A biodegradable self-cascading copper-based nanozyme for augmented cancer catalytic therapy and cuproptosis.

Nanozyme-mediated catalytic therapy is a promising and potent approach for tumor treatment; however, its therapeutic efficiency is limited by insufficient HO and excess glutathione (GSH) within the complex tumor microenvironment. Herein, we propose a self-cascading nanozyme strategy that self-supplies HO, consumes GSH, and induces cuproptosis to address these challenges. This design features a triphenylphosphine-functionalized copper-doped mesoporous silica nanoplatform (denoted as DCM) that exhibits multi-enzymatic activity, degradability, and mitochondrial targeting capacity. In this system, DCM can initiate a cascade catalytic reaction for the self-supply of HO by leveraging its cascaded oxidase- and superoxide dismutase-mimicking properties. DCM induces long-lasting catalytic therapy by continuously generating hydroxyl radicals by catalyzing the generated HO via its peroxidase-mimicking capacity. In addition, excessive endogenous GSH can be consumed by Cu(II) in DCM, further amplifying oxidative stress in tumor cells. Moreover, DCM can degrade and release Cu ions under an acidic tumor microenvironment, reducing its potential long-term biotoxicity and initiating cuproptosis through the accumulation of released Cu ions in the mitochondria. GSH depletion further promotes Cu(I) overload in mitochondria, enhancing cuproptosis. This study introduces a novel paradigm for synergistic cuproptosis and nanocatalytic therapy against tumors through the rational design of degradable cascade catalytic nanozymes.