Monocyte/Macrophage‐Mediated Transport of Dual‐Drug ZIF Nanoplatforms Synergized with Programmed Cell Death Protein‐1 Inhibitor Against Microsatellite‐Stable Colorectal Cancer

Abstract Microsatellite‐stable colorectal cancer (MSS‐CRC) exhibits resistance to programmed cell death protein‐1 (PD‐1) therapy. Improving the infiltration and tumor recognition of cytotoxic T‐lymphocytes (CTLs) is a promising strategy, but it encounters huge challenges from drug delivery and mechanisms aspects. Here, a zeolitic imidazolate framework (ZIF) coated with apoptotic body membranes derived from MSS‐CRC cells is engineered for the co‐delivery of ginsenoside Rg1 (Rg1) and atractylenolide‐I (Att) to MSS‐CRC, named as Ab@Rg1/Att‐ZIF. This system is selectively engulfed by Ly‐6C+ monocytes during blood circulation and utilizes a “hitchhiking” mechanism to migrate toward the core of MSS‐CRC. Ab@Rg1/Att‐ZIF undergoes rapid disassembly in the tumor, released Rg1 promotes the processing and transportation of tumor antigens in dendritic cells (DCs), enhancing their maturation. Meanwhile, Att enhances the activity of the 26S proteasome complex in tumor cells, leading to increased expression of major histocompatibility complex class‐I (MHC‐I). These coordinated actions enhance the infiltration and recognition of CTLs in the center of MSS‐CRC, significantly improving the tumor inhibition of PD‐1 treatment from ≈5% to ≈69%. This innovative design, involving inflammation‐guided precise drug co‐delivery and a rational combination, achieves synergistic engineering of the tumor microenvironment, providing a novel strategy for successful PD‐1 treatment of MSS‐CRC.