A dual-polysaccharide (carboxylated chitosan-carboxymethyl cellulose sodium) gastrointestinal dynamic response in situ hydrogel for optimized oral targeted inflammatory bowel disease therapy

Hydrogels characterized by a three-dimensional polymer network are promising vehicles for oral colon-targeted drug delivery, yet conventional systems relying on intragastric cross-linking agents face clinical limitations. Here, we present a cross-linker-independent oral in situ hydrogel (CCS/CMC-Na) functionalized with Ti₃C₂ MXene nanosheets for optimized inflammatory bowel disease (IBD) therapy. The CCS/CMC-Na hydrogel exhibits a liquid-gel state transition in simulated gastric fluids while gradually returning to a liquid state in simulated colonic fluids, enabling precise targeting of inflamed colon tissues and protecting encapsulated drugs from gastric degradation. The integration of Ti₃C₂ not only enhances mechanical stability but also introduces multifunctional therapeutic capabilities: repairing all levels of intestinal barriers, reducing oxidative stress, inhibiting apoptosis, modulating Regulatory T cells (Treg)/T helper 17 (Th17) cell differentiation and NF-κB/IκB inflammatory pathway, and remodeling the intestinal microbiota. In murine models of acute and chronic colitis, Ti₃C₂@CCS/CMC-Na significantly alleviates disease severity, outperforming clinical first-line drug 5-ASA. Crucially, this system eliminates the need for dual-tube administration, simplifies dosing protocols, and demonstrates excellent biocompatibility over 50 days, addressing key challenges in current IBD therapies. By integrating precise targeting, multimodal therapeutic actions, and scalable fabrication, Ti₃C₂@CCS/CMC-Na represents great clinical translational potential, offering a safer and more effective treatment option for IBD.