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Herein, we developed an epigenetic metal\u2010organic framework (MOF) nanoagonist (CMZ\u2010Pt\u2010SA@HA) that overcomes cisplatin (CisPt) resistance while restoring immune activation. The platform consists of Mn\u2010ZIF\u20108 encapsulating CaO\n                    <jats:sub>2<\/jats:sub>\n                    and co\u2010loaded with CisPt and SAHA (a histone deacetylase inhibitor), then modified with hyaluronic acid to enable tumor targeting and controlled release. CMZ\u2010Pt\u2010SA@HA is multifunctional: SAHA downregulates resistance proteins epigenetically, CaO\n                    <jats:sub>2<\/jats:sub>\n                    triggers calcium overload and oxygen release, and Mn\n                    <jats:sup>2+<\/jats:sup>\n                    \/Zn\n                    <jats:sup>2+<\/jats:sup>\n                    enhances oxidative stress and STING signaling, collectively strengthening chemo\u2010metalloimmunotherapy. These mechanisms intensify CisPt\u2010induced DNA damage and stimulate immune activation. CMZ\u2010Pt\u2010SA@HA applies a three\u2010step \u201cPOP\u201d strategy to overcome PROC's triple defenses: (I) Pre\u2010targeting to enhance DNA\u2010CisPt adducts; (II) On\u2010targeting to block DNA repair; and (III) Post\u2010targeting to induce apoptosis by relieving hypoxia, arresting the cell cycle, damaging mitochondria, and activating cGAS\u2010STING. Whether used alone in subcutaneous tumors in preclinical ID8 and patient\u2010derived xenograft mouse models, or combined with anti\u2010PD\u2010L1 therapy in ascites metastasis models, CMZ\u2010Pt\u2010SA@HA consistently showed strong therapeutic efficacy. Its Mn\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010based magnetic resonance imaging (MRI) capability further supports image\u2010guided therapy and clinical translation.\n                  <\/jats:p>","DOI":"10.1002\/adma.202517286","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T09:23:28Z","timestamp":1770110608000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Epigenetic Metal\u2010Organic Framework Nanoagonist Overcomes Triple Defenses to Enable Effective Chemo\u2010Metalloimmunotherapy in Platinum\u2010Resistant Ovarian Cancer"],"prefix":"10.1002","volume":"38","author":[{"given":"Ling","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine Dongguan Institute of Clinical Cancer Research The Tenth Affiliated Hospital Southern Medical University (Dongguan People's Hospital)  Dongguan P. R. China"},{"name":"Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical Sciences Southern Medical University  Guangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Dongguan Institute of Clinical Cancer Research The Tenth Affiliated Hospital Southern Medical University (Dongguan People's Hospital)  Dongguan P. R. China"},{"name":"Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical Sciences Southern Medical University  Guangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Dongguan Institute of Clinical Cancer Research The Tenth Affiliated Hospital Southern Medical University (Dongguan People's Hospital)  Dongguan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Dongguan Institute of Clinical Cancer Research The Tenth Affiliated Hospital Southern Medical University (Dongguan People's Hospital)  Dongguan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Dongguan Institute of Clinical Cancer Research The Tenth Affiliated Hospital Southern Medical University (Dongguan People's Hospital)  Dongguan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanbo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Dongguan Institute of Clinical Cancer Research The Tenth Affiliated Hospital Southern Medical University (Dongguan People's Hospital)  Dongguan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Dongguan Institute of Clinical Cancer Research The Tenth Affiliated Hospital Southern Medical University (Dongguan People's Hospital)  Dongguan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery The Tenth Affiliated Hospital Southern Medical University (Dongguan People's Hospital)  Dongguan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingchen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Dongguan Institute of Clinical Cancer Research The Tenth Affiliated Hospital Southern Medical University (Dongguan People's Hospital)  Dongguan P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutic Sciences Faculty of Science National University of Singapore  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1688-5558","authenticated-orcid":false,"given":"Zhiqiang","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Dongguan Institute of Clinical Cancer Research The Tenth Affiliated Hospital Southern Medical University (Dongguan People's Hospital)  Dongguan P. R. China"},{"name":"Dongguan Key Laboratory of Innovative Molecular Imaging Dongguan People's Hospital  Dongguan P. R. 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