Colon-Targeting Angelica sinensis Polysaccharide Nanoparticles with Dual Responsiveness for Alleviation of Ulcerative Colitis

Intestinal immune dysfunction and gut microbiota dysbiosisarecritically causative factors in the pathogenesis of ulcerative colitis(UC); however, the current first-line drugs for UC treatment in clinicsoften remain great challenges due to their nontargeting therapeuticefficacy and severe side effects. In the current study, colon-targetingnanoparticles based on Angelica sinensis polysaccharide with pH- and redox-responsiveness were fabricatedto specifically release the naturally active compound ginsenosideRh(2) in the colonic inflammatory site, which greatly alleviatedthe UC symptoms and improved the gut microbial homeostasis. Thesedual responsive Rh-2-loaded nanoparticles (Rh-2/LA-UASP NPs) with a particle size of 117.00 +/- 4.80 nm wereprepared using the polymer LA-UASP obtained by grafting A. sinensis polysaccharide with urocanic acid and alpha-lipoic acid (alpha-LA). As expected, these Rh-2/LA-UASP NPs achieved dual pH- and redox-responsive drug releaseat pH 5.5 and 10 mM GSH. The stability, biocompatibility, and in vivo safety experiments exhibited these prepared nanoparticleshad excellent colon-targeting ability and significant accumulationof Rh-2 in the inflammatory colon. Meanwhile, these Rh-2/LA-UASP NPs could escape from lysosomes and be efficientlyinternalized into intestinal mucosal cells, thereby effectively inhibitingthe release of proinflammatory cytokines. The animal experiments indicatedthat Rh-2/LA-UASP NPs significantly improved the integrityof intestinal mucosa and increased the colon length compared withUC mice. Additionally, the weight loss, histological damage, and inflammationlevel were greatly ameliorated. The homeostasis of intestinal floraand the level of short-chain fatty acids (SCFAs) were significantlyimproved after being treated with Rh-2/LA-UASP NPs in UCmice. Our study proved that these Rh-2/LA-UASP NPs withdual pH-and redox-responsiveness are promising candidates for UC treatment.