A Chemiluminescence‐Activated Photodynamic Platform to Penetrate MRSA Biofilms and Counteract H 2 S‐Mediated Defense

The rapid escalation of antibiotic resistance has profoundly limited the effectiveness of conventional antimicrobial therapies, underscoring an urgent need for alternative antibacterial strategies. In this study, we present an innovative, antibiotic‐free dual‐action antibacterial platform designed to effectively eradicate recalcitrant methicillin‐resistant Staphylococcus aureus (MRSA) biofilm‐associated infections. Building upon conventional antimicrobial photodynamic therapy (APDT), a chemiluminescence‐based activation system is introduced to enable in situ APDT excitation, thereby overcoming the limited tissue penetration depth associated with external light sources. The byproduct CO 2 gas not only disrupts the biofilm structure but also provides physical propulsion to drug‐loaded nanocarriers, facilitating the deep and uniform penetration of antimicrobial agents into the biofilm. Furthermore, hypericin functions not only as a photosensitizer that induces reactive oxygen species generation and oxidative stress in MRSA but also as an inhibitor of cystathionine β‐synthase (CBS), thereby disrupting the bacterial H 2 S‐based self‐defense pathway. Collectively, the in situ activation of photosensitizers via chemiluminescence represents a novel antibacterial strategy that overcomes the intrinsic limitations of light penetration. By enabling precise, localized activation of multiple antibacterial mechanisms, this approach offers a promising therapeutic solution for the treatment of recalcitrant MRSA infections and related diseases, with strong potential for clinical translation.