Engineered Exosomes for Oral Administration: Breaking Gastrointestinal Barriers for Disease Therapy

Extracellular vesicles (EVs) and exosomes are nanoscale vesicles from diverse biological sources, including animals, plants, and bacteria. Due to their pharmacological activity, high biosafety, and biocompatibility, they attract attention in intercellular signaling and therapeutic delivery. Oral administration is more convenient than invasive routes. Engineering strategies (surface modification, hybridization, gastric acid-resistant encapsulation) significantly enhance gastrointestinal stability and targeting. This review summarizes research progress of engineered EVs or exosomes for oral administration in disease treatment. We discuss exosomes from different sources, compare their biogenesis, isolation, purification, characterization methods, examine engineering strategies for gastrointestinal stability, and summarize application potential. We place special emphasis on the clinical trials of oral exosome administration that have not yet obtained clinical approval, and further discuss the current challenges and prospects for clinical translation. Establishing unified production, quality control, and regulatory standards for exosomes in preclinical stage, analyzing structural characteristics and mechanisms of crossing the gastrointestinal barrier, and combining with the quantitative analysis of exosomes in the gastrointestinal tract combining quantitative analysis of exosomes in the gut will help formulate more effective clinical translation strategies.