An Oral Nanomedicine Elicits <i>In Situ</i> Vaccination Effect against Colorectal Cancer

Oral administration is the most preferred approach for treating colon diseases, and <i>in situ</i> vaccination has emerged as a promising cancer therapeutic strategy. However, the lack of effective drug delivery platforms hampered the application of <i>in situ</i> vaccination strategy in oral treatment of colorectal cancer (CRC). Here, we construct an oral core-shell nanomedicine by preparing a silk fibroin-based dual sonosensitizer (chlorin e6, Ce6)- and immunoadjuvant (imiquimod, R837)-loaded nanoparticle as the core, with its surface coated with plant-extracted lipids and pluronic F127 (p₁₂₇). The resultant nanomedicines (Ce6/R837@Lp₁₂₇NPs) maintain stability during their passage through the gastrointestinal tract and exert improved locomotor activities under ultrasound irradiation, achieving efficient colonic mucus infiltration and specific tumor penetration. Thereafter, Ce6/R837@Lp₁₂₇NPs induce immunogenic death of colorectal tumor cells by sonodynamic treatment, and the generated neoantigens in the presence of R837 serve as a potent <i>in situ</i> vaccine. By integrating with immune checkpoint blockades, the combined treatment modality inhibits orthotopic tumors, eradicates distant tumors, and modulates intestinal microbiota. As the first oral <i>in situ</i> vaccination, this work spotlights a robust oral nanoplatform for producing a personalized vaccine against CRC.