Functional chitosan/HP-β-CD hydrogel for targeted co-delivery of Rhubarb-derived nanovesicles and kaempferol for alleviating ulcerative colitis.

Ulcerative colitis (UC) remains a major challenge in clinical treatment due to its multivariate pathology. Developing an oral formulation that encapsulates and delivers multiple active ingredients to target colon tissues by suppressing intestinal inflammation and restoring the intestinal barrier is crucial for effectively treating UC. Here, we developed rhubarb-derived nanovesicles (RNs) and a supramolecular hydrogel platform formed by furfural-functionalized chitosan-mannose polymer and synthesized 3-maleimide HP-β-CD, with kaempferol (Kae) integrated into the hydrophobic cavity. The hydrogel's cross-linking network effectively encapsulates RNs, forming the Kae/CMCHD@RNs system. Rheology, SEM, TGA, degradation behavior, in vitro drug release, and a macrophage-targeted permeability test were performed. The results indicate that the hydrogel utilizes pH/enzyme sensitivity to ensure sustained release in the colon, while also facilitating targeted delivery to macrophages. In vivo imaging further reveals a prolonged local drug retention time in the colon. Moreover, both in vitro and in vivo studies demonstrate RNs and Kae exhibit synergistic therapeutic effects for UC, including inflammation reduction, oxidative stress alleviation, M1-to-M2 macrophage repolarization, and restoration of the intestinal barrier. Consequently, this study underscores the potential of Kae/CMCHD@RNs as a promising therapeutic approach for managing UC.