Zein-Coated Eicosapentaenoic Acid-Based Glibenclamide Nanocarriers for Treating Ulcerative Colitis

Ulcerative colitis (UC) is a major subcategory of inflammatory bowel disease, driven by complex mechanisms such as leukocyte infiltration, oxidative stress, and microbial dysbiosis. Oral administration is the most preferred route of drug administration but faces major limitations such as inefficient targeting, instability in the harsh gastric conditions, lack of mucoadhesiveness, and low colon residence time due to frequent diarrhea and rapid peristalsis. NLRP3 inflammasome is critical to the pathogenesis of UC, which augments inflammation by releasing of IL-1β and IL-18. Glibenclamide (Glib), a hydrophobic sulfonylurea and BCS class-II drug, is a potent NLRP3 inhibitor with poor solubility and bioavailability, which limit its therapeutic efficacy. Thus, it remains underexplored for the therapeutic alleviation of UC. To address this limitation, we engineered lipid-based gastroresistant zein-eicosapentaenoic acid smart nanocarriers (ZESNs) to develop a gastroresistant esterase-responsive nanocarrier system, with triglycerol monostearate (TGMS, an amphiphilic stabilizer), eicosapentaenoic acid (EPA, an ω-3 fatty acid), and a mucoadhesive coating of zein to bypass the harsh gastrointestinal environment. ZESNs exhibited high encapsulation efficiency and stability along with excellent cytocompatibility and anti-inflammatory potential in RAW 264.7 cells. Oral administration of Glib-loaded ZESNs (G@ZESNs) markedly restored the gut barrier integrity, improved goblet cell expression, and diminished mucosal ulceration in mice with colitis, moreover G@ZESNs also demonstrating colonic residence up to 48 h. In conclusion, the above findings validate G@ZESNs as a promising therapeutic nanoplatform, offering the dual advantage of improved drug solubility and inflammation-responsive immune system modulation. This study underlines the translational capabilities of biomaterial-based smart nanocarrier systems as next-generation therapeutic strategies for UC.