Abstract
Programmed cell death protein 1 (PD-1) inhibitors are integral to contemporary cancer immunotherapy. However, their objective response rate in microsatellite-stable colorectal cancer (MSS CRC) remains below 5 %. This limited efficacy is primarily due to insufficient tumor-infiltrating lymphocytes (TILs), a consequence of the combined effects of low tumor immunogenicity and impaired dendritic cell (DC)-mediated antigen presentation. The combination of ursolic acid (Ua) and ginsenoside Rg3 (Rg3) enhances TIL infiltration by inducing immunogenic cell death (ICD) in tumor cells and promoting DC maturation. Due to their poor oral bioavailability, an oral ZIF nanoplatform was engineered with a chitosan oligosaccharide (Cos) and inulin (In) bilayer coating [(In/Cos)@Ua-Rg3-ZIF] for targeted delivery of Ua and Rg3 to the CRC microenvironment. Efficient dual-drug co-loading was achieved with a loading efficiency of 24.07 wt%. After oral administration, the (In/Cos) coating protects the formulation from degradation in the upper gastrointestinal tract, while specific enzymatic cleavage by colonic microbiota releases Ua-Rg3-ZIF into tumor tissues. The ZIF platform responds to elevated adenosine triphosphate (ATP) in the tumor microenvironment, enabling controlled release of Ua and Rg3 to enhance cytotoxic T lymphocyte (CTL) levels. In vivo studies demonstrate that combining (In/Cos)@Ua-Rg3-ZIF with α-PD-1 results in an 80.86 % tumor inhibition rate, significantly outperforming monotherapies. This strategy presents an innovative oral delivery system capable of resisting gastrointestinal degradation and facilitating microbiota-responsive drug release, effectively enhancing antitumor immunity and improving the therapeutic outcome of immunotherapy in MSS CRC.