Engineering Magnesium Oxide as a Mitochondrial Electron Transport Chain Inhibitor for Enhanced Photodynamic Therapy in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options due to its resistance to conventional targeted therapies. TNBC cells heavily rely on oxidative phosphorylation (OXPHOS), making mitochondrial electron transport chain (ETC) inhibition a promising therapeutic approach. However, existing ETC inhibitors pose severe cytotoxicity risks, highlighting the need for biocompatible alternatives. In this study, we develop an MgO-ICG suspension (MgO-ICG@S), utilizing magnesium oxide (MgO), biocompatible pharmaceutical excipients that are already in widespread use as both an ETC-blocking agent and a drug carrier for the photosensitizer indocyanine green (ICG). This approach enables a bidirectional ETC blockade by disrupting ETC electronic transmission and functionality while inducing a unique mitochondria-targeted drug delivery effect. Additionally, laser irradiation activates ICG, generating reactive oxygen species (ROS) that further sensitize tumor cells to ETC inhibition. The combination of ETC blockade and photodynamic therapy (PDT) creates a synergistic cycle of oxidative damage, amplifying antitumor effects and significantly improving therapeutic outcomes. This study offers a promising strategy for effective, targeted TNBC treatment and provides valuable insights into the development of biocompatible ETC-blocking agents for clinical applications.