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The herpes simplex virus thymidine kinase\/ganciclovir (HSV\u2010TK\/GCV) suicide gene therapy system has shown promise in cancer treatment, but its clinical applicability is limited by off\u2010target cytotoxicity. Here, we developed a\n                    <jats:styled-content>br<\/jats:styled-content>\n                    east c\n                    <jats:styled-content>a<\/jats:styled-content>\n                    ncer\u2010specific\n                    <jats:styled-content>s<\/jats:styled-content>\n                    uicide gene circuit (BRAS) that integrates the screened cancer\u2010specific promoters\n                    <jats:italic>RRM2<\/jats:italic>\n                    and\n                    <jats:italic>MAFK<\/jats:italic>\n                    with a microRNA specific to nontumor cells, utilizing the distinct molecular profiles of tumor and nontumor cells. This multi\u2010input logic gate circuit enables precise, specific expression of HSV\u2010TK in breast cancer cells with hardly expression in normal cell. We show that BRAS selectively induces apoptosis in patient\u2010derived TNBC cells while sparing normal cells. In two orthotopic breast cancer models, BRAS significantly suppressed tumor growth without affecting body weight or general health, underscoring its therapeutic potential. This approach intelligently combines molecular signals from both cancerous and healthy cells to precisely regulate therapeutic gene expression, making it a promising platform for the next\u2010generation cancer therapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202514749","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T16:01:12Z","timestamp":1770220872000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Logic\u2010Gated HSV\u2010TK\/GCV Suicide Gene Circuit for Triple\u2010Negative Breast Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Shasha","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Breast Surgery Tongji Hospital School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Tongji Hospital School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingli","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Tongji Hospital School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Tongji Hospital School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yicheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Tongji Hospital School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijia","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Tongji Hospital School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyun","family":"Yong","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Tongji Hospital School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Medical Technology Shanxi Medical University  Taiyuan Shanxi Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4480-1040","authenticated-orcid":false,"given":"Longliang","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Tongji Hospital School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2118-6647","authenticated-orcid":false,"given":"Meiyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai 411 Hospital China RongTong Medical Healthcare Group Co. Ltd. 411 Hospital School of Medicine Shanghai University  Shanghai China"},{"name":"Chongqing Key Laboratory of Precision Optics Chongqing Institute of East China Normal University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7390-1673","authenticated-orcid":false,"given":"Fengfeng","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Tongji Hospital School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010021\u201000565\u20102"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010021\u201000652\u2010x"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010024\u201002108\u20104"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010023\u201001805\u2010y"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201023\u20100519"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21763"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj\u20102022\u2010071674"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2024.122960"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.16827"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201007\u20101240"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2016.1211640"},{"key":"e_1_2_9_13_1","first-page":"5276","article-title":"Tumor Chemosensitivity Conferred by Inserted Herpes Thymidine Kinase Genes: Paradigm for a Prospective Cancer Control Strategy","volume":"46","author":"Moolten F. 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