Harnessing Edible Extracellular Vesicles for Inflammatory Bowel Disease: From Natural Immunomodulators to Bioengineered Oral Nanotherapeutics

Inflammatory bowel disease (IBD) is a chronic, relapsing disorder of the gastrointestinal (GI) tract driven by complex interactions among mucosal immune dysregulation, epithelial barrier degradation, and microbial dysbiosis. Current therapies achieve only partial disease control and are limited by systemic toxicity, suboptimal response rates, and an inability to simultaneously restore epithelial integrity and microbial homeostasis. Colon-targeted oral delivery offers direct mucosal access with reduced systemic exposure; however, conventional oral formulations remain constrained by GI barriers, including proteolytic degradation, bile salt emulsification, and mucus entrapment, highlighting the need for more biocompatible delivery platforms. Edible extracellular vesicles (EEVs), encompassing plant- and milk-derived vesicles, have emerged as biogenic vehicles with the potential to partially withstand these delivery barriers. Their relative structural stability and cross-kingdom regulatory cargoes may allow EEVs to better traverse the oral-gut axis. Mechanistic studies reveal that these vesicles reprogram the intestinal inflammatory milieu by modulating immune networks, fortifying the epithelial barrier, and restoring microbiota homeostasis. Furthermore, their biodistribution enables therapeutic targeting beyond the colon, mitigating extraintestinal manifestations. In this review, we summarize the biophysical properties and immunomodulatory mechanisms of natural EEVs. We also discuss the translational limitations of native EEVs, including batch variability and payload leakage, and highlight the bioengineering strategies developed to address these challenges. Finally, we explore how integrating stimuli-responsive architectures from synthetic nanomedicine with EEVs' GI resilience may inform the design of next-generation oral platforms for IBD management.