pH-responsive microgels containing multifunctional ginsenoside Rh2-based liposomes remodel intestinal environment to enhance celastrol therapy for ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease closely associated with intestinal mucosal barrier damage, abnormal immune responses, and gut microbiota dysbiosis. Celastrol (Cel), a natural triterpenoid compound, has shown great potential in modulating macrophage polarization and inhibiting inflammation. However, its clinical translation is hampered by poor solubility and nonspecific biodistribution. To address these issues, we developed a novel drug delivery system. Initially, functional liposomes (Rh2-LPs@Cel) were constructed by substituting cholesterol with ginsenoside Rh2. This strategy not only reduced drug leakage and enhanced the formulation stability, but also imparted intrinsic bioactivity to the carrier. Subsequently, these liposomes were coated with chitosan-sodium alginate to form a pH-responsive microgel (M/Rh2-LPs@Cel) for colon-targeted delivery. Experimental results showed that this microgel could precisely deliver drugs to the colon after oral administration. It effectively promoted the polarization of macrophages towards an anti-inflammatory phenotype, reduced the levels of pro-inflammatory factors, reshaped the diversity of the gut microbiota, elevated short-chain fatty acid levels, and repaired the intestinal epithelial barrier, thereby alleviating the colonic pathological damage induced by dextran sulfate sodium in mice. It is worth noting that M/Rh2-LPs@Cel did not show significant toxicity in vitro or in vivo. In conclusion, this work presents a promising approach for UC that combines efficient drug delivery, targeted release, and multiple therapeutic effects. Our findings provide a valuable foundation for the clinical application of natural bioactive compounds in inflammatory bowel disease management.