The prevalence of ulcerative colitis (UC) is increasing annually, while current non-targeted drugs for UC have limited effectiveness, easily relapsed, and serious side effects. Herein, curcumin (Cur)-loaded nanoparticle with conlon-targeted property based on Mesona chinensis polysaccharides (MCP) was developed for the synergistic and targeted improvement of UC. Results show that MCP-zein nanoparticles (ZmNPs) have good encapsulation of Cur, targeted delivery of Cur to the colon, and prolonged its retention time. In vivo safety assessments have shown that ZmNPs have good safety and biocompatibility. As expected, Cur-ZmNPs effectively alleviated the symptoms of Dextran sulfate sodium (DSS)-induced UC by decreasing colonic inflammation by inhibiting the TLR4/MAPK pathway, regulating the levels of oxidative stress and immune homeostasis of UC mice. Oral administration of Cur-ZmNPs can reduce apoptosis of intestinal epithelial cells, alleviate colonic mucosal damage and repair intestinal barrier function. Cur-ZmNPs also had a positive effect on improving gut microbiota disorders and promoting the production of SCFAs. This study provides a novel strategy for synergistic alleviation of UC by MCP-based NPs loaded with food bioactives.