Boosting Tumor Apoptosis and Ferroptosis with Multienzyme Mimetic Au Single-Atom Nanozymes Engaged in Cascade Catalysis

Nanozyme-based catalytic therapy has garnered much attention in cancer treatment for converting endogenous substrates into reactive oxygen species (ROS), which induce oxidative stress damage in tumors. However, the effectiveness of nanozymes is hindered by the limited availability of these endogenous substrates in the tumor microenvironment. To address this, a novel gold-based single-atom nanozyme (AuSAN), glucose oxidase (GOx, G), and lactate oxidase (LOx, L) are meticulously engineered into a highly ordered biomimetic composite nanozyme M/GLB@AuSAN, forming an interconnected cascade catalysis that catalyzes the carbon sources of tumor into ROS as a sustained antitumor strategy. The loaded GOx and LOx aerobically catalyze glucose and lactate to produce H2O2, which is then rapidly converted into <middle dot>OH, O2 center dot-, and O2 by AuSAN. The generated O2 serves as a positive feedback substrate for further GOx- and LOx-mediated aerobic catalysis, significantly amplifying cascade catalysis, and thereby enhancing ROS accumulation. The abundant intracellular ROS and scarce carbon sources effectively exacerbate protein phosphorylation, lipid peroxidation, and mitochondrial damage, ultimately provoking tumor apoptosis and ferroptosis in vitro and in vivo. Therefore, the integrated design of GOx/LOx/AuSAN provides a promising strategy to combine multiple enzymatic activities, deplete carbon sources, and enhance ROS production, resulting in the suppression of melanoma progression. In this study, a nanozyme/natural enzymes hybrid biomimetic M/GLB@AuSAN composite nanozyme with interconnected cascade catalysis is fabricated for tumor-specific catalytic therapy. M/GLB@AuSAN steers the conversion of glucose and lactate into ROS, involving the cyclic utilization of O2 to maintain high efficiency of entire catalysis, which further promotes ROS-induced apoptosis and ferroptosis. image