Milk-derived extracellular vesicles loaded with miR-146a-5p as a novel therapeutic strategy for allergic airway inflammation.

Previous studies have demonstrated that miR-146a-5p can effectively inhibit the function of group 2 innate lymphoid cells (ILC2s), which play a pivotal role in the initiation of allergic airway inflammation (AAI), thereby alleviating AAI. However, the application of miR-146a-5p faces challenges such as susceptibility to degradation and difficulty in crossing the cellular membrane. Extracellular vesicles (EVs), which naturally transport proteins and nucleic acids, have been proposed as promising RNA delivery vehicles. EVs can protect microRNAs (miRNAs) from degradation and facilitate their penetration across cellular membranes. However, the lack of scalable sources of EVs remains a challenge for their mass production, particularly in clinical application. Bovine milk has emerged as an advantageous source for the large-scale production of EVs because of its low cost and easy accessibility. Moreover, bovine milk-derived EVs (mEVs) have shown low immunogenicity and outstanding cross-species biosafety. In this study, we present the manufacturing methods and immune regulatory effects of mEVs loaded with miR-146a-5p (miR146a-5p-mEVs). Our findings indicated that mEVs exhibited outstanding biosafety and did not elicit significant systemic toxicity. Importantly, miR146a-5p-mEVs exhibited significant immunoregulatory functions in AAI, suggesting that miR146a-5p-mEVs could serve as a novel strategy for the treatment of allergic airway disease.