Abstract

The unique tumor microenvironment provides unique opportunities for the chemodynamic therapy (CDT), but the efficacy of CDT is often limited by insufficient catalytic efficiency and low endogenous hydrogen peroxide (H 2 O 2 ) concentrations. To address these challenges, we developed a series of glutathione (GSH)-responsive trimetallic nanoscale metal-organic frameworks (nMOF), denoted SMCZ, loaded with doxorubicin (DOX) and surface-modified with hyaluronic acid (HA) to construct a targeted therapeutic platform (SMCZ@DOX-HA). SMCZ@DOX-HA enabled HA-mediated tumor targeting and GSH-triggered release of therapeutic components, wherein DOX induced chemotherapy and enhanced intracellular H 2 O 2 production, while synergistically acting Mn 2+ /Cu + ions efficiently convert H 2 O 2 into toxic •OH and deplete GSH to reinforce CDT and remodel the tumor microenvironment (TME). Additionally, Zn 2+ exacerbated oxidative stress by disrupting mitochondrial function, thereby sensitizing cancer cells to the cytotoxic effects of both DOX and the generated •OH. Consequently, the developed SMCZ@DOX-HA demonstrated potent tumor suppression in vivo with minimal systemic toxicity. This efficacy was driven by a synergistic mechanism combining chemotherapy and reinforced CDT, with Zn 2+ -induced mitochondrial dysfunction serving as a critical potentiating component.