An Oral ROS-Responsive Nanoparticle–Hydrogel System for Intestinal Epithelial Regeneration and Barrier Restoration in Inflammatory Bowel Disease

Background: Intestinal epithelial barrier disruption contributes to persistent inflammation in inflammatory bowel disease (IBD). CHIR99021 (CHIR) can promote epithelial regeneration and barrier repair, but its oral use is limited by premature gastric release and insufficient intestinal retention. This study aimed to develop an oral formulation that improves intestinal delivery of CHIR and supports barrier restoration. Methods: CHIR-loaded lipid nanoparticles (LNPs@CHIR) were prepared using glyceryl monostearate and Eudragit L100 and incorporated into a thiolated hyaluronic acid (HS) precursor to form HS/LNPs@CHIR (HSL@C). The system was characterized for particle size, mucoadhesion, and drug release, and its therapeutic effects were evaluated in IEC-6 cells and a mouse model of colitis. Results: LNP encapsulation reduced premature CHIR release under simulated gastric conditions, whereas the HS component enabled reactive oxygen species (ROS)-responsive gelation and ROS-scavenging activity. After oral administration, HSL@C exhibited prolonged colonic retention for up to 24 h. HSL@C promoted intestinal epithelial regeneration and barrier restoration while alleviating tissue injury and pro-inflammatory cytokine production. Conclusions: HSL@C integrates gastric protection, prolonged intestinal retention, ROS-responsive gelation, and epithelial regeneration within an oral delivery system, collectively supporting its potential as a promising barrier-restorative nanoparticle–hydrogel platform for the treatment of IBD.