Milk-derived extracellular vesicles in cardiovascular therapy: emerging biological functions and therapeutic perspectives.

Cardiovascular diseases remain a leading cause of morbidity and mortality worldwide and impose a substantial clinical and socioeconomic burden. Despite advances in medical, interventional, and surgical treatments, considerable residual cardiovascular risk persists, highlighting the need for effective and sustainable therapeutic approaches. Milk-derived extracellular vesicles (MDEVs) are heterogeneous lipid-bilayer vesicles present in human and bovine milk and have attracted increasing interest as potential orally administered biological nanocarriers. MDEVs carry diverse bioactive cargo, including proteins, lipids, messenger RNAs, microRNAs, and long non-coding RNAs, while their membrane-associated components may contribute to gastrointestinal stability, cargo protection, and interactions with intestinal cells. Emerging preclinical evidence suggests that MDEVs may influence inflammatory responses, oxidative stress, myocardial fibrosis, angiogenesis, and gut-heart axis signaling. However, direct evidence from cardiovascular disease models remains limited, and several proposed mechanisms are supported primarily by studies conducted in intestinal, metabolic, oncological, or other non-cardiovascular settings. MDEVs can also be engineered to carry nucleic acids, peptides, proteins, and small-molecule drugs or to introduce tissue-targeting properties. Nevertheless, their systemic absorption, biodistribution, cardiovascular tissue accumulation, and long-term safety after oral administration remain insufficiently defined. Moreover, milk source, processing conditions, isolation methods, co-isolated non-vesicular components, cargo composition, dose metrics, administration routes, and disease models may substantially affect the reported biological effects. Continued advances in purification, standardized characterization, rigorous biodistribution analysis, safety assessment, and scalable manufacturing are therefore required to determine the translational potential of MDEVs in cardiovascular therapy.