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Epigenetic Metal-Organic Framework Nanoagonist Overcomes Triple Defenses to Enable Effective

Ling Lin1,2, Qiaoling Zhang1,2, Xue Liu1

  • 1Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, P. R. China.

Advanced Materials (Deerfield Beach, Fla.)
|February 3, 2026
PubMed

Insights

A novel nanoagonist overcomes platinum-resistant ovarian cancer by restoring immune activation and enhancing chemotherapy. This epigenetic metal-organic framework (MOF) nanoagonist shows strong therapeutic efficacy in preclinical models.

Area of Science:

  • Biomedical Engineering
  • Nanomedicine
  • Cancer Therapy

Background:

  • Platinum-resistant ovarian cancer (PROC) exhibits poor response to chemotherapy and immune evasion via cGAS-STING pathway suppression.
  • Developing novel strategies is crucial to overcome resistance and restore anti-tumor immunity in PROC.

Purpose of the Study:

  • To develop a multifunctional metal-organic framework (MOF) nanoagonist (CMZ-Pt-SA@HA) that overcomes cisplatin resistance and reactivates the immune system in PROC.
  • To investigate the therapeutic efficacy and underlying mechanisms of CMZ-Pt-SA@HA in preclinical PROC models.

Main Methods:

  • Fabrication of CMZ-Pt-SA@HA: Mn-ZIF-8 MOF encapsulating CaO2, co-loaded with cisplatin (CisPt) and SAHA, modified with hyaluronic acid for tumor targeting.
  • Evaluation of CMZ-Pt-SA@HA's multi-pronged attack: epigenetic modification, calcium overload, oxygen release, oxidative stress, and STING pathway activation.
  • Assessment of therapeutic efficacy in subcutaneous and metastatic preclinical PROC models (ID8 and patient-derived xenografts), alone and in combination with anti-PD-L1 therapy.
  • Utilizing Mn2+-based MRI for image-guided therapy.

Main Results:

  • CMZ-Pt-SA@HA effectively downregulates resistance proteins, enhances CisPt-induced DNA damage, and stimulates immune activation by targeting the cGAS-STING pathway.
  • The nanoagonist demonstrated strong therapeutic efficacy in reducing tumor burden and improving outcomes in various preclinical PROC models.
  • Combination therapy with anti-PD-L1 showed enhanced efficacy in ascites metastasis models.
  • MRI capability facilitated image-guided treatment assessment.

Conclusions:

  • CMZ-Pt-SA@HA represents a promising chemo-metalloimmunotherapy strategy for overcoming platinum resistance in ovarian cancer.
  • The multifunctional nanoagonist restores immune surveillance and exhibits significant therapeutic potential for PROC.
  • The developed platform offers a translatable approach for image-guided cancer therapy.
Keywords:
cGAS‐STING pathwaychemo‐metalloimmunotherapyepigenetic reprogrammingplatinum‐resistant ovarian cancertriple defenses

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