“Targeted Delivery–Long-Acting Adhesion–Synergistic Treatment” Integrated Adhesive Bilayer Microgels Loaded with Costunolide for Ulcerative Colitis Therapy

Oral colon-targeted drug delivery platforms are highly important for the treatment of ulcerative colitis (UC). In this study, an adhesive bilayer microgel (Cp@GTL) integrating time-lag positioning, interfacial mucoadhesive retention, and enzyme-triggered release was engineered for targeted colonic delivery. The adhesive bilayer microgels were loaded with costunolide (Cos), a natural sesquiterpene lactone exhibiting potent anti-inflammatory activity. The inner gel layer was constructed by crosslinking gelatin and low-methoxyl pectin through tannic acid and Ca2+ chelation, forming an interpenetrating network that confers colonic mucoadhesion and enzyme-responsive degradation properties. The outer shell was fabricated via polyelectrolyte complexation between anionic sodium alginate and cationic chitosan, endowing the system with resistance to gastric acid erosion through pH-responsive structural stabilization. In vitro release studies demonstrated that the microgels effectively retarded Cos release under simulated upper gastrointestinal conditions. Following oral administration in a dextran sulfate sodium (DSS)-induced UC mouse model, Cp@GTL significantly alleviated colitis symptoms, suppressed pro-inflammatory cytokine levels, and ameliorated colonic tissue damage. Furthermore, Cp@GTL exhibited prolonged colonic retention for up to 48 h with high drug accumulation at the target site, while also modulating gut microbiota composition, enhancing microbial diversity, and reducing the abundance of pathogenic bacteria, thereby synergistically contributing to the amelioration of DSS-induced colitis. This naturally derived bilayer microgel integrates time-programmed colonic positioning, interfacial mucoadhesive retention, and enzyme-triggered drug release, enabling coordinated anti-inflammatory intervention and gut microbiota regulation. It provides a promising strategy for enhancing the intestinal application of Cos in UC-associated inflammation and offers a versatile material platform and interfacial engineering approach for the targeted amelioration of intestinal inflammatory disorders.