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

Abstract

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_5.4O) into an oxidized alginate-carboxymethyl chitosan network. In the acidic biofilm-infected phase (pH < 6.5), the HAs shells aggregate, controllably releasing Cu_5.4O 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 <i>Staphylococcus aureus</i> and <i>Escherichia coli</i> and dispersing 87.46% of biofilms. As the wound pH rises post-infection (pH ≥ 7.0), HAs dissolves, liberating more Cu_5.4O 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. <i>In vivo</i>, 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.