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 H₂ O₂ and produce O₂ , while the AMCccatalyzes glucose oxidation reaction to generate H₂ O₂ 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 H₂ O₂ . 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 H₂ O₂ . 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.