Intestinal inflammatory disorders, such as ulcerative colitis, are driven by excessive pro-inflammatory M1 macrophages, leading to tissue damage and chronic inflammation. MicroRNA-223 (miRNA-223) presents a promising therapeutic approach by shifting macrophage polarization from the M1 to the anti-inflammatory M2 phenotype, thereby reducing inflammation. However, oral delivery of miRNA-223 is hindered by its instability in the harsh gastrointestinal (GI) environment and the challenge of targeting colonic macrophages. To overcome these obstacles, we developed an oral nanogene delivery system using laminarin, a natural β-1,3 glucan polysaccharide derived from kelp, as the primary delivery unit. miRNA-223 is encapsulated within peptide dendrimers, which are then coated with laminarin to enhance stability and enable targeted delivery via dectin-1 receptors on macrophages. This laminarin-mediated formulation protects miRNA-223 from degradation in the GI tract and facilitates its selective uptake by inflamed colonic macrophages. In vitro and in vivo studies demonstrated that the laminarin-coated nanogene complex preserves miRNA-223 integrity, targets inflamed colonic regions, and promotes M2 polarization, resulting in reduced inflammation and improved outcomes in a colitis mouse model. This work highlights the potential of natural laminarin-based nanocarriers for effective oral miRNA delivery, offering a novel strategy for treating inflammatory bowel diseases through precise modulation of macrophage phenotypes.Copyright © 2025 Elsevier B.V. All rights reserved.