Designing Single‐Atom Active Sites on sp2‐Carbon Linked Covalent Organic Frameworks to Induce Bacterial Ferroptosis‐Like for Robust Anti‐Infection Therapy

With the threat posed by drug-resistant pathogenic bacteria, developing non-antibiotic strategies for eradicating clinically prevalent superbugs remains challenging. Ferroptosis is a newly discovered form of regulated cell death that can overcome drug resistance. Emerging evidence shows the potential of triggering ferroptosis-like for antibacterial therapy, but the direct delivery of iron species is inefficient and may cause detrimental effects. Herein, an effective strategy to induce bacterial nonferrous ferroptosis-like by coordinating single-atom metal sites (e.g., Ir and Ru) into the sp2 -carbon-linked covalent organic framework (sp2 c-COF-Ir-ppy2 and sp2 c-COF-Ru-bpy2 ) is reported. Upon activating by light irradiation or hydrogen peroxide, the as-constructed Ir and Ru single-atom catalysts (SACs) can significantly expedite intracellular reactive oxygen species burst, enhance glutathione depletion-related glutathione peroxidase 4 deactivation, and disturb the nitrogen and respiratory metabolisms, leading to lipid peroxidation-driven ferroptotic damage. Both SAC inducers show potent antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, clinically isolated methicillin-resistant Staphylococcus aureus (MRSA), and biofilms, as well as excellent biocompatibility and strong therapeutic and preventive potential in MRSA-infected wounds and abscesses. This delicate nonferrous ferroptosis-like strategy may open up new insights into the therapy of drug-resistant pathogen infection.