Exacerbated intestinal inflammation, oxidative stress imbalance, and damage to intestinal mucosal barrier are closely related to the pathogenesis and progression of ulcerative colitis (UC). Selenium nanoparticles (Se NPs) have demonstrated promising potential to alleviate UC symptoms, however, their poor solubility and stability leading to aggregation and large precipitates have significantly limit their clinical application. In this study, we aimed to enhance the performance of Se NPs by functionalizing them with Porphyra haitanensis polysaccharide, yielding PHP-Se NPs. As expected, these PHP-Se NPs exhibited reduced particle size (70.51 ± 2.92 nm), enhanced cellular uptake compared to native Se NPs, and preferential accumulation in the colonic tissue, providing targeted UC treatment. In vivo animal experiments revealed that PHP-Se NPs significantly improved weight loss, shortened colon length, and higher disease activity index (DAI) scores in DSS-induced UC mice. Moreover, PHP-Se NPs significantly inhibited the levels of inflammatory factors in colitis tissues and oxidative stress in serum of UC mice, improved histological damage in colitis tissues, and restored the intestinal mucosal barrier. Taken together, our study offers an innovative approach to augment the bioavailability of Se NPs, presenting a promising strategy for the effective prevention and management of UC.Copyright © 2023. Published by Elsevier B.V.