Abstract
Breast cancer is one of the most common gynecological malignancies and poses a severe health risk to women. In recent years, ferroptosis therapy has been considered a promising therapeutic strategy for breast cancer by promoting intracellular reactive oxygen species (ROS) production and lipid peroxidation (LPO) accumulation. However, insufficient intracellular ROS levels and suboptimal drug accumulation within breast cancer lesions hinder the efficacy of ferroptosis as a single oncological treatment modality. In this study, we developed a self-targeting biomineralized apoferritin-based nanovector, encapsulating the ferroptosis inducer dihydroartemisinin (DHA), to create a synergistic antitumor nano-platform (Ca/DHA@AFn) capable of achieving dual-mode calcicoptosis and ferroptosis therapy. The Ca/DHA@AFn nanoparticles exhibited uniform distribution, with an average particle size of approximately 20 nm and a drug loading efficiency of 2.32%. MTT assay results demonstrated that Ca/DHA@AFn significantly decreased the viability of 4T1 cells compared to the controls (DHA, Ca@AFn, and DHA@AFn), indicating enhanced therapeutic efficacy. In vivo experiments in mice revealed that Ca/DHA@AFn nanoparticles, through combined calcicoptosis/ferroptosis induction, exhibited superior synergistic antitumor effects compared to single-modality treatments, significantly extending survival and demonstrating high biocompatibility. This study introduces a novel and safe biomineralized apoferritin-based nano-platform leveraging calcicoptosis/ferroptosis dual therapy, showing strong antitumor efficacy against breast cancer cells and presenting a promising strategy for breast cancer treatment.