Interface-Engineered Oral Hybrid Nanotherapeutics Combining Cerium Nanozymes and Extracellular Vesicles for Multimodal Regulation of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder driven by oxidative stress, immune dysregulation, and gut microbiota imbalance. Current therapies often fail to address these interconnected mechanisms, resulting in unsatisfactory clinical outcomes. Here, we engineered an orally administered inflamed colon-targeted hybrid nanotherapeutic (ICHN) encapsulating mitochondrion-targeted cerium nanozymes (Ce-TPP), mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), and prebiotic inulin to synergistically target IBD pathogenesis. In vitro, Ce-TPP mitigated H2O2-induced oxidative damage in RAW264.7 cells, while MSC-EVs polarized macrophages toward anti-inflammatory M2 phenotypes, suppressing pro-inflammatory cytokines. In murine dextran sulfate sodium (DSS)-induced colitis models, ICHNs attenuated intestinal inflammation, improved gut barrier integrity (via tight junction upregulation), and restored gut microbiota composition. Mechanistically, this hybrid nanotherapeutics neutralized oxidative stress through Ce-TPP's multienzymatic ROS scavenging, modulated immune homeostasis via MSC-EV-driven macrophage reprogramming, and enriched beneficial symbionts (e.g., Akkermansia, Roseburia) while suppressing pathobionts (e.g., Escherichia/Shigella). By integrating antioxidative, immunoregulatory, and microbiota-modulating functions, ICHNs represent a transformative oral nanotherapeutic platform for multitargeted IBD management, bridging the gap between mechanistic complexity and clinical feasibility.