Bacterial DNA‐Targeting AIE Photosensitizer for Efficient Eradication of Intracellular Bacteria and Biofilm‐Associated Infections

ABSTRACT Methicillin‐resistant Staphylococcus aureus (MRSA), often residing within biofilms and host cells, exhibits heightened resistance to conventional antibiotics and immune clearance, resulting in persistent and recurrent infections. Given the central role of DNA in bacterial proliferation and virulence, it represents an ideal target for the development of next‐generation antibacterial agents. In this study, we report the development of a DNA‐targeting photosensitizer (PS), TPE‐CN, designed for the effective treatment of MRSA‐associated infections. TPE‐CN demonstrates high specificity for bacterial DNA, along with excellent membrane permeability, enabling disruption of both bacterial DNA and membrane structures. This allows for the efficient eradication of planktonic MRSA. Moreover, TPE‐CN can also selectively colocalize with the lysosome of macrophages, facilitating effective eradication of intracellular bacteria while preserving host cell integrity. Furthermore, in vivo studies further validate the potent antimicrobial effects of TPE‐CN, resulting in accelerated wound healing in severe MRSA infection models. Collectively, this work presents a novel molecular design strategy for precise bacterial DNA targeting, offering a promising therapeutic avenue for combating drug‐resistant pathogens and advancing the development of next‐generation antimicrobial therapies.