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

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. In this study, a rapid method is firstly developed to synthesize unprecedented trimetalic nanozyme (AuMnCu, AMC) with a targeting peptide (AMCc), which exhibits excellent peroxidase-like, catalase-like, and glucose oxidase-like activities. AMCc consumes endogenous H 2 O 2 and produce O 2 , while the released Cu and Mn ions in TME catalyze glucose oxidation reaction to generate H 2 O 2 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 H 2 O 2 . Meanwhile, the reactive oxygen species damage was 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 H 2 O 2 . Further studies depict that the well-designed AMCc exhibit the excellent photothermal performance, and achieve TME-responsive sustainable starvation/photothermal-enhanced chemodynamic synergistic effects in vitro and in vivo. Overall, this work demonstrates a promising approach to design "all-in-one" nanozyme for theranostics by remodeling the TME. This article is protected by copyright. All rights reserved.