Oral delivery of mesenchymal stem cell-derived extracellular vesicles to treat intestinal inflammation

Despite advances in therapy for inflammatory bowel disease (IBD), current treatments are still associated with poor clinical outcomes and severe systemic side effects. Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) could have therapeutic applications in IBD due to their regenerative potential and immunomodulatory properties. Previous studies investigating the potential of MSC-EVs in IBD have largely administered the vesicles by injection, which does not offer the significant benefits of oral administration, including direct and localised 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. The 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. We demonstrated that coated EVs were resistant to GI fluids and digestive enzymes, and the formulation released intact vesicles in colonic fluid. Preliminary in vivo studies in a dextran sodium sulfate-induced colitis mouse model showed that coated EVs reduced disease severity, whereas uncoated EVs performed similarly to the control group. Interestingly, coated MSC-EVs elicited a stronger therapeutic response compared to EVs administered intravenously at the same dose. These findings indicate that oral delivery of MSC-EVs could be an effective route of administration, with appropriate formulation, to treat intestinal inflammation.