MIL-100(Fe)-based Co-Delivery Platform as Cascade Synergistic Chemotherapy and Immunotherapy Agents for Colorectal Cancer via the cGAS-STING Pathway

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.