Abstract

Hepatocellular carcinoma (HCC) exhibits intratumoral heterogeneity and poor responsiveness to conventional therapies, necessitating strategies that combine high therapeutic potency with minimal systemic toxicity. Arsenic trioxide (AsⅢ) is a potent chemotherapeutic agent for HCC; nevertheless, its application in solid tumors is limited by off-target toxicity and dose-limiting adverse effects. Herein, we report a valence-activated nanozyme platform that enables tumor-confined generation of therapeutically active AsⅢ from low-toxicity arsenate (AsV) for safe and effective HCC treatment. A manganese dioxide-coated arsenate-zinc sulfide core-shell-shell nanozyme (AsV-ZnS@MnO2 NPs) was engineered to undergo pH-responsive disassembly in the mildly acidic tumor microenvironment, resulting in the release of H2S, AsV, and Mn2+. The generated H2S drives the in situ reduction of AsV to AsⅢ, thereby activating arsenic chemotherapy. Simultaneously, Mn2+ catalyzes Fenton-like reactions with endogenous H2O2 to generate hydroxyl radicals (·OH), while the produced AsⅢ further amplifies oxidative stress, leading to enhanced chemodynamic therapy. In addition, Mn2+ serves as a T1-weighted magnetic resonance imaging contrast agent for noninvasive therapeutic monitoring. Through this tightly coupled cascade of arsenic activation, oxidative amplification, and imaging guidance, the nanozyme achieves potent antitumor efficacy with reduced systemic toxicity. This reaction-programmed strategy provides a promising approach for arsenic-based nanomedicine in hepatocellular carcinoma therapy.