microenvironment regulation for comprehensive diabetic wound healing

Chronic diabetic wounds are trapped in a vicious cycle of hyperglycemia, oxidative stress, hypoxia, infection, and inflammation. Current treatments target only a few of these problems and cannot break the cycle. Here, a self-assembled dual-component hydrogel (Au NS@Ce‑RA@Gel, ACG) is designed by crosslinking a cerium‑rosmarinic acid metal‑phenolic network (Ce‑RA) grown on gold nanostar with phenylboronic acid‑modified carboxymethyl chitosan. Through polyphenol-assisted coordination, the Ce(III)/Ce(IV) ratio is tuned to endow Ce-RA with superoxide dismutase (SOD)- and catalase (CAT)-like activities. Meanwhile, Au NS provides intrinsic glucose oxidase (GOx)-like activity for enzyme-free glucose oxidation, enabling ACG to integrate GOx-, SOD-, and CAT-like catalytic functions. In infected diabetic wounds, ACG responds to glucose and ROS fluctuations to coordinately regulate local glucose burden, oxidative stress, hypoxic stress, and inflammation, while maintaining redox-buffering capacity during photothermal treatment and enabling efficient photothermal antibacterial activity (54.32% photothermal conversion efficiency). It achieves > 80% wound closure by day 6, outperforming clinical silver sulfadiazine. Mechanistically, ACG attenuates TNF/NF‑κB‑related inflammatory signaling by reducing the pathological stimuli that sustain chronic inflammation, while concurrently enriching TGF‑β/ErbB‑associated repair programs linked to cell motility and tissue remodeling. By coupling catalytic microenvironment regulation with immune remodeling and tissue repair, ACG offers a streamlined strategy for restoring a pro-healing wound microenvironment.