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

Abstract

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.