Dietary and orally-delivered miRNAs: are they functional and ready to modulate immunity?

MicroRNAs (miRNAs), that is, short non-coding RNA molecules, have been found in different common foods, like fruits and vegetables, meat and its products, milk (including human breast milk) and dairy products, as well as honey and herbs. Moreover, they are isolated from supernatants from cultures of various mammalian cells. A growing amount of evidence appears to support the idea of using miRNAs as therapeutics. One possible and promising route of administration is oral, which is considered noninvasive and well-tolerated by patients. Association with extracellular vesicles (EVs), nanoparticles, RNA-binding proteins, lipoproteins, or lipid derivatives, protects miRNAs from an unfavorable gastrointestinal environment (including salivary and pancreatic RNases, low pH in the stomach, digestive enzymes, peristaltic activity and microbial enzymes). Such protection likely favors miRNA absorption from the digestive tract. Internalization of miRNA by gastric and intestinal cells as well as effects on the gut microbiota by orally delivered miRNA have recently been described. Furthermore, gene regulation by orally administered miRNAs and their immunomodulatory properties indicate the possibility of cross-species or cross-kingdom communication through miRNA. In addition to the local effects, these molecules may enter the circulatory system and reach distant tissues, and thus cell-free nucleic acids are promising candidates for future selective treatments of various diseases. Nonetheless, different limitations of such a therapy imply a number of questions for detailed investigation.