Lemon‐Derived Extracellular Vesicles Engineered Oral Capsules for Enhanced Colorectal Cancer Chemotherapy by Mechanical Stress‐Induced Intestinal Epithelial Barrier Opening

The effectiveness of colorectal cancer (CRC) treatment remains constrained due to the limited drug delivery efficiency resulting from the intestinal epithelial barriers. Although solid nanoparticle-mediated drug delivery systems can enhance drug penetration, most of them are digested and excreted from the body, with only a small portion successfully crossing the intestinal epithelial barrier. Herein, we demonstrated lemon-derived extracellular vesicles (EVs)-engineered oral capsules loaded with capecitabine (EVOC), enabling them to trigger temporary opening of the intestinal epithelial barrier as a result of mechanical stress and thereby greatly enhancing the drug delivery efficiency. The EVOC enabled them to induce cellular stress responses within the intestinal epithelial barrier due to their much larger dimensions than cells, resulting in cytoskeleton relaxation and thereby breaking the original balance of tight junctions among cells. This cellular stress response could temporarily open the intestinal epithelial barrier, allowing highly efficient drug penetration into tumor tissues. The concentration of 5-fluorouracil (metabolite of capecitabine) accumulated in tumor tissues within the EVOC group was approximately 13-fold higher than that in the free capecitabine group and 6-fold higher than that in the capecitabine@EV nanodrugs. As expected, the EVOC group significantly enhanced the chemotherapy efficiency of CRC.