Site-Specific Engineered Cationic Ferrocene COF with pH-Switchable Dual Enzyme Activities for Infected Wound Care

Abstract Infected wounds are trapped in self-perpetuating acidic and hypoxic microenvironments, yet designing intelligent systems that can sense and remodel such niches remains challenging. Here, we report EBP-Fc-COF, a cationically engineered ferrocene covalent organic framework (COF) for microenvironment-adaptive antibacterial therapy. The material is synthesized via a tandem Knoevenagel condensation and a Menshutkin-type reaction, in which the phosphine centers, owing to their higher nucleophilicity and lower electronegativity than the adjacent pyridinic-N sites, undergo chemoselective ethylation with bromoethane, yielding permanent quaternary phosphonium cations exclusively at the P-centers. This site-specific functionalization affords a uniform spherical morphology and a high photothermal conversion efficiency (η = 59.23%). The therapeutic mechanism relies on dual spatiotemporal synergy. The cationic framework electrostatically anchors to negatively charged bacterial membranes, providing spatial targeting. Concurrently, the system exhibits pH-switchable enzyme-mimetic activities for temporal adaptation: at acidic infection pH, it predominantly shows peroxidase-like (POD-like) activity, catalyzing H2O2 into ·OH for localized bacterial killing at the anchored interface. At neutral healing pH, it switches to catalase-like (CAT-like) activity, decomposing H2O2 into O2 to relieve hypoxia. Red-light irradiation further boosts the antibacterial performance by orchestrating cationic, photothermal, and enzymatic actions, achieving efficient disruption of bacteria and biofilms. In an infected wound model, the combination of EBP-Fc-COF, H2O2, and laser irradiation achieved ∼90% wound closure within nine days. Although not used in the in vivo wound healing experiments, this hydrogel composite was incorporated into a polyacrylamide matrix as an independent and preliminary formulation exploration, which serves solely as an initial feasibility assessment for potential future dressing development and are not part of the therapeutic efficacy validation. The optimized formulation (50 μg/mL) exhibited a uniform porous architecture, favorable swelling, excellent biocompatibility, high photothermal stability, reversible joint conformability, and maintained structural integrity after 200 bending cycles, providing an initial feasibility assessment for future development. This work establishes a P-centered precision engineering strategy for COF-based smart platforms, providing a paradigm for spatiotemporally synergistic, microenvironment-adaptive wound therapy.