pH/ROS Dual-Sensitive Natural Polysaccharide Nanoparticles Enhance "One Stone Four Birds" Effect of Rhein on Ulcerative Colitis.

Rhein (RH), a natural anthraquinone compound, is considered an effective treatment candidate for ulcerative colitis (UC), whose multiple biological activities contribute to UC, including anti-inflammation, antioxidation, intestinal barrier repair, and microflora regulation. However, the application of RH is severely limited by its low water solubility, low bioavailability, and poor colonic targeting. Although some nanoparticles have been developed for the oral delivery of RH, most of them mainly highlighted only one effect of some drug delivery strategies but the above multiple biological activities. Therefore, a multiple polysaccharide-based nanodelivery system, comprising chitosan (CS) and fucoidan (FU), with pH/reactive oxygen species (ROS) sensitivity and mucosal adhesion, was developed and first used to load RH as a comprehensive treatment for UC. Briefly, RH-F/C-NPs were prepared using the polyelectrolyte self-assembly method; the average size of RH-F/C-NPs was 233.1 ± 5.7 nm, and the encapsulation rate of RH was 93.67 ± 1.60%. And it could maintain gastric stability and release RH in the colon with the designed pH/ROS sensitivity contributed by the polysaccharide-based structures. Cellular uptake experiments showed that both NCM 460 cells and RAW 264.7 cells had a good uptake of RH-F/C-NPs. Importantly, the effects of RH were highlighted in experiments, the results of which showed that RH-F/C-NPs could significantly reduce DSS-induced inflammation by inhibiting the TLR4/NF-κB-mediated anti-inflammatory pathway, the Nrf2/HO-1-mediated antioxidant pathway, colonic mucosal barrier repair, and intestinal microflora regulation. In addition, pharmacokinetic studies have shown that F/C-NPs contribute to the increase in the plasma concentration and the accumulation of RH in the colon to some extent. In short, this study is the first to develop an oral multiple polysaccharide-based nanosystem with pH/ROS dual sensitivity to study the "one stone four birds" therapeutic effect of RH on UC.