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While poly (ADP-ribose) polymerase inhibitors (PARPi) show efficacy in TNBCs with DNA repair deficiencies, only\u2009~\u200920% 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\u2013100% 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.<\/jats:p>","DOI":"10.1186\/s13046-025-03572-8","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T16:29:30Z","timestamp":1767025770000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Combine mitochondrial-targeted gene therapy and chemotherapy to treat triple-negative breast cancer"],"prefix":"10.1186","volume":"44","author":[{"given":"Tanvi","family":"Varadkar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoxin Zora","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiashuai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anusua","family":"Sarkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhantao","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srijita","family":"Chowdhury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwayeon","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lufang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoguang Margaret","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"issue":"8","key":"3572_CR1","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1200\/JCO.2007.14.4147","volume":"26","author":"C Liedtke","year":"2008","unstructured":"Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, et al. 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PubMed PMID: 39186778; PMCID: PMC11565169 the study, as well as a patent for PCT\/US2024\/037838 pending and a patent for PCT\/US2024\/037844 pending. X.M. Liu reports grants from NIH and Department of Defense and nonfinancial support from the Ohio State University during the conduct of the study, as well as a patent for PCT\/US2024\/037838 pending and a patent for PCT\/US2024\/037844 pending. No disclosures were reported by the other authors.","DOI":"10.1158\/0008-5472.CAN-23-4099"},{"issue":"4","key":"3572_CR32","first-page":"197","volume":"117","author":"PE N","year":"2019","unstructured":"N PE, L Z. Precisely control mitochondrial membrane potential with light to manipulate cell fate decisions. 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Patent in protection of the anti-CD276 monoclonal antibody (PCT\/US2024\/037844 \u201cChimeric antibody compositions and methods of use thereof\u201d) was licensed by BiFormyxBio. The corresponding author X. Margaret Liu serves as consultant with equity in BiFormyxBio. The authors declare no other competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"328"}}