Glucose oxidase-loaded supramolecular nanocatalyst for nitric oxide and chemodynamic synergistic therapy via in situ cascade reactions.

Nitric oxide (NO) induces apoptosis in cancer cells at high concentrations, which is a promising modality in tumor treatment. However, the short half-life and limited action radius severely impede its therapeutic efficacy. Chemodynamic therapy (CDT) exhibits a potent ability for tumor ablation through in situ generation of hydroxyl radicals (•OH). Regrettably, the limited availability of H2O2 and the insufficient acidity within the tumor impair the substantial •OH production. Herein, we fabricate a novel supramolecular nanocatalyst (GOx@FcNPs) for NO and CDT synergistic treatment. GOx@FcNPs can effectively accumulate in cancer cells, trigger continuous cascade reactions that elevate intracellular acidity and amounts of H2O2, and produce massive NO and •OH, which can further react to yield more cytotoxic peroxynitrite (ONOO-), resulting in a synergistic enhancement effect. Antitumor mechanisms revealed that GOx@FcNPs simultaneously activate both ferroptosis and apoptosis pathways. GOx@FcNPs possessed a remarkable suppressive effect on the invasion and migration of cancer cells via down-regulation of hypoxia-inducible factor 1α (HIF-1α) expression and inhibition of ATP production. In vivo antitumor investigations confirmed that GOx@FcNPs exhibit a strong inhibitory effect on tumor growth and satisfactory biocompatibility. This work presents a valuable strategy for overcoming the inherent limitations of single treatments to develop synergistic treatment modalities.