Extracellular vesicle-based therapies in IBD: immunomodulation, regeneration, and translation

Inflammatory bowel disease (IBD) is sustained by dysregulated mucosal immune activation, maladaptive immune-cell crosstalk, epithelial barrier failure, and impaired tissue repair. This narrative review critically evaluates unmodified native mammalian EVs, donor-conditioned EVs, milk-derived EVs, post-isolation engineered EV products, and plant-derived EV-like nanoparticles (PELNs) as candidate immunomodulatory and mucosal-repair platforms. The evidence is dominated by chemically induced rodent colitis, particularly acute mucosal injury models; controlled efficacy data in patients with luminal ulcerative colitis or Crohn's disease are not available, and the small uncontrolled perianal-fistula study provides only preliminary local safety and feasibility observations. Reported outcomes include changes in inflammatory myeloid states, tolerance-associated dendritic-cell states, Treg/Th17 balance, epithelial protection, barrier restoration, tissue repair, and, for a narrower subset of preparations, stem/progenitor-associated regeneration. Mechanistic intervention studies include dendritic-cell AMPK dependence for broccoli-derived nanoparticles and PD-1/PHB1-related activity for engineered PD-L1/miR-27a-3p EVs, whereas many macrophage, microbiota, barrier, and cargo-delivery claims remain associative or preparation-specific. Engineering may improve exposure, target-cell engagement, cargo control, or receptor signaling, but each proposed advantage requires direct comparison with an appropriate unmodified or clinically relevant comparator and introduces additional manufacturing and safety requirements. We therefore separate product identity, disease-relevant regional or systemic exposure, target-cell engagement, functional intracellular cargo delivery, surface-receptor signaling, pharmacodynamic response, and repair outcomes. Translation will require reproducible dose metrics, mechanism-linked validation, validated lot-release potency assays, chronic repeat-dose safety, and phenotype-relevant human models.