Oxygen‐Immunomodulated Nanocatalysts Enhance Anti‐Infection by Trained Immunity

Abstract Biofilm infection microenvironment (BIM) in orthopedic implant‐associated infections forms a robust barrier that resists antimicrobial agents and evades the host's immune system, yet there are currently limited effective targeted therapies against the characteristics of the BIM. Here, an emerging nanocatalytic immunotherapy strategy is proposed for treatment based on microenvironmental oxygen regulation. It is reported that the light‐activated oxygen immune regulators (LAOIR) can effectively target and disrupt biofilms in the initial phase of phototherapy by generating singlet oxygen (¹O₂). The LAOIR‐induced hypoxic microenvironment prolongs neutrophil lifespan and mitigates the immune tolerance induced by lipoteichoic acid (LTA) caused by killed bacteria. As the biofilm disintegrates and oxygen recovers, the neutrophil “immune switch” is triggered, and neutrophils are exhibited enhanced bactericidal activity during immune training with LTA exposure, such as NETosis and phagocytosis. Meanwhile, LAOIR therapy mediates neutrophils to express increased levels of proinflammatory cytokines IL‐6, IL‐1β, and the chemokine receptors CCR2 and CXCR2, promoting immune recruitment and resulting in a more robust therapeutic effect compared to vancomycin. In vitro and in vivo experiments have demonstrated that LAOIR outperform clinical antibiotics in the treatment of bacterial infections, providing direct evidence for the utilization of oxygen‐modulated immune response strategies in the treatment of orthopedic implants.