Bioactive metal-phenolic network and prebiotic hydrogel synergize with mesenchymal stem cell-derived extracellular vesicles for microenvironment-modulating therapy of inflammatory bowel disease

Mesenchymal stem cell-derived extracellular vesicles (MVs) hold great promise for inflammatory bowel disease (IBD) therapy. However, oral delivery of MVs therapeutic efficacy is severely compromised by the harsh gastrointestinal environment and the hostile inflammatory milieu, characterized by excessive oxidative stress and dysbiosis. To surmount these biological barriers, we engineered Inu@MPN@MV, a multifunctional oral delivery platform that integrates MVs with a caffeic acid-Fe³⁺ metal-phenolic network (MPN) coating and an inulin-based hydrogel matrix. In this synergistic system, the inulin hydrogel provides gastric protection and enables colon-specific release, while simultaneously functioning as a prebiotic to foster a beneficial microbial niche. Concurrently, the MPN coating endows the vesicles with potent ROS-scavenging capabilities, shielding them from oxidative damage and promoting their accumulation at inflamed sites. In a dextran sulfate sodium (DSS)-induced colitis model, oral administration of Inu@MPN@MV yielded superior therapeutic outcomes compared to controls, effectively ameliorating clinical symptoms, restoring epithelial barrier integrity, and mitigating oxidative injury. Mechanistically, the formulation orchestrates a synergistic interplay between the immunoregulatory cargo of MVs and the microenvironment-modulating properties of the carrier. This combination reprograms macrophage polarization toward an anti-inflammatory phenotype, remodels gut microbiota composition, and restores metabolic homeostasis. Collectively, this study presents a rationally designed bioactive oral system where carrier components actively potentiate the intrinsic therapeutic effects of MVs, offering a robust strategy for IBD management. Graphic abstract illustrating the multi-functional synergistic regulatory mechanism of Inu@MPN@MV in the treatment of IBD. Inu@MPN@MV is designed to protect MV during gastrointestinal transit, enable colonic release and retention, scavenge reactive oxygen species, modulate gut microbiota, regulate macrophage polarization, and promote epithelial barrier repair in DSS-induced colitis