Ultrasound-Enhanced Mitochondrial Targeting for Synergistic Mitoxantrone-Based Nanotherapy in Triple-Negative Breast Cancer

Mitoxantrone (MTO)-based combination therapies hold great promise in enhancing therapeutic outcomes for aggressive cancers, such as triple-negative breast cancer (TNBC). In this study, we designed a core–shell nanoparticle system (MTO@IR780@BSA-GA-Fe@PLGA, PMIBs) that integrates MTO chemotherapy, sonodynamic therapy (SDT) via IR780, and Fenton reaction-enhanced oxidative stress. The system demonstrated pH-responsive release of therapeutic agents, mitochondrial targeting, and synergistic anticancer effects when combined with ultrasound (US) irradiation. PMIBs significantly enhanced reactive oxygen species (ROS) production, increased mitochondrial damage, and improved apoptosis rates, resulting in a tumor growth inhibition rate far superior to that of conventional treatments. These findings highlight the potential of this US-enhanced nanoplatform in addressing challenges associated with TNBC treatment, offering a highly effective and minimally invasive therapeutic strategy.