Abstract: Bacterial biofilms, especially those caused by multidrug-resistant bacteria, have emerged as one of the greatest dangers to global public health. The acceleration of antimicrobial resistance to conventional antibiotics and the severe lack of new drugs necessitates the development of novel agents for biofilm eradication. Photodynamic therapy (PDT) is a promising non-antibiotic method for treating bacterial infections. However, its application in biofilm eradication is hampered by the hypoxic microenvironment of biofilms and the physical protection of extracellular polymeric substances. In this study, we develop a composite nanoplatform with oxygen (O₂) self-supplying and heat-sensitizing capabilities to improve the PDT efficacy against biofilms. CaO₂/ICG@PDA nanoparticles (CIP NPs) are fabricated by combining calcium peroxide (CaO₂) with the photosensitizer indocyanine green (ICG) via electrostatic interactions, followed by coating with polydopamine (PDA). The CIP NPs can gradually generate O₂ in response to the acidic microenvironment of the biofilm, thereby alleviating its hypoxic state. Under near-infrared (NIR) irradiation, the nanoplatform converts O₂ into a significant amount of singlet oxygen (¹O₂) and heat to eradicate biofilm. The generated heat enhances the release of O₂, accelerates the generation of ¹O₂ in PDT, increases cell membrane permeability, and increases bacterial sensitivity to ¹O₂. This nanoplatform significantly improves the efficacy of PDT in eradicating biofilm-dwelling bacteria without fostering drug resistance. Experiments on biofilm eradication demonstrate that this nanoplatform can eradicate over 99.9999% of methicillin-resistant Staphylococcus aureus (MRSA) biofilms under 5-min NIR irradiation. Notably, these integrated advantages enable the system to promote the healing of MRSA biofilm-infected wounds with negligible toxicity in vivo, indicating great promise for overcoming the obstacles associated with bacterial biofilm eradication.

Key words: Bacterial biofilm, Multidrug-resistant bacteria, Photodynamic therapy, Oxygen supplying, Photothermal therapy