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Dysregulated mucosal immune responses and colonic fibrosis impose two formidable challenges for ulcerative colitis treatment. It indicates that monotherapy could not sufficiently deal with this complicated disease and combination therapy may provide a potential solution. A chitosan-modified poly(lactic-co-glycolic acid) nanoparticle (CS-PLGA NP) system was developed for co-delivering patchouli alcohol and simvastatin to the inflamed colonic epithelium to alleviate the symptoms of ulcerative colitis via remodeling immune microenvironment and anti-fibrosis, a so-called "two-birds-one-stone" nanotherapeutic strategy. The bioadhesive nanomedicine enhanced the intestinal epithelial cell uptake efficiency and improved the drug stability in the gastrointestinal tract. The nanomedicine effectively regulated the Akt/MAPK/NF-κB pathway and reshaped the immune microenvironment through repolarizing M2Φ, promoting regulatory T cells and G-MDSC, suppressing neutrophil and inflammatory monocyte infiltration, as well as inhibiting dendritic cell maturation. Additionally, the nanomedicine alleviated colonic fibrosis. Our work elucidates that the colon-targeted codelivery for combination therapy is promising for ulcerative colitis treatment and to address the unmet medical need. [ABSTRACT FROM AUTHOR]