Rapid Synthesis of Trimetallic Nanozyme for Sustainable Cascaded Catalytic Therapy via Tumor Microenvironment Remodulation

Abstract Tumor microenvironment (TME)‐responsive nanozyme‐catalyzed cancer therapy shows great potential due to its specificity and efficiency. However, breaking the self‐adaption of tumors and improving the sustainable remodeling TME ability remains a major challenge for developing novel nanozymes. Here, a rapid method is developed first to synthesize unprecedented trimetalic nanozyme (AuMnCu, AMC) with a targeting peptide (AMCc), which exhibits excellent peroxidase‐like, catalase‐like, and glucose oxidase‐like activities. The released Cu and Mn ions in TME consume endogenous H₂O₂ and produce O₂, while the AMCccatalyzes glucose oxidation reaction to generate H₂O₂ and gluconic acid, which achieves the starvation therapy by depleting the energy and enhances the chemodynamic therapy effect by lowering the pH of the TME and producing extra H₂O₂. Meanwhile, the reactive oxygen species damage is amplified, as AMCc can constantly oxidize intracellular reductive glutathione through the cyclic valence alternation of Cu and Mn ions, and the generated Cu⁺ elevate the production of ·OH from H₂O₂. Further studies depict that the well‐designed AMCc exhibits the excellent photothermal performance and achieves TME‐responsive sustainable starvation/photothermal‐enhanced chemodynamic synergistic effects in vitro and in vivo. Overall, a promising approach is demonstrated here to design “all‐in‐one” nanozyme for theranostics by remodeling the TME.