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

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 CaO₂ 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, CaO₂ triggers calcium overload and oxygen release, and Mn²⁺/Zn²⁺ 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 Mn²⁺-based magnetic resonance imaging (MRI) capability further supports image-guided therapy and clinical translation.