Biological membrane infections of wounds remain a major clinical challenge because these infections and persistent inflammation hinder the dynamic adaptation of traditional therapies to the constantly changing microenvironment of the wound. This study successfully developed an intelligent hydrogel dressing (HCOC), which achieves programmed and pH-responsive therapy by integrating ultra-small mixed-valent copper nanozymes (Cu5.4O) encapsulated by humic acid (HAs) into an oxidized alginate-carboxymethyl chitosan network. During the acidic biological membrane infection period (pH < 6.5), the HAs shells aggregate and release Cu5.4O in a controlled manner to initiate chemical kinetic therapy (CDT), while enabling HAs-mediated photothermal therapy (PTT). This synergistic CDT/PTT achieves excellent antibacterial effects, eliminating 99.99% of methicillin-resistant Staphylococcus aureus and Escherichia coli, and eradicating 87.46% of the biofilm. After the infection, the wound pH increases (pH ≥ 7.0), and the HAs dissolve, releasing more Cu5.4O nanozymes. These enzymes switch to a potent antioxidant mode - eliminating 90% of reactive oxygen species - and promote M2 macrophage polarization by inhibiting NF-κB and activating Wnt/β-catenin signaling. In vivo, HCOC combined with near-infrared irradiation accelerates wound healing, achieving a 91.65% closure rate within 7 days, significantly enhancing angiogenesis (approximately 90 CD31+ cells per field), and enhancing M2 macrophage infiltration (approximately 110 CD163+ cells per field). This study establishes a paradigm-shifting platform for precise trauma management through microenvironment-responsive sequential therapy. This research was published in Bioactive Materials under the title "Smart microenvironment-adaptive nanocatalytic hydrogel for sequential antibacterial, anti-inflammatory and regenerative therapy of biofilm-infected wounds".
Reference: DOI: 10.1016/j.bioactmat.2026.02.043