Exosome-mediated macrophage regulation in the development and treatment of inflammatory bowel disease

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic, relapsing–remitting inflammatory disorder of the gastrointestinal tract marked by persistent mucosal immune dysregulation. Among the central cellular players in IBD pathogenesis are macrophages. They are highly plastic and heterogeneous immune cells and pivotal in orchestrating tissue inflammation, injury responses, and epithelial repair. Macrophage polarization into pro-inflammatory or anti-inflammatory/reparative phenotypes critically shapes the trajectory of intestinal inflammation, with their balance tightly linked to disease activity and progression. Therefore, macrophages are thought essential for the constant regeneration of intestinal epithelial cells and maintaining the immune homeostasis of the intestinal mucosa. Recently, emerging evidence has highlighted the therapeutic potential of exosomes, nanoscale extracellular vesicles enriched with lipids, proteins, nucleic acids, and other bioactive cargos, in modulating immune responses and inflammation processes. Owing to their intrinsic properties such as targeted molecular delivery, biodegradability, and biological stability, exosomes represent a compelling platform for therapeutic intervention in IBD. Notably, exosomes have been shown to influence macrophage polarization and pyroptosis, thereby altering the inflammatory milieu of the gut. In this review, we comprehensively examine the molecular composition and functional attributes of exosomes, delineate their interactions with macrophage subsets, and discuss how exosomes derived from various cellular sources modulate macrophage-mediated immunity in the context of IBD. We further explore current progress and future directions for the clinical translation of exosome-based therapies, addressing both their therapeutic promise and the challenges that remain in harnessing their full potential.