This study investigates the therapeutic potential of ginger exosome-like nanoparticles (GELNs)-derived miRNAs in alleviating intestinal inflammation. GELNs were isolated and characterized, and their ability to modulate macrophage polarization was assessed. The study identified osa-miR164d as a key regulator of macrophage polarization, specifically targeting TAB1 to promote M2 polarization and inhibit inflammation. To enhance delivery and simplify the system, biomimetic exosomes loaded with osa-miR164d (osa-miR164d-MGELNs) were developed. In vitro and in vivo experiments demonstrated that osa-miR164d-MGELNs effectively reduced inflammation and improved colitis by reprogramming macrophage polarization. The findings provide new insights into the role of GELNs-derived miRNAs in cross-kingdom communication and offer a potential therapeutic strategy for intestinal inflammation.This study investigates the therapeutic potential of ginger exosome-like nanoparticles (GELNs)-derived miRNAs in alleviating intestinal inflammation. GELNs were isolated and characterized, and their ability to modulate macrophage polarization was assessed. The study identified osa-miR164d as a key regulator of macrophage polarization, specifically targeting TAB1 to promote M2 polarization and inhibit inflammation. To enhance delivery and simplify the system, biomimetic exosomes loaded with osa-miR164d (osa-miR164d-MGELNs) were developed. In vitro and in vivo experiments demonstrated that osa-miR164d-MGELNs effectively reduced inflammation and improved colitis by reprogramming macrophage polarization. The findings provide new insights into the role of GELNs-derived miRNAs in cross-kingdom communication and offer a potential therapeutic strategy for intestinal inflammation.