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mLumiOpto is a Mitochondrial-Targeted Gene Therapy for Treating Cancer
Cancer Research ( IF 12.5 ) Pub Date : 2024-09-17 , DOI: 10.1158/0008-5472.can-24-0984 Kai Chen 1 , Patrick Ernst 2 , Anusua Sarkar 1 , Seulhee Kim 1 , Yingnan Si 3 , Tanvi Varadkar 1 , Matthew D Ringel 4 , Xiaoguang Liu 1 , Lufang Zhou 1
Cancer Research ( IF 12.5 ) Pub Date : 2024-09-17 , DOI: 10.1158/0008-5472.can-24-0984 Kai Chen 1 , Patrick Ernst 2 , Anusua Sarkar 1 , Seulhee Kim 1 , Yingnan Si 3 , Tanvi Varadkar 1 , Matthew D Ringel 4 , Xiaoguang Liu 1 , Lufang Zhou 1
Affiliation
Mitochondria are important in various aspects of cancer development and progression. Targeting mitochondria in cancer cells holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we developed mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial membrane (IMM) potential and induce cancer cell death. The therapeutic approach included synthesis of a blue light-gated cationic channelrhodopsin (CoChR) in the IMM and co-expression of a blue bioluminescence-emitting nanoluciferase (NLuc) in the cytosol of the same cells. The mLumiOpto genes were selectively delivered to cancer cells in vivo by an adeno-associated virus (AAV) carrying a cancer-specific promoter or cancer-targeted monoclonal antibody-tagged exosome-associated AAV (mAb-Exo-AAV). Induction with NLuc luciferin elicited robust endogenous bioluminescence, which activated CoChR, triggering cancer cell mitochondrial depolarization and subsequent cell death. Importantly, mLumiOpto demonstrated remarkable efficacy in reducing tumor burden and killing tumor cells in glioblastoma and triple-negative breast cancer xenograft mouse models. Furthermore, the approach induced an anti-tumor immune response, increasing infiltration of dendritic cells and CD8+ T cells in the tumor microenvironment. These findings establish mLumiOpto as a promising therapeutic strategy by targeting cancer cell mitochondria in vivo.
更新日期：2024-09-17
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