Colon‐Targeted Ginseng Polysaccharides‐Based Microspheres for Improving Ulcerative Colitis via Anti‐Inflammation and Gut Microbiota Modulation

Abstract Natural plant‐derived polysaccharides exhibit substantial potential for treating ulcerative colitis (UC) owing to their anti‐inflammatory and antioxidant properties and favorable safety profiles. However, their practical application faces several challenges, including structural instability in gastric acid, imprecise targeting of inflamed regions, and limited intestinal retention times. To address these limitations, pH‐responsive, colon‐targeting microspheres (pWGPAC MSs) are developed for delivering phosphorylated wild ginseng polysaccharides (pWGP) to alleviate UC. These pWGPAC MSs are fabricated by incorporating pWGP into calcium‐crosslinked alginate microspheres with subsequent chitosan surface modification to enhance mucosal adhesion. These pWGPAC MSs demonstrated exceptional stability under acidic conditions while enabling targeted release in the colon. In a mouse model of UC, the pWGPAC MSs effectively mitigated mucosal injury, attenuated inflammation, and restored intestinal barrier function. Further mechanistic investigations revealed that these pWGPAC MSs modulated the TLR4/MYD88 signaling pathway and promoted M2 macrophage polarization. Integrated microbiome and metabolome analyses demonstrated that these pWGPAC MSs regulated the gut microbiota composition and decreased pro‐inflammatory metabolite levels. In addition, these microspheres demonstrated promising safety profiles. Collectively, these findings establish pWGPAC MSs as a promising therapeutic strategy for the treatment of UC and provide a solid foundation for future clinical applications.