Oral Delivery of Mesenchymal Stem Cell-Derived Extracellular Vesicles To Treat Intestinal Inflammation

Abstract Despite advances in therapy for inflammatory bowel disease (IBD), current treatments are associated with poor clinical outcomes and systemic side effects. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have therapeutic potential in IBD due to their regenerative and immunomodulatory properties. However, most studies administer MSC-EVs by injection, which does not offer the significant benefits of oral administration, including direct and localized access to the site(s) of intestinal inflammation. Here, we evaluated the stability of MSC-EVs for oral delivery by assessing particle size, concentration, and EV markers. MSC-EVs disintegrated in gastrointestinal (GI) fluids, with cryogenic electron microscopy confirming the loss of structural integrity. To address this, we developed a double-coating formulation consisting of chitosan and Eudragit S100 to enhance GI stability and facilitate colon-targeted delivery. Coated EVs were resistant to GI fluids and digestive enzymes, and the formulation released structurally intact, biologically active vesicles in colonic fluid. Preliminary in vivo studies showed that orally administered coated EVs reduced disease severity in a colitis mouse model and elicited a stronger therapeutic response than uncoated EVs administered orally or intravenously at the same dose. These findings indicate that, with appropriate formulation, oral delivery of MSC-EVs could be an effective route of administration to treat intestinal inflammation.