Anti-Tumor Immunotherapy of Scutellaria Baicalensis-Derived Vesicles on Immune Checkpoint Modulation in Colorectal Cancer.

Immune checkpoint blockade (ICB) targeting PD-1/PD-L1 shows promising therapeutic potential in cancer patients. However, the efficacy of its antibody in colorectal cancer remains limited due to the immunosuppressive tumor microenvironment (TME) and related intestinal adverse effects. Plant-derived vesicle (PDV) is emerging natural nanomedicine treating various diseases, especially in cancer therapy. PDV is exhibited with high biocompatibility and low system toxicities, offering a novel strategy to treat colorectal cancer. In this work, we isolated and characterized Scutellaria baicalensis-derived vesicles (SBV). SBV exhibited typical vesicular morphology (~104.5 nm) and encapsulated several typical flavonoids, such as baicalin and baicalein, which showed high binding affinity to PD-L1 in silico. In vitro, SBV inhibited colorectal cancer cell viability and down-regulated the protein expression of PD-L1. Proteomic analysis indicated that SBV regulated multi-pathways including p53 signaling pathway, cell cycle, apoptosis, and endocytosis. In vivo, oral administration of SBV markedly suppressed tumor growth in a MC38 xenograft model. Furthermore, SBV down-regulated PD-L1 expression and enhanced tumor immunity with increased CD3/CD8 T cell population and granzyme E (GZME) expression. Notably, the combination treatment of SBV and TOR exhibited synergistic effects in tumor suppression and reduced the colon toxicity induced by Toripalimab (TOR). Our findings suggested SBV serves as a natural nanomedicine with dual potentials, not only could SBV inhibit PD-L1, but also could enhance the systemic anti-tumor immunity in colorectal cancer while reducing the colon toxicity related with PD-1 blockade, providing new insights into the potential application of PDV in cancer immunotherapy.