A biomimetic nanozyme platform for spatiotemporally programmed cascade catalysis and potentiated chemodynamic...

Metal-nanozyme-mediated chemodynamic therapy (CDT) has emerged as a promising strategy for the treatment of deep-seated tumors; however, its therapeutic efficacy is often limited by insufficient reactive oxygen species (ROS) generation and poor spatiotemporal control of enzyme-like activity within the tumor microenvironment (TME). Here, we report a biomimetic nanoplatform, CuO@MSN/TH302@GOx@CM (CMTGM), which integrates a programmed multi-enzyme cascade consisting of a copper oxide (CuO) core, a dendritic mesoporous silica (MSN) intermediate shell, the hypoxia-activated prodrug TH302, and surface-conjugated glucose oxidase (GOx). This hierarchical architecture enables stepwise activation and release of distinct enzyme-mimetic functions. Furthermore, CMTGM is cloaked with a homologous tumor cell membrane to enhance tumor-targeting capability. Following internalization of CMTGM into the tumor cells, GOx catalyzes glucose oxidation to generate H₂O₂ and gluconic acid, thereby disrupting tumor metabolism and acidifying the microenvironment, which accelerates MSN degradation and promotes the release of Evofosfamide (TH302) while exposing the CuO core. The Cu²⁺ ions released from the core exert glutathione peroxidase-like activity, depleting intracellular glutathione, and peroxidase-like activity, converting H₂O₂ into highly cytotoxic hydroxyl radicals, thereby amplifying CDT. Meanwhile, GOx-mediated oxygen consumption aggravates hypoxia and activates TH302, which further enhances therapeutic efficacy. This spatiotemporally programmed cascade involving substrate self-supply, responsive degradation, catalytic amplification, and prodrug activation eventually triggers multiple programmed cell death pathways and enhances immunogenic cell death, ultimately eliciting systemic anti-tumor immunity. In both in vitro and in vivo studies, CMTGM demonstrated efficient tumor targeting, robust tumor suppression, and favorable biosafety of in a 4 T1 breast cancer model. This study provides a generalizable strategy for the rational design of programmable catalytic nanomedicines with integrated multifunctionality.