Abstract
Triple-negative breast cancer (TNBC) is an aggressive and chemotherapy resistant subtype with high metastatic potential and frequent recurrence after standard treatment. While poly (ADP-ribose) polymerase inhibitors (PARPi) show efficacy in TNBCs with DNA repair deficiencies, only ~ 20% of patients respond, underscoring the need for more effective therapies. Mitochondria, as central regulators of cancer cell survival, present a compelling therapeutic target. Here, we introduce a novel gene-chemotherapy combining our mitochondria-targeted luminoptogenetics technology (cmLumiOpto), which directly disrupts mitochondrial membrane potential and induces cancer cell death, with PARPi to enhance TNBC treatment outcomes. To achieve targeted delivery, we conjugated a high-affinity anti-CD276 monoclonal antibody (mAb) that selectively binds human and mouse TNBCs to an exosome-associated adeno-associated virus (mAb-Exo-AAV). In vitro studies confirmed successful transfection, internalization, and functional expression of cmLumiOpto, leading to significantly enhanced cytotoxicity when combined with PARPi. In vivo, the combination therapy achieved a 95-100% reduction in tumor burden, suppressed patient-derived xenograft growth, and inhibited metastasis in four TNBC mouse models. Post-treatment analyses confirmed mitochondrial depolarization, downregulation of DNA replication, cytokine upregulation, and immune cell infiltration in tumor. These findings highlight the potential of mitochondria-targeted gene therapy combined with chemotherapy as a powerful and innovative strategy for TNBC treatment.