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Probing milk extracellular vesicles for intestinal delivery of RNA therapies.

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Zhang, Yunyue 
Belaid, Mona 
Luo, Xiang 
Daci, Armond 
Limani, Rinë 


BACKGROUND: Oral delivery remains unattainable for nucleic acid therapies. Many nanoparticle-based drug delivery systems have been investigated for this, but most suffer from poor gut stability, poor mucus diffusion and/or inefficient epithelial uptake. Extracellular vesicles from bovine milk (mEVs) possess desirable characteristics for oral delivery of nucleic acid therapies since they both survive digestion and traverse the intestinal mucosa. RESULTS: Using novel tools, we comprehensively examine the intestinal delivery of mEVs, probing whether they could be used as, or inform the design of, nanoparticles for oral nucleic acid therapies. We show that mEVs efficiently translocate across the Caco-2 intestinal model, which is not compromised by treatment with simulated intestinal fluids. For the first time, we also demonstrate transport of mEVs in novel 3D 'apical-out' and monolayer-based human intestinal epithelial organoids (IEOs). Importantly, mEVs loaded with small interfering RNA (siRNA) induced (glyceraldehyde 3-phosphate dehydrogenase, GAPDH) gene silencing in macrophages. Using inflammatory bowel disease (IBD) as an example application, we show that administration of anti-tumour necrosis factor alpha (TNFα) siRNA-loaded mEVs reduced inflammation in a IBD rat model. CONCLUSIONS: Together, this work demonstrates that mEVs could either act as natural and safe systems for oral delivery or nucleic acid therapies, or inform the design of synthetic systems for such application.


Acknowledgements: We thank Kailin Qin from King’s College London for his valuable assistance in capturing TEM images.

Funder: King’s-China Scholarship Council PhD Scholarship Programme


Extracellular vesicles, Inflammatory bowel disease, Intestinal epithelium, Oral nucleic acid delivery, siRNA, Humans, Rats, Animals, Caco-2 Cells, Milk, RNA, Small Interfering, Nanoparticles, Inflammatory Bowel Diseases, Intestinal Mucosa, Nucleic Acids

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J Nanobiotechnology

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Springer Science and Business Media LLC