2. Academic Validation
  3. MIL-100(Fe)-based Co-delivery platform as cascade synergistic chemotherapy and immunotherapy agents for colorectal cancer via the cGAS-STING pathway

MIL-100(Fe)-based Co-delivery platform as cascade synergistic chemotherapy and immunotherapy agents for colorectal cancer via the cGAS-STING pathway

  • Acta Biomater. 2025 Sep 15:204:582-595. doi: 10.1016/j.actbio.2025.08.021.
Pai Wang 1,  Heshi Liu 1,  Lei Guo 2,  Yixin Tang 2,  Tianwei Lan 2,  Rui Zhou 2,  Huiqing Xu 2,  Lu Wang 2,  Xue Wang 2,  Baiqiao Chen 2,  Yixing Wang 2,  Siyuan Wang 2,  Chang Liu 2,  Jie Chen 3,  Caina Xu 4,  Quan Wang 5,  Huayu Tian 6
Affiliations

Affiliations

  • 1 Department of Gastrocolorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
  • 2 College of Basic Medical Sciences, the Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China.
  • 3 Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China.
  • 4 College of Basic Medical Sciences, the Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China. Electronic address: xucaina@jlu.edu.cn.
  • 5 Department of Gastrocolorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China. Electronic address: wquan@jlu.edu.cn.
  • 6 Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China; State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China; Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen, 361005, China. Electronic address: thy@xmu.edu.cn.
PMID: 40812610 DOI: 10.1016/j.actbio.2025.08.021
Abstract

Colorectal Cancer (CRC) remains a major global health burden as the third most commonly diagnosed malignancy and the second leading cause of cancer-related mortality worldwide. While combination chemotherapy and immune agonists hold potential to overcome tumor heterogeneity through multi-pathway modulation, their therapeutic efficacy remains limited by off-target drug distribution and immunosuppressive tumor microenvironment (TME). To address this, we developed a tumor-targeted chemo-immunotherapy platform by encapsulating irinotecan (CPT-11) and resiquimod (R848) in hyaluronic acid (HA) coated MIL-100(Fe) metal-organic frameworks (CRMH NPs), enabling CD44-mediated delivery and synergistic anti-tumor responses. The system enabled controlled drug release in the acidic TME, promoting immunogenic cell death (ICD), inducing the cGAS-STING pathway and activating immune cells. In vitro, CRMH NPs induced significant ICD, as evidenced by the release of damage-associated molecular patterns (DAMPs) like high mobility group box 1 (HMGB1) and calreticulin (CRT), and matured dendritic cells (DCs), which triggered by TLR7 Agonist, enhancing immune responses. It also activated the cGAS-STING pathway, which could efficiently induce the targeted cells to produce type I interferon (IFN) and proinflammatory cytokines, thereby enhancing T cell activation and recruitment. In vivo, CRMH NPs significantly reduced tumor growth in CT26 mouse models, activated innate immune signaling, and increased immune cell infiltration, demonstrating superior anti-tumor effects compared to free drugs and Other nanoparticle formulations. Furthermore, CRMH NPs upregulated PD-L1 expression on tumor cells, suggesting potential synergy with immune checkpoint blockade therapy. Combining CRMH NPs with anti-PD-L1 therapy enhanced anti-tumor immunity, particularly in distant tumors, highlighting a promising approach to overcoming immune evasion and achieving durable tumor regression. These findings supported CRMH NPs as a versatile and effective platform for chemo-immunotherapy in CRC. STATEMENT OF SIGNIFICANCE: Colorectal Cancer (CRC) remains a major global health challenge with limited treatment efficacy due to tumor heterogeneity and immunosuppression. This study introduces a novel tumor-targeted nanoparticle platform, CRMH NPs, which co-deliver the chemotherapeutic drug irinotecan (CPT-11) and the immune agonist resiquimod (R848) using hyaluronic acid-coated MIL-100(Fe) metal-organic frameworks. CRMH NPs enhance drug delivery, induce immunogenic cell death, and activate the cGAS-STING pathway, synergizing chemotherapy and immunotherapy. Demonstrating superior tumor suppression and immune activation in preclinical models, this platform overcomes key limitations of current therapies, such as off-target effects and immune evasion. Its combination with anti-PD-L1 therapy further improves outcomes, offering a promising strategy for durable CRC treatment. This work advances nanomedicine and immuno-oncology, providing a transformative approach for Cancer therapy.

Keywords

Chemotherapeutics; Colorectal cancer; Immunotherapy; MOF; TLR7 agonist; cGAS-STING pathway.

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