An enhanced sonodynamic antibacterial strategy using bismuth porphyrin metal-organic frameworks to inhibit bacterial endogenous antioxidant H2S metabolism.

Surgical site infections (SSIs) represent a global healthcare burden, a challenge intensified by the increasing prevalence of antibiotic resistance. To address drug-resistant bacterial infections, various non-antibiotic therapeutic strategies have been explored, among which sonodynamic therapy (SDT) has emerged as a promising approach due to its deep tissue penetration and controllability. Nevertheless, bacteria are not defenseless against SDT and can produce endogenous hydrogen sulfide (H₂S) as an antioxidant to resist reactive oxygen species (ROS)-mediated killing, thereby limiting therapeutic efficacy. Herein, we reported a dual-functional and synergistic sonodynamic antibacterial strategy based on two-dimensional bismuth porphyrin metal-organic frameworks (Bi-TCPP). Bi-TCPP simultaneously functioned as an efficient sonosensitizer to generate singlet oxygen (1O₂) under ultrasound irradiation and as an effective scavenger of bacterial-derived H₂S through strong Bi³⁺-H₂S interactions. By weakening the bacterial antioxidant reduction system and disrupting redox homeostasis, this strategy enabled efficient bacterial eradication via low-level ROS, thereby significantly amplifying SDT-mediated antibacterial efficacy. The effectiveness of this synergistic strategy was systematically demonstrated against multiple bacterial species, including drug-resistant strains and different survival states such as planktonic bacteria and biofilms in vitro. It was further validated in vivo, highlighting its potential as an alternative therapeutic approach for treating drug-resistant bacterial infections.