A pH‐responsive Cascade Nano‐Reactor Elevates ROS Generation by Remodeling Biofilm Microenvironment for Enhanced Antibacterial Treatment

Abstract Biofilms are the root of most chronic and persistent infections and pose a significant threat to human health. Reactive oxygen species (ROS) generation platforms have been used to combat biofilm‐associated infections. However, biofilm microenvironments (BME) such as hypoxia and overexpressed antioxidants restrict the efficacy of ROS‐based therapies. To address the problem, this study incorporates calcium peroxide (CaO₂) and berberine (BBR) into Fe and Zn containing bimetal metal–organic frameworks (FZ) to construct a composite ROS nanogenerator (CBFZ), which is able to remodel BME and further promotes ROS generation for enhance biofilm eradication. CBFZ degrades to release CaO₂, Fe³⁺, Fe^2+, and BBR in biofilm, where CaO₂ decomposes into O₂ and H₂O₂ to relieve hypoxia, and Fe³⁺ consumes glutathione (GSH). Subsequently, the remodeled BME boosts the ROS production of the O₂‐dependent BBR‐mediated photodynamic therapy and H₂O₂‐dependent Fe²⁺‐based chemodynamic therapy, and the depleted GSH minimizes ROS scavenging in the meantime, ultimately maintaining a high level of ROS in biofilm. It is demonstrated that CBFZ can effectively eradicate biofilm by killing the embedded bacteria and dispersing the biofilm matrix. Moreover, CBFZ exhibits an outstanding therapeutic effect in a murine model with subcutaneous biofilm infection. Overall, this work offers a propagable strategy to enhance ROS‐based antibiofilm therapy.