The use of nonâantibiotic strategies to combat refractory drugâresistant bacterial infections, especially biofilms and accompanying inflammation, has recently aroused widespread interest. Herein, a photoâtherapeutic nanocomposite with bioâresponsive oxygen (O2) selfâsupplying is introduced by integrating manganese dioxide (MnO2) nanozymes onto photosensitizer (indocyanine green, ICG)âloaded mesoporous polydopamine nanoparticles (MPDA), namely MIâMPDA NPs. MIâMPDA can activate O2 generation in the infection microenvironment, thereby effectively alleviating biofilm hypoxia. Under nearâinfrared light (NIR) irradiation, continuous O2 supplying further boosts the level of singlet oxygen (1O2), enabling robust biofilm elimination through O2âpotentiated photodynamic/photothermal therapy. Interestingly, MIâMPDA downâregulates the factor expression of inflammatory signaling pathways through MnO2âmediated reactive oxygen species scavenging, which ameliorates the inflammatory condition. Meanwhile, O2 supplying prevents the M1âphenotype switch of macrophages from the overexpression of hypoxiaâinducible factorâ1α (HIFâ1α), thereby prompting macrophage reprogramming toward proâregenerative M2âphenotype. In the mouse models of subcutaneous implantâassociated infection caused by methicillinâresistant Staphylococcus aureus (MRSA) biofilms and burn infection caused by Pseudomonas aeruginosa biofilms, NIRâirradiated MIâMPDA not only effectively eliminates the formed biofilms, but also alleviates the oxidative stress and accompanying inflammation, and drives the cascade reaction of immunomodulationâwound healing. Overall, this O2âpotentiated photoâtherapeutic strategy provides a reliable tool for combating biofilm infections and inflammation from drugâresistant bacteria.