Glioblastoma (GBM) is a highly aggressive brain tumor with limited therapeutic options and a five-year survival rate below 10%. We developed a cancer-selective mitochondrial luminoptogenetic gene therapy (cmLumiOpto) to disrupt mitochondrial function and induce direct tumor cell death. The therapeutic gene was delivered via recombinant adeno-associated virus (rAAV) that is produced in stirred-tank bioreactor and purified with ion-exchange liquid chromatography. The AAV delivered cmLumiOpto showed high transduction efficiency, functional gene expression, and cytotoxicity across multiple GBM cell lines. In intracranial GBM xenograft models, cmLumiOpto effectively suppressed or blocked tumor growth and extended survival. To further enhance therapeutic efficacy, we combined cmLumiOpto with antibody-drug conjugate (ADC) aiming to clear the GBM cells and stop recurrence with the synergistic anti-tumor mechanisms. The success of this study could offer a new treatment strategy for GBM treatment.
