DNA-Targeted Sonodynamic Activation Enhances Antibacterial Efficacy in Deep and Hypoxic Infections

Deep-seated bacterial infections remain difficult to eradicate because both antibiotic delivery and photodynamic therapy are intrinsically constrained by tissue depth, biofilm protection, and hypoxic microenvironments. Sonodynamic therapy (SDT) offers noninvasive activation with clinically relevant penetration depth, but its antibacterial application has been limited by the scarcity of sonosensitizers that combine high activity, target specificity, and clinically relevant molecular scaffolds. Here, we establish TLD1433, a clinically advanced Ru(II) photosensitizer, as a DNA-targeting sonosensitizer for antibacterial therapy. Under ultrasound activation, TLD1433 exhibits strong sonodynamic activity, dominant singlet oxygen generation, and superior antibacterial efficacy relative to conventional sonosensitizers. Mechanistically, TLD1433 preferentially associates with bacterial DNA, thereby enabling localized oxidative damage to an essential intracellular target. In parallel, it catalyzes endogenous H2O2 decomposition to generate O2, thereby relieving biofilm hypoxia and amplifying sonodynamic efficacy. As a result, ultrasound-activated TLD1433 shows potent antibacterial efficacy in a murine Pseudomonas aeruginosa pneumonia model and in patient-derived bronchoalveolar lavage fluid under deep-tissue conditions. This work establishes a mechanistically distinct antibacterial sonodynamic strategy based on a clinically advanced ruthenium complex, providing a design framework for target-specific sonosensitizers against deep and hypoxic bacterial infections.