Smart microenvironment-adaptive nanocatalytic hydrogel for sequential antibacterial, anti-inflammatory, and regenerative therapy of biofilm-infected wounds

Biofilm-infected wounds remain a major clinical challenge, as biofilm infections and persistent inflammation hinder conventional therapies from dynamically adapting to the evolving wound microenvironment. Herein, a smart hydrogel dressing (HCOC) is successfully developed for programmed and pH-responsive therapy by integrating humic acid (HAs)-encapsulated ultrasmall mixed-valence copper nanozymes (Cu 5.4 O) into an oxidized alginate-carboxymethyl chitosan network. In the acidic biofilm-infected phase (pH < 6.5), the HAs shells aggregate, controllably releasing Cu 5.4 O to initiate chemodynamic therapy (CDT), while simultaneously enabling HAs-mediated photothermal therapy (PTT). This synergistic CDT/PTT achieves exceptional antibacterial efficacy, eradicating > 99.99% of Methicillin-Resistant Staphylococcus aureus and Escherichia coli and dispersing 87.46% of biofilms. As the wound pH rises post-infection (pH ≥ 7.0), HAs dissolves, liberating more Cu 5.4 O nanozymes, which switch to potent antioxidant modes—scavenging > 90% of reactive oxygen species—and promoting M2 macrophage polarization by suppressing NF-κB and activating Wnt/β-catenin signaling. In vivo , HCOC combined with NIR irradiation accelerates infected wound healing, achieving 91.65% closure within 7 days, significantly enhancing angiogenesis (∼90 CD31 + cells/field), and boosting M2 macrophage infiltration (∼110 CD163 + cells/field). This work establishes a paradigm-shifting platform for precision wound management through microenvironment-responsive sequential therapy. • A smart hydrogel autonomously switches from antibacterial to pro-healing mode based on wound pH. • Cu 5.4 O nanozyme has dual functions: ROS generation in acid, antioxidant activity in neutral/alkaline. • Synergistic chemodynamic/photothermal therapy eradicates > 99.99% of biofilms in antibacterial stage. • Humic acids acts as pH-responsive switch, controlling nanozyme release to prevent tissue damage. • Therapy combats biofilm infection, oxidative stress, and promotes anti-inflammatory macrophage reprogramming.