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In this study, we present nucleic acid-functionalized gold nanorods (NAF AuNRs), a biocompatible nanomaterial designed for the oral treatment of dextran sulfate sodium (DSS)-induced colitis. The NAF AuNRs alleviate immune responses by inhibiting pro-inflammatory macrophages and enhancing the expression of barrier proteins in intestinal epithelial cells. Due to the negatively charged nucleic acid shell, NAF AuNRs preferentially target anionic, inflamed colon tissues upon oral administration, reducing pro-inflammatory cytokine levels and promoting the recovery of intestinal barrier in DSS-induced colitis mice. 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