Phage-Ce6-Manganese Dioxide Nanocomposite-Mediated Photodynamic, Photothermal, and Chemodynamic Therapies to Eliminate Biofilms and Improve Wound Healing

Biofilms have become one of the fundamental issues for chronic infections, while traditional therapies are often ineffective in removing quiescent (persister) cells from biofilms, resulting in a variety of implant-related or nosocomial infections. Recently, bacteriophage (phage) therapy has reflourished in research and clinical trials. However, phage therapy alone manifested many intrinsic defects, including poor biofilm penetration, incomplete clearance of quiescent cells, etc. In this study, a phage-Chlorin e6 (Ce6)-manganese dioxide nanocomposite (PCM) was constructed by mild biomineralization. The results demonstrated that PCM contained both the vigorous activities of host bacterial targeting and efficient delivery of Ce6 to penetrate the biofilm. Assisted with NIR irradiation, robust reactive oxygen species (ROS) was triggered within the biofilm. In the weak acidic and GSH-rich infection niche, PCM was degraded into ultra-small nanosheets, endowing PCM with moderate photothermal therapy (PTT) effects and considerable Mn2+ release, thus exerting strong chemodynamic therapy (CDT) effects in situ. In vivo application demonstrated that the combination of PCM application and NIR irradiation strikingly reduced the pathogen loading, activated innate and adaptive immunity, promoted neocollagen rearrangement, and attenuated cicatricial tissue formation. Our research may pave a new way for bacterial treatment, biofilm-related infections, and other diseases caused by bacteria.