Epigenetic Metal‐Organic Framework Nanoagonist Overcomes Triple Defenses to Enable Effective Chemo‐Metalloimmunotherapy in Platinum‐Resistant Ovarian Cancer

ABSTRACT Platinum‐resistant ovarian cancer (PROC) responds poorly to platinum chemotherapy and evades immune surveillance by suppressing the cGAS‐STING pathway, leading to poor outcomes. Herein, we developed an epigenetic metal‐organic framework (MOF) nanoagonist (CMZ‐Pt‐SA@HA) that overcomes cisplatin (CisPt) resistance while restoring immune activation. The platform consists of Mn‐ZIF‐8 encapsulating CaO 2 and co‐loaded with CisPt and SAHA (a histone deacetylase inhibitor), then modified with hyaluronic acid to enable tumor targeting and controlled release. CMZ‐Pt‐SA@HA is multifunctional: SAHA downregulates resistance proteins epigenetically, CaO 2 triggers calcium overload and oxygen release, and Mn 2+ /Zn 2+ enhances oxidative stress and STING signaling, collectively strengthening chemo‐metalloimmunotherapy. These mechanisms intensify CisPt‐induced DNA damage and stimulate immune activation. CMZ‐Pt‐SA@HA applies a three‐step “POP” strategy to overcome PROC's triple defenses: (I) Pre‐targeting to enhance DNA‐CisPt adducts; (II) On‐targeting to block DNA repair; and (III) Post‐targeting to induce apoptosis by relieving hypoxia, arresting the cell cycle, damaging mitochondria, and activating cGAS‐STING. Whether used alone in subcutaneous tumors in preclinical ID8 and patient‐derived xenograft mouse models, or combined with anti‐PD‐L1 therapy in ascites metastasis models, CMZ‐Pt‐SA@HA consistently showed strong therapeutic efficacy. Its Mn 2+ ‐based magnetic resonance imaging (MRI) capability further supports image‐guided therapy and clinical translation.