Mucoadhesive and Self-Assembled Chitosan Oligosaccharide-Glycyrrhizin Nanoparticle for Oral Nanotherapeutic in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by severe oxidative stress and intestinal barrier dysfunction. Conventional oral therapies are often limited by low bioavailability and off-target effects. Herein, we report the development of mucoadhesive nanotherapeutics engineered from low molecular weight chitosan oligosaccharide (COS) and glycyrrhizin (GL), a natural anti-inflammatory compound. Hydrophilic COS, selected for its potent antioxidant and mucoadhesive properties, was chemically conjugated with hydrophobic GL to facilitate self-assembly into stable COS-GL nanoparticles (∼129 nm). These nanoparticles exhibit enhanced retention at inflamed intestinal sites and preferential uptake by activated immune and epithelial cells. In vitro evaluations using transwell coculture systems and intestinal organoids revealed that COS-GL nanoparticles effectively suppress pro-inflammatory cytokine secretion, promote M1-to-M2 macrophage remodeling, neutralize reactive oxygen species (ROS), and restore intestinal barrier integrity by upregulating tight junction proteins. In a DSS-induced colitis mouse model, orally administered COS-GL nanoparticles outperform both their individual components and the standard therapeutic 5-aminosalicylic acid (5-ASA), mitigating inflammation and promoting mucosal healing. These findings establish COS-GL nanoparticles as a promising and effective nanotherapeutic platform for the targeted oral treatment of IBD.