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Here, we report the development and characterization of dual aptamer\u2010based PROTACs targeting SET domain bifurcated histone lysine methyltransferase 1 (SETDB1), a key epigenetic regulator implicated in breast cancer progression, drug resistance, and tumor immune evasion.\u00a0Using the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) process, we identified a high\u2010affinity single\u2010stranded DNA (ssDNA) aptamer against SETDB1. This aptamer was conjugated to the nucleolin\u2010targeting aptamer\u00a0AS1411, generating a single\u2010strand PROTAC (AP\u2010SETDB1\u2010S6A) and a partial double\u2010strand PROTAC (AP\u2010SETDB1\u2010D2), both of which exhibit good serum stability. These two PROTACs directly penetrate breast cancer cells and effectively recruit the E3 ligase mouse double minute 2 homolog (MDM2) to SETDB1, inducing proteasome\u2010dependent degradation of SETDB1. Functional assays demonstrated that both AP\u2010SETDB1\u2010S6A and AP\u2010SETDB1\u2010D2 significantly inhibit\u00a0breast cancer cell proliferation and migration,\u00a0and\u00a0resensitize\u00a0drug\u2010resistant breast cancer cells to tamoxifen. Notably,\u00a0they\u00a0further\u00a0enhance the\u00a0cytotoxic activity of\u00a0CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells against breast cancer cells and directly target breast cancer cells to suppress tumor growth\u00a0in vivo. This study establishes dual aptamers\u2010based PROTACs targeting SETDB1, offering effective therapeutic strategies for breast cancer treatment.\n                  <\/jats:p>","DOI":"10.1002\/advs.202521159","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T15:18:16Z","timestamp":1767799096000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Dual Aptamers\u2010Based SETDB1 PROTACs as Effective Anti\u2010Tumor Strategies for Breast Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Yanxuan","family":"Guo","sequence":"first","affiliation":[{"name":"The Province and Ministry Co\u2010Sponsored Collaborative Innovation Center for Medical Epigenetics State Key Laboratory of Experimental Hematology Key Laboratory of Breast Cancer Prevention and Therapy (Tianjin Medical University) Ministry of Education Key Laboratory of Immune Microenvironment and Disease (Tianjin Medical University) Ministry of Education Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingge","family":"Lv","sequence":"additional","affiliation":[{"name":"The Province and Ministry Co\u2010Sponsored Collaborative Innovation Center for Medical Epigenetics State Key Laboratory of Experimental Hematology Key Laboratory of Breast Cancer Prevention and Therapy (Tianjin Medical University) Ministry of Education Key Laboratory of Immune Microenvironment and Disease (Tianjin Medical University) Ministry of Education Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyu","family":"Huang","sequence":"additional","affiliation":[{"name":"The Province and Ministry Co\u2010Sponsored Collaborative Innovation Center for Medical Epigenetics State Key Laboratory of Experimental Hematology Key Laboratory of Breast Cancer Prevention and Therapy (Tianjin Medical University) Ministry of Education Key Laboratory of Immune Microenvironment and Disease (Tianjin Medical University) Ministry of Education Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"The Province and Ministry Co\u2010Sponsored Collaborative Innovation Center for Medical Epigenetics State Key Laboratory of Experimental Hematology Key Laboratory of Breast Cancer Prevention and Therapy (Tianjin Medical University) Ministry of Education Key Laboratory of Immune Microenvironment and Disease (Tianjin Medical University) Ministry of Education Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Hangzhou Institute of Medicine Chinese Academy of Sciences  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Lan","sequence":"additional","affiliation":[{"name":"The Province and Ministry Co\u2010Sponsored Collaborative Innovation Center for Medical Epigenetics State Key Laboratory of Experimental Hematology Key Laboratory of Breast Cancer Prevention and Therapy (Tianjin Medical University) Ministry of Education Key Laboratory of Immune Microenvironment and Disease (Tianjin Medical University) Ministry of Education Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Medical University  Tianjin 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