A Photo‐Therapeutic Nanocomposite with Bio‐Responsive Oxygen Self‐Supplying Combats Biofilm Infections and Inflammation from Drug‐Resistant Bacteria

Abstract The use of non‐antibiotic strategies to combat refractory drug‐resistant bacterial infections, especially biofilms and accompanying inflammation, has recently aroused widespread interest. Herein, a photo‐therapeutic nanocomposite with bio‐responsive oxygen (O 2 ) self‐supplying is introduced by integrating manganese dioxide (MnO 2 ) nanozymes onto photosensitizer (indocyanine green, ICG)‐loaded mesoporous polydopamine nanoparticles (MPDA), namely MI‐MPDA NPs. MI‐MPDA can activate O 2 generation in the infection microenvironment, thereby effectively alleviating biofilm hypoxia. Under near‐infrared light (NIR) irradiation, continuous O 2 supplying further boosts the level of singlet oxygen ( 1 O 2 ), enabling robust biofilm elimination through O 2 ‐potentiated photodynamic/photothermal therapy. Interestingly, MI‐MPDA down‐regulates the factor expression of inflammatory signaling pathways through MnO 2 ‐mediated reactive oxygen species scavenging, which ameliorates the inflammatory condition. Meanwhile, O 2 supplying prevents the M1‐phenotype switch of macrophages from the overexpression of hypoxia‐inducible factor‐1 α (HIF‐1 α ), thereby prompting macrophage reprogramming toward pro‐regenerative M2‐phenotype. In the mouse models of subcutaneous implant‐associated infection caused by methicillin‐resistant Staphylococcus aureus (MRSA) biofilms and burn infection caused by Pseudomonas aeruginosa biofilms, NIR‐irradiated MI‐MPDA not only effectively eliminates the formed biofilms, but also alleviates the oxidative stress and accompanying inflammation, and drives the cascade reaction of immunomodulation‐wound healing. Overall, this O 2 ‐potentiated photo‐therapeutic strategy provides a reliable tool for combating biofilm infections and inflammation from drug‐resistant bacteria.