Calcium-enhanced COF platforms for synergistic photothermal-antibacterial therapy: Unlocking calcium-mediated membrane disruption and ion overload for bacterial and biofilm eradication in wound care and clinical nursing.

The escalating threat of antibiotic-resistant bacteria and biofilm-associated infections necessitates the development of non-antibiotic therapeutic strategies with novel mechanisms of action. Here, we report a synergistic antibacterial platform based on a calcium-functionalized covalent organic framework (BQ-Ca-COF), designed to exploit the dual role of calcium ions (Ca2+) as both structural modulators and bioactive effectors. Using a solvothermal approach, we synthesized a series of COFs incorporating a dipyrazino [2,3-f:2',3'-h] quinoxalin (DPQ) linkage, enabling precise regulation of both framework architecture and Ca2+ incorporation. The optimized BQ-Ca-COF exhibits a hierarchically porous structure and achieves a remarkable photothermal conversion efficiency of 58% under 638 nm laser irradiation. Crucially, Ca2+ serve as the linchpin of a multi-stage synergistic cascade, with their role evolving across each phase of the therapeutic process. Beyond merely integrating into the COF skeleton as a structural enhancer, Ca2+ optimizes electronic properties to amplify photothermal heat generation. Upon release, these ions then transition to function as membrane destabilizers, electrostatically disrupting bacterial membranes and increasing their permeability that sensitizes bacteria to subsequent photothermal insult. This sensitization sets the stage triggers an uncontrolled influx of extracellular Ca2+. The resulting "calcium overload" disrupts bacterial homeostasis, causes an imbalance in membrane potential, and triggers apoptosis-like death. High temperatures directly cause protein conformational instability and loss of function, leading to a significant decrease in the activity of transmembrane proteins such as the calcium efflux pump. Moreover, elevated temperatures compromise membrane lipid fluidity and integrity, further disrupting calcium transporter function. The resulting breakdown of calcium ion homeostasis triggers a lethal cascade, culminating in irreversible bacterial death. This synergistic mechanism enables BQ-Ca-COF to achieve >99% eradication of both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli, along with nearly complete (∼100%) biofilm disruption, substantially outperforming calcium-free control (BQ-COF). The material exhibits excellent biocompatibility, low cytotoxicity, and promotes cell migration. When processed into a medical hydrogel dressing for clinical wound care evaluation, BQ-Ca-COF maintains stable photothermal performance even after 100 bending cycles and causes no skin irritation during prolonged wear. In a mouse infection model, BQ-Ca-COF combined with laser irradiation significantly accelerated wound healing compared to controls, with no evidence of systemic toxicity. This work establishes a new paradigm for designing COF-based multifunctional antibacterial platforms and, more importantly, elucidates the pivotal and multifaceted role of Ca2+ as structural architects, membrane permeabilizers, and mediators of fatal ion overload in achieving potent, resistance-free antibacterial therapy against clinically relevant infections.