Orally administered 5-ASA-loaded full-active nanodrug for targeted therapy of inflammatory bowel disease

Objectives: Inflammatory bowel disease (IBD) is a chronic, relapsing-remitting intestinal disorder that generally requires long-term pharmacological intervention. Clinically, mesalazine (5-aminosalicylic acid, 5-ASA) serves as the first-line anti-inflammatory agent for mild-to-moderate ulcerative colitis, owing to its antioxidant activity and biosafety profile. However, oral 5-ASA formulations suffer from limited therapeutic efficacy due to non-specific gastrointestinal distribution and poor local absorption at inflamed colonic sites. To address these limitations, we developed a self-targeting, full-active pharmaceutical ingredient nanodrug (FAND) by encapsulating 5-ASA within M2 macrophage-derived exosomes (M2-Exo), aiming to achieve synergistic IBD treatment through integrated oxidative stress mitigation and immune modulation. Methods: 5-ASA@M2-Exo was fabricated via electroporation and characterized for particle size, morphology, and physicochemical properties. The targeting and anti-inflammatory mechanisms were evaluated in CT-26 cells and lipopolysaccharide-induced macrophages. In vivo therapeutic efficacy and biosafety were assessed in a dextran sulfate sodium-induced mouse colitis model, with colon length, disease activity index (DAI), histopathological analysis, cytokine profiling, and myeloperoxidase (MPO) activity measured as primary endpoints. Results: 5-ASA@M2-Exo exhibited favorable physicochemical properties and significantly enhanced cellular uptake of 5-ASA at inflamed sites via chemokine receptor-mediated tropism. Mechanistically, the nanodrug exerted a quadruple synergistic effect including targeted scavenging of reactive oxygen species, regulation of cytokine homeostasis, promotion of epithelial cell proliferation, and repolarization of macrophages. In vivo, oral administration of 5-ASA@M2-Exo markedly attenuated body weight loss, reduced DAI scores, restored colon length, and preserved colonic histological architecture, which were accompanied by significantly reduced colonic MPO activity and pro-inflammatory cytokine levels. Notably, complete blood count analysis and histological examination of major organs confirmed favorable biosafety. Conclusions: This full-active nanodrug represents a promising, safe, and synergistic therapeutic strategy for the long-term management of IBD. Our approach advances the development of next-generation nanotherapeutics for inflammatory diseases.