Microenvironment-Activated Fe-MOF Nanoplatform Enables Controlled Doxorubicin Release and Ferroptosis-Associated Oxidative Damage in MCF-7 Breast Cancer Cells

Miao Yuan,1,* Yang Wu,1,* Jing Zheng,1,* Chaoran Wang,1 Jiarong Wang,1 Yifan Zheng,1 Yunqi Wang,1 Baiqi Wang1,2 1Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin, 300070, People’s Republic of China; 2National Demonstration Center for Experimental Preventive Medicine Education (Tianjin Medical University), Tianjin, 300070, People’s Republic of China*These authors contributed equally to this workCorrespondence: Baiqi Wang, Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, No. 22, Qixiangtai Road, Heping Dist, Tianjin, 300070, People’s Republic of China, Tel +86-22-83336630, Fax +86-22-83336603, Email [email protected]: Doxorubicin (DOX) is a cornerstone chemotherapeutic for breast cancer; however, its clinical efficacy is limited by inefficient intracellular delivery and dose-limiting off-target toxicity. Microenvironment-responsive nanoplatforms offer a promising strategy to enhance tumor selectivity and therapeutic performance.Methods: A core–shell nanosystem (UTMD) was constructed by coating an NH2-MIL-88B(Fe) metal–organic framework (Fe-MOF) shell onto a UCNP@TiO2 scaffold. The Fe-MOF shell was designed as a dual pH- and glutathione (GSH)-responsive gatekeeper for controlled DOX release. The nanosystem was characterized for structural features, drug loading, and stimulus-responsive release behavior. Cellular uptake, intracellular trafficking, cytotoxicity, and redox-related biochemical changes were evaluated in MCF-7 breast cancer cells and HEK-293 normal cells.Results: UTMD achieved high encapsulation efficiency (86.5%) and maintained stability under physiological conditions, while enabling accelerated DOX release in acidic and reducing environments. The nanosystem enhanced cellular internalization and promoted nuclear accumulation of DOX in MCF-7 cells. In addition, UTMD induced significant intracellular redox imbalance, characterized by GSH depletion, increased reactive oxygen species levels, and elevated lipid peroxidation, accompanied by mitochondrial membrane potential depolarization. These changes are consistent with ferroptosis-associated oxidative damage. Compared with free DOX, UTMD exhibited improved cytocompatibility in HEK-293 cells.Discussion: The Fe-MOF shell functions as a microenvironment-responsive gatekeeper that coordinates controlled drug release with iron-mediated oxidative stress. This integrated design links chemotherapy with ferroptosis-associated mechanisms, improving therapeutic selectivity and mechanistic interpretability.Conclusion: UTMD represents a microenvironment-activated nanoplatform that enables controlled DOX delivery and ferroptosis-associated oxidative damage. This strategy enhances antitumor efficacy while reducing off-target toxicity, offering potential for improved breast cancer therapy. On the left, UTMD is shown with enhanced internalization into a cell. Inside the cell, acidic pH and high GSH lead to Fe-MOF degradation and triggered DOX release. This results in MCF-7 cell damage, labeled as the chemo-ferroptosis effect and improved cytocompatibility in HEH-293 cells. Below, a diagram shows ferroptosis-associated oxidative damage. GSH decreases, leading to increased ROS, lipid peroxidation and mitochondrial depolarization. The process is labeled as activation-gated chemo-ferroptosis therapy.Activation-gated chemo-ferroptosis boosts cell uptake, damage and oxidative stress.Keywords: Fe-based metal–organic framework, pH/GSH-responsive nanoplatform, doxorubicin delivery, ferroptosis, lipid peroxidation, breast cancer