Thioketal-linked glycol chitosan nanosystem for targeted and sustained drug delivery of mesalazine in inflammatory bowel disease.

Inflammatory bowel disease (IBD), a chronic inflammatory disorder, necessitates precise therapeutic strategies due to current limitations in achieving sustained remission and targeted delivery. In this study, we introduce the Glyro system, an innovative orally active nanosystem engineered for localized IBD therapy. This nanosystem integrates reactive oxygen species (ROS)-responsive drug release with enhanced mucoadhesion. Utilizing a thioketal (TK) linker, the system ensures the precise release of a covalently conjugated therapeutic drug, maintaining its original chemical structure, exclusively within the ROS-rich inflammatory microenvironment. Concurrently, its glycol chitosan component promotes strong mucosal adhesion and prolonged retention at inflamed sites, enabling sustained therapeutic efficacy. As a proof-of-concept, we synthesized GlyroM, a Glyro system covalently conjugated with mesalazine, a representative IBD chemical drug. In a colitis mouse model, orally administered GlyroM effectively localized to inflamed intestinal tissue, significantly alleviating oxidative damage and disease symptoms, and promoting mucosal healing. Furthermore, the long-term retention of GlyroM in there resulted in high therapeutic efficacy even at low mesalazine doses, demonstrating a favorable safety profile with reduced systemic drug toxicity. Collectively, this study highlights the Glyro nanosystem as a promising and smart platform with significant potential to improve therapeutic outcomes in IBD and broad applicability in other inflammation-related diseases.