Vol. 1 No. 1 (2025)

Articles

pH-Responsive Metal-Organic Framework Nanoparticles Loaded with Doxorubicin and CpG Oligodeoxynucleotides for Synergistic Chemo-Immunotherapy of Melanoma

Published 2025-08-13

  • Jonathan R. Miller
    • ,
  • Prof. Dr. Andreas K. Fischer

Jonathan R. Miller
Department of Nanomedicine and Drug Delivery, Faculty of Pharmacy and Biochemistry, Ludwig-MaximiliansUniversität München, Munich, 81377, Germany

Prof. Dr. Andreas K. Fischer
Department of Oncology and Hematology, University Hospital Munich (LMU), Munich, 81377, Germany

Abstract

Melanoma, the most aggressive form of skin cancer, is characterized by high metastatic potential and resistance to conventional therapies. Chemotherapy (e.g., doxorubicin, DOX) can kill tumor cells but often induces immunosuppression, while immunotherapy (e.g., CpG oligodeoxynucleotides, CpG ODNs) activates anti-tumor immunity but has limited efficacy in poorly immunogenic tumors. Herein, we developed a pH-responsive metal-organic framework (MOF) nanoparticle system (ZIF-8) loaded with DOX (chemotherapeutic) and CpG ODNs (TLR9 agonist) for synergistic chemo-immunotherapy of melanoma. The ZIF-8 MOFs were synthesized via a solvothermal method, surface-modified with polyethylene glycol (PEG) to enhance biocompatibility, and co-loaded with DOX (hydrophobic, loaded in MOF pores) and CpG ODNs (hydrophilic, adsorbed on MOF surface via electrostatic interaction). The resulting DOX/CpG@ZIF-8-PEG nanoparticles exhibit uniform size (~120 nm), high drug loading efficiency (DOX: 28.5 ± 2.3%, CpG ODNs: 15.2 ± 1.8%), and pH-responsive release (92.3% DOX and 87.6% CpG ODNs released at pH 5.0 vs. 18.5% DOX and 12.8% CpG ODNs at pH 7.4 after 48 h). In vitro studies show that DOX/CpG@ZIF-8-PEG induces 82.3% apoptosis in B16-F10 melanoma cells, promotes dendritic cell (DC) maturation (CD80⁺CD86⁺ DCs: 68.5% vs. 21.3% for saline), and enhances cytotoxic T cell activation (IFN-γ⁺ CD8⁺ T cells: 45.6% vs. 8.7% for saline). In vivo, the nanoparticles significantly inhibit B16-F10 melanoma growth (tumor volume reduction: 81.2% vs. saline) and lung metastasis (metastatic nodules: 6.3 vs. 45.7 for saline), while prolonging mouse survival (median survival: 56 days vs. 23 days for saline). This work demonstrates the potential of MOF-based nanocarriers for co-delivery of chemotherapeutics and immunostimulants, bridging nanomaterial engineering, chemotherapy, and immunology for precision cancer therapy.

Keywords

Metal-Organic Frameworks; ZIF-8; Chemo-Immunotherapy; Melanoma; Doxorubicin; CpG Oligodeoxynucleotides; pH-Responsive Release; Anti-Tumor Immunity

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