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

Abstract 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 sp 2 ‐carbon‐linked covalent organic framework (sp 2 c‐COF‐Ir‐ppy 2 and sp 2 c‐COF‐Ru‐bpy 2 ) 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.