Multipath Synergistic Immune Activation of Hydrogels Delivering STING Agonist and siXkr8 for Long‐Lasting Colorectal Cancer Therapy

Abstract Colorectal cancer (CRC) poses a significant threat to global public health, and immunotherapy has emerged as a promising alternative to its treatment. Nevertheless, owing to the tumor immunosuppressive microenvironment (TIME), the efficacy of single‐agent immunotherapy remains limited. Herein, CSZ@Gel is designed by co‐loading cyclic diguanosine (CDG) and siXkr8 in zeolitic imidazolate framework‐8 (ZIF‐8) nanoparticles and subsequently integrating them into α‐tocopherol polyethylene glycol succinate (TPGS) hydrogels. ZIF‐8 is found to undergo degradation under acidic conditions releasing its cargo and Zn 2+ to induce cell pyroptosis. CDG triggers the activation of the stimulator of interferon genes (STING) pathway, leading to enhanced release of proinflammatory cytokines release, dendritic cell (DC) maturation and CD8 + T cell infiltration. siXkr8 inhibits the expression of scramblase mXkr8 and decreases the phosphatidylserine translocation to the cell surface, thus decreasing immature DCs and regulatory T cells (Tregs) and reversing TIME. In a murine CRC model, CSZ@Gel exhibits significant tumor growth suppression effects, extends the median survival time of mice to more than 60 days, and significantly inhibits CRC recurrence after resection by long‐term synergistic anti‐tumor immune activation. These findings suggest that CSZ@Gel provides an innovative drug delivery platform with clinical translation potential through comprehensive strategies for sustained CRC immunotherapy.