Copper-Based Metal-Organic Framework Nanoplatform for miRNA Delivery: Synergistic Antitumor Therapy

Abstract

Maopu Tu,1,* Xiaoyu Deng,2,* Bin Lai,1,* Jiao Liu,1 Yingzhou Tao,2 Shaohua Xu,2 Xiaodong Li,1 Xiaoqiang Niu,1 Zhixin Li,3 Jiahui Huang,2 Jiaxin Li,2 Shengxun Mao,1 Xi Ouyang,1 Jiaqing Cao1 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China; 2Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, 330004, People’s Republic of China; 3Institute for Advanced Study, Research Center for Differentiation and Development of TCM Basic Theory, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, 330004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiaqing Cao, Email [email protected] Xi Ouyang, Email [email protected]: 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 Cu2+. The increased intracellular Cu2+ 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. Keywords: chemodynamic therapy, microRNA, cuproptosis, gene therapy, nanoparticles, metal-organic frameworks

Keywords

• chemodynamic therapy
• microRNA
• cuproptosis
• gene therapy
• nanoparticles
• metal-organic frameworks