Abstract
BACKGROUND: Chemodynamic therapy (CDT) is a promising antitumor strategy that damages tumor cells by generating reactive oxygen species (ROS) to induce oxidative stress. However, antioxidant mechanisms in tumor cells greatly reduce CDT efficacy. METHODS: We propose using MOF-199 nanoparticles (NPs) with tumor microenvironment responsiveness as a carrier for miR-4521 to construct miR-4521@MOF-199 for cancer treatment. Polyacrylamide gel electrophoresis evaluated MOF-199's loading and protective capacity for miR-4521. In vitro and in vivo experiments assessed the system's antitumor effect and biosafety, with mechanisms explored. RESULTS: The miR-4521@MOF-199 NPs effectively protected and delivered miR-4521 to tumor cells. Within high-glutathione (GSH) tumor microenvironments, NP degradation released both miR-4521 and Cu(2+). The increased intracellular Cu(2+) triggered tumor cell apoptosis via ROS-mediated CDT while activating cuproptosis through proteotoxic stress. Concurrently, miR-4521 disrupts the oxidative stress defense mechanisms of tumor cells by inhibiting FOXM1 expression, thereby enhancing the efficacy of CDT. Furthermore, the silencing of FOXM1 can further impede tumor progression through gene regulatory mechanisms. Experimental results demonstrate that miR-4521@MOF-199 exhibits potent antitumor efficacy and high biocompatibility via synergistic CDT, gene therapy, and cuproptosis. CONCLUSION: This multifunctional nanosystem exhibits potent antitumor effects and low toxicity, providing a promising research direction for multimodal combinatorial cancer therapy based on CDT.