Spatial Distortion-Engineered Cationic Ru-Covalent Organic Framework Overcoming Aggregation-Caused Quenching for Synergistic Photodynamic/Photothermal Anti-Infective Therapy

Decades of antibiotic misuse have spurred an antimicrobial resistance crisis, creating an urgent demand for alternative treatment options. Although phototherapy has therapeutic potential, the efficacy of the most advanced photosensitizers (PS) is essentially limited by aggregation-induced quenching, which significantly reduces their therapeutic effect. To address these challenges, we developed a cationic metallocovalent organic framework (CRuP-COF) via a solvent-mediated dual-reaction synthesis strategy. This material (ζ = +21.07 ± 1.04 mV) was fabricated through synergistic Knoevenagel polycondensation and SN₂ nucleophilic substitution, using bromoethane as a bifunctional modulator to copolymerize tris(4,4'-dicarboxaldehyde-2,2'-bipyridine)Ru(II) (Rubpy-6CHO) and <i>meso</i>-tetrakis(6-methylpyridin-3-yl)porphyrin (TMPP). The spatially distorted Ru(II) centers create staggered π-conjugation networks, effectively suppressing π-π stacking interactions, thereby preventing the photoactivity decay commonly observed in conventional porphyrin systems. Pyridinic N-ethylation generates a permanent cationic surface potential, enabling selective electrostatic adhesion to negatively charged bacterial membranes. This targeting mechanism, combined with the hierarchical porous structure and high specific surface area, optimizes mass and energy transport while minimizing thermal and reactive oxygen species (ROS) dissipation. CRuP-COF demonstrates superior photothermal conversion efficiency and sustained ROS generation (mixed Type I/II mechanisms), exhibiting 50% higher antibacterial potency than its noncationic analog RuP-COF. At 200 μg/mL, it achieves remarkable >98% eradication rates against both Gram-positive (<i>Staphylococcus aureus</i>) and Gram-negative (<i>Escherichia coli</i>) pathogens. The system further demonstrates self-amplifying therapeutic effects, where localized photothermal heating accelerates ROS production, which, in turn, enhances bacterial membrane permeability to facilitate cationic targeting. Biosafety assessments confirm excellent biocompatibility with minimal hemolytic activity and high cellular viability at therapeutic concentrations. This integrated approach establishes a paradigm in antimicrobial development, offering a potent, targeted, and resistance-proof therapeutic solution that meets the urgent demands of modern infection control.