Colon-targeted mucin/cyclosporine A co-loaded microspheres synergistically ameliorate ulcerative colitis via immunosuppression and mucosal barrier repair.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon and rectum, associated with epithelial barrier defects and dysregulated immune responses. Here, we developed Eudragit S100-coated mucin/CyA co-loaded calcium alginate microspheres (E-CMAMs) for synergistic UC therapy via immunosuppression and mucosal barrier repair. E-CMAMs were prepared by a high-voltage electrostatic method and an emulsification-solvent evaporation method. Their characteristics were analyzed by inverted optical microscope, SEM, FTIR, and DSC. E-CMAMs exhibited excellent pH-responsive behavior, as they remained stable in acidic gastric fluid, swelled moderately in neutral intestinal fluid, and rapidly disintegrated in the alkaline colonic environment, which enabled the colon-specific release of CyA. Moreover, E-CMAMs effectively protected CyA from degradation by gastric acid and proteolytic enzymes. In vivo gastrointestinal fate and distribution study showed that E-CMAMs maintained structural integrity in the upper gastrointestinal tract and released fluorescent dye upon reaching the colon. In DSS-induced UC mice, E-CMAMs significantly alleviated colitis symptoms, suppressed inflammatory responses (MPO, TNF-α, IL-1β, and IL-6 reduced), and restored intestinal barrier integrity by reconstructing the mucus layer and upregulating tight junction proteins (Occludin and ZO-1). Finally, E-CMAMs demonstrated excellent biosafety, with no detectable toxicity in major organs. The combination of CyA-mediated immunosuppression and mucin-mediated mucosal repair achieved superior efficacy, with excellent biosafety. This colon-targeted co-delivery strategy offers a promising approach for more effective and safer UC therapy.