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<p>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.</p>

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Combine mitochondrial-targeted gene therapy and chemotherapy to treat triple-negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月29日

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  • Tanvi Varadkar,
  • Zhuoxin Zora Zhou,
  • Jiashuai Zhang,
  • Anusua Sarkar,
  • Zhantao Du,
  • Srijita Chowdhury,
  • Hwayeon Lim,
  • Lufang Zhou,
  • Xiaoguang Margaret Liu

摘要

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.