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Plant-derived vesicles (PDVs) were attractive for therapeutic applications, including as potential nanocarriers. However, a concern with oral delivery of PDVs is whether they would remain intact in the gastrointestinal tract. We found that 82% of cabbage PDVs were destroyed under conditions mimicking the upper digestive tract. To overcome this limitation, we developed a delivery method whereby lyophilized Eudragit S-100-coated cabbage PDVs were packaged into a capsule (Cap-cPDVs). Lyophilization and suspension of PDVs in phosphate-buffered saline did not have an appreciable effect on PDV structure, number of PDVs, or therapeutic effect. However, packaging the lyophilized Eudragit S-100-coated PDVs into capsules allowed them to pass through the upper gastrointestinal tract for delivery into the colon better than did suspension of PDVs in phosphate-buffered saline. Cap-cPDVs demonstrated robust therapeutic effect in a dextran sulfate sodium-induced colitis mouse model. These findings could have broad implications for oral delivery of PDVs. Citation Format: Yuan Liu, Adrian Lankenau-Ahumada, Emine Bayraktar, Paul Schwartz, Mamur Chowdhury, Sixiang Shi, Manu M. Sebastian, Htet Khant, Natalia De Val, Zuliang Jie, Nicholas B. Jennings, Cristian Rodriguez-Aguayo, Jody Swain, Elaine Stur, Lingegowda S. Mangala, Yutuan Wu, Supriya Nagaraju, Brooke Erimas, Chun Li, Gabriel Lopez-Berestein, Janet Braam, Anil K. Sood. Enhancing oral delivery of plant-derived vesicles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2720.