Elaborate Design and Mechanism Insight of Monodispersed AuCuPt Alloy Nanozyme with Promoted Antitumor Activity

Abstract The abrogation of the self-adaptive redox evolution of tumors is promising for improving therapeutic outcomes. In this study, we designed a novel trimetallic alloy nanozyme AuCuPt-PpIX (ACPP), which mimics up to five naturally occurring enzymes—glucose oxidase (GOD), superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and glutathione peroxidase (GPx). Facilitated by these enzyme-mimicking traits, the constructed ACPP nanozymes can not only disrupt the established redox homeostasis in tumors through a series of enzymatic cascade reactions but also achieve cyclic regeneration of the relevant enzyme substrates. Density functional theory (DFT) calculations have theoretically explained the synergistic effect of multi-metallic doping and the possible mechanism of enzymatic catalysis. The doped Cu and Pt sites are conducive to the adsorption, activation, and dissociation of reactant molecules, whereas the Au sites are conducive to desorption, which significantly improves catalytic efficiency via a synergistic effect. Additionally, ACPP nanozymes can improve the effect of protoporphyrin (PpIX)-enabled sonodynamic therapy (SDT) by alleviating hypoxia and initiating ferroptosis by inducing lipid peroxidation (LPO) and inhibiting GPX4 activity, thus achieving multi-modal synergistic therapy. This study presents a typical paradigm to enable the use of multi-metallic alloy nanozymes for the treatment of tumor cells with self-adaptive properties.