Hydrogel-transformable sucralfate microspheres restored gut epithelial wound and reshaped microbiota in colitis via autophagy

Inflammatory bowel disease (IBD) is characterized by gut barrier disruption, necessitating combined physical protection and epithelial repair. Herein, we engineered sucralfate microspheres (HSM-TD) via microfluidic encapsulation of hydrochloric acid-modified sucralfate (HSF) and autophagy-enhancing teduglutide (TD) to synergize physical protection and gut epithelial restoration. HSM-TD with particle size of 150 μm ensured stability of its encapsulated cargoes in stomach/intestine and spontaneous formation of TD-containing HSF hydrogel on colonic mucosa. HSF could overcome the pH-dependent limitations of conventional sucralfate by forming a robust, adhesive hydrogel on colon mucosa. This pH-independent HSF hydrogel mimicked native mucus, exhibiting superior viscoelasticity, strain-dependent self-recovery with linear viscoelastic region of 19.6 % strain, and strong mucosal. In DSS-induced colitis mice, HSM-TD outperformed free TD or HSM alone, reducing body weight loss, decreasing disease active index, restoring colon length, and suppressing inflammation. Moreover, HSM-TD reshaped gut microbiota diversity, normalizing Firmicutes/Proteobacteria ratios and enriching probiotics like Lactobacillus . Mechanistically, HSF formed a transilient mucus-like barrier to prevent the pathogenic bacteria or toxins invasion, while TD restored gut epithelial barriers, upregulating tight junction proteins (ZO-1, CLDN-5, OCLN) and MUC2 expression. By synergizing immediate physical protection with epithelial repair, HSM-TD offered a transformative strategy for IBD therapy.