Tannic Acid-Fe-Functionalized Mesoporous Polydopamine Nanoplatform for Synergistic NO/Calcium Overload-Enhanced Ferroptosis and Photothermal Therapy in Breast Cancer

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation and redox imbalance, has emerged as a promising strategy for treating drug-resistant cancers. However, its therapeutic efficacy is often limited by the antioxidant-rich tumor microenvironment (TME), which inhibits reactive oxygen species (ROS) accumulation. In this study, we introduced a tumor-responsive nanoplatform (MLCT) designed to synergistically amplify ferroptosis through a combination of iron catalysis, calcium overload, nitric oxide (NO) release, and photothermal stimulation. The MLCT platform consisted of mesoporous polydopamine (MPDA), calcium peroxide (CaO₂), l-arginine (LA), and a tannic acid-Fe³⁺ (TA-Fe) shell, facilitating TME-responsive release of therapeutic agents. <i>In vitro</i>, MLCT effectively depleted glutathione (GSH) and sustained NO generation, resulting in elevated ROS levels and mitochondrial dysfunction. Additionally, upon near-infrared (NIR) irradiation, localized hyperthermia further potentiated ferroptotic activity. <i>In vivo</i>, MLCT combined with NIR treatment resulted in an 86.34% reduction in tumor growth, with minimal systemic toxicity. These results highlighted the potential of MLCT as a precision-engineered ferroptosis platform for enhanced cancer therapy.