The field of extracellular vesicle RNA (EV-RNA) research in inflammatory bowel disease (IBD) is rapidly advancing, offering exciting possibilities for both diagnosis and treatment. This comprehensive review, led by Professor Xiyang Wei and his team from Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, provides a thorough exploration of EV-RNAs' diverse roles in IBD. By synthesizing the latest findings from multi-omics studies and animal experiments, the review highlights the potential of EV-RNAs as non-invasive biomarkers and therapeutic targets.
IBD, a lifelong gastrointestinal disorder, poses significant challenges for patients. Current diagnostic methods, such as invasive endoscopy, are often unreliable and uncomfortable. Treatment options, including conventional anti-inflammatory drugs and biological therapies, frequently cause systemic side effects and can lead to drug resistance. This underscores the urgent need for more accurate, non-invasive diagnostic tools and safer, targeted treatment strategies.
EV-RNAs, which are RNA molecules associated with extracellular vesicles (EVs), play a crucial role in IBD pathogenesis. Pathogenic EV-RNAs can trigger excessive inflammation, damage the intestinal barrier, and disrupt gut microbiota balance, exacerbating disease progression. Conversely, beneficial EV-RNAs can alleviate inflammation, repair intestinal tissue, and restore mucosal homeostasis, showcasing strong therapeutic potential.
One of the most exciting clinical applications of EV-RNAs is their use as non-invasive diagnostic biomarkers. Unlike traditional endoscopy, EV-RNAs are protected by vesicles, allowing for stable detection in easily accessible biological fluids like plasma and saliva. Specific EV-RNA signatures, such as elevated levels of long non-coding RNA H19 in plasma EVs, can distinguish active IBD from remission with high accuracy, as evidenced by AUC values ranging from 0.95 to 0.97. Salivary EV-derived microRNA panels have also demonstrated good diagnostic performance, offering a truly non-invasive and patient-friendly tool for early screening and real-time monitoring of disease activity.
In terms of treatment, the review outlines various EV-RNA-based therapeutic strategies with remarkable effects in preclinical IBD models. Mesenchymal stem cell-derived EVs (MSC-EVs) carry immunomodulatory miRNAs that can suppress inflammation, promote intestinal barrier repair, and alleviate colitis in animal models. These cell-free EVs offer a safer alternative to whole-cell stem cell therapy, with reduced risks of immune rejection and tumorigenesis.
The review also highlights the potential of dietary and plant-derived EVs as oral therapeutic platforms. EVs extracted from natural sources like bovine colostrum, Coptis chinensis, Centella asiatica, and tea contain functional miRNAs that can survive the acidic gastrointestinal tract. These EVs directly target inflamed intestinal tissues and exert anti-inflammatory effects, providing a patient-friendly oral treatment option with minimal systemic side effects. For instance, Coptis chinensis EVs deliver a specific miRNA that restores zinc homeostasis in immune cells, inhibiting neutrophil-induced intestinal tissue damage, while bovine colostrum EVs carry a miRNA that blocks the NF-κB inflammatory signaling pathway.
Engineered EVs represent another cutting-edge direction in EV-RNA research. Researchers can modify EVs to display targeting molecules and load specific therapeutic RNAs, enabling precise and personalized delivery to inflamed intestinal tissues. In preclinical models, these engineered EVs have shown synergistic therapeutic effects, suppressing pathogenic T cell activation and delivering regulatory RNAs to correct disease-causing molecular defects, offering new hope for patients with refractory IBD who do not respond to conventional therapies.
Despite the promising findings, the team acknowledges several challenges that need to be addressed for clinical translation. A lack of standardized protocols for EV isolation, purification, and RNA detection can lead to inconsistencies in study results across different laboratories. Large-scale multi-center clinical trials are necessary to verify the diagnostic and therapeutic efficacy of EV-RNAs in human patients, and clear regulatory pathways for EV-based therapeutics are required.
Professor Wei emphasizes the rapid progress in the field and the pivotal role of EV-RNAs in IBD management. The review integrates the latest evidence to demonstrate that EV-RNAs are not passive bystanders but core regulators that can be targeted for both diagnosis and treatment. The team hopes that this work will guide future research, accelerate the translation of these discoveries from the laboratory to the clinic, and ultimately bring more effective and personalized treatment to IBD patients worldwide.
