Ginger exosome-like nanoparticles (GELNs) derived miRNAs, particularly osa-miR164d, have been shown to regulate macrophage polarization and alleviate intestinal inflammation. GELNs were isolated and characterized, revealing their structural and functional properties. Osa-miR164d was identified as a key miRNA that directly targets the TAB1 gene, promoting M2 macrophage polarization and inhibiting inflammatory responses through the TNF signaling pathway. The study also developed osa-miR164d-loaded biomimetic exosomes (osa-miR164d-MGELNs) that efficiently reprogram macrophages to alleviate colitis-related symptoms. These findings demonstrate that GELNs-derived miRNAs can modulate immune responses and provide a novel strategy for treating intestinal inflammation. The study highlights the potential of plant-derived exosome-like nanoparticles in delivering miRNAs for therapeutic applications, offering new insights into cross-kingdom communication and immune modulation. The results suggest that osa-miR164d could be a promising therapeutic agent for inflammatory diseases, particularly in the context of intestinal inflammation. The research also emphasizes the importance of understanding the molecular mechanisms underlying miRNA function in macrophage polarization and its implications for developing targeted therapies.Ginger exosome-like nanoparticles (GELNs) derived miRNAs, particularly osa-miR164d, have been shown to regulate macrophage polarization and alleviate intestinal inflammation. GELNs were isolated and characterized, revealing their structural and functional properties. Osa-miR164d was identified as a key miRNA that directly targets the TAB1 gene, promoting M2 macrophage polarization and inhibiting inflammatory responses through the TNF signaling pathway. The study also developed osa-miR164d-loaded biomimetic exosomes (osa-miR164d-MGELNs) that efficiently reprogram macrophages to alleviate colitis-related symptoms. These findings demonstrate that GELNs-derived miRNAs can modulate immune responses and provide a novel strategy for treating intestinal inflammation. The study highlights the potential of plant-derived exosome-like nanoparticles in delivering miRNAs for therapeutic applications, offering new insights into cross-kingdom communication and immune modulation. The results suggest that osa-miR164d could be a promising therapeutic agent for inflammatory diseases, particularly in the context of intestinal inflammation. The research also emphasizes the importance of understanding the molecular mechanisms underlying miRNA function in macrophage polarization and its implications for developing targeted therapies.