cmLumiOpto gene therapy in combination with chemotherapy to treat triple negative breast cancer.

Triple-negative breast cancer (TNBC) is aggressive, resistant to chemotherapy, and prone to recurrence. While PARP inhibitors (PARPi) help some patients, most do not respond. We developed a novel therapy combining mitochondria-targeted luminoptogenetics (cmLumiOpto) with PARPi to enhance treatment. Delivered via an anti-CD276 monoclonal antibody-conjugated exosome-AAV (mAb-Exo-AAV), cmLumiOpto disrupts mitochondrial membrane potential, inducing cancer cell death. In vitro, the combination increased cytotoxicity; in vivo, it reduced tumor burden by 95–100%, suppressed xenograft growth, and blocked metastasis in TNBC models. Mechanistic studies showed mitochondrial depolarization, DNA damage, cytokine release, and immune infiltration, highlighting a promising strategy for TNBC therapy. The mechanism of action was further explained through bulk RNA sequencing post-treatment. These findings highlight the therapeutic potential of our cmLumiOpto gene therapy for treatment of triple negative breast cancers. Overall design: Metastasized 4t1 tumour cells were harvested from the lungs of BALB/cJ mice after three weeks of treatment with cmLumiOpto gene therapy in combination with PARPi.Total RNA was extracted from the harvested tumour cells using the RNeasy Plus Mini Kit (Qiagen, Germantown, MD, USA). Bulk RNA sequencing with cDNA library construction were performed at Novogene America (Sacramento, CA, USA) using the Illumina HiSeq™ X Ten platform.