Stepwise Degradable Nanocarriers Enabled Cascade Delivery for Synergistic Cancer Therapy

Abstract Hypoxia‐activated prodrugs have brought new opportunities for safe and effective tumor ablation, but their therapeutic efficacy is limited by insufficient activation in tumor microenvironments. Herein, a novel cascade delivery system with tandem functions by integrating a hypoxia‐activated prodrug (AQ4N) and glucose oxidase (GOx) is designed to improve its efficacy. Innovative yolk–shell organosilica nanoparticles with a tetrasulfide bridged composition, a small‐pore yolk, and a large‐pore shell featuring a shell‐to‐yolk stepwise degradability are constructed as a carrier for AQ4N and GOx, one enzyme that catalyzes the oxidation of glucose to produce hydrogen peroxide. The glutathione (GSH) is depleted by tetrasulfide bond in the framework and induces shell degradation for fast release of GOx, which in turn induces starvation (glucose removal), oxidative cytotoxicity (H 2 O 2 production and GSH depletion), and hypoxia (oxygen consumption). Finally, the hypoxia activates the liberated prodrug AQ4N for chemotherapy. The cascading and synergistic functions including GSH depletion, starvation, oxidative cytotoxicity, and chemotherapy lead to improved performance in tumor inhibition and antimetastasis.