Milk-derived extracellular vesicles (mEVs) have been proposed as a potential nanomedicine for intestinal disorders; however, their impact on intestinal barrier integrity in gut inflammation and associated metabolic diseases has not been explored yet. Here, mEVs derived from bovine and human breast milk exert similar protective effects on epithelial tight junction functionality in vitro, survive harsh gastrointestinal conditions ex vivo, and reach the colon in vivo. Oral administration of mEVs restores gut barrier integrity at multiple levels, including mucus, epithelial, and immune barriers, and prevents endotoxin translocation into the liver in chemical-induced experimental colitis and diet-induced nonalcoholic steatohepatitis (NASH), thereby alleviating gut disorders, their associated liver inflammation, and NASH. Oral administration of mEVs has potential in the treatment of gut inflammation and gut-liver axis–associated metabolic diseases via protection of intestinal barrier integrity.

Food‐derived extracellular vesicles (FEVs) are nanoscale membrane vesicles obtained from dietary materials such as breast milk, plants and probiotics. Distinct from other EVs, FEVs can survive the harsh degrading conditions in the gastrointestinal tract and reach the intestines. This unique feature allows FEVs to be promising prebiotics in health and oral nanomedicine for gut disorders, such as inflammatory bowel disease. Interestingly, therapeutic effects of FEVs have recently also been observed in non‐gastrointestinal diseases. However, the mechanisms remain unclear or even mysterious. It is speculated that orally administered FEVs could enter the bloodstream, reach remote organs, and thus exert therapeutic effects therein. However, emerging evidence suggests that the amount of FEVs reaching organs beyond the gastrointestinal tract is marginal and may be insufficient to account for the significant therapeutic effects achieved regarding diseases involving remote organs such as the liver. Thus, we herein propose that FEVs primarily act locally in the intestine by modulating intestinal microenvironments such as barrier integrity and microbiota, thereby eliciting therapeutic impact remotely on the liver in non‐gastrointestinal diseases via the gut‐liver axis. Likewise, drugs delivered to the gastrointestinal system through FEVs may act via the gut‐liver axis. As the liver is the main metabolic hub, the intestinal microenvironment may be implicated in other metabolic diseases. In fact, many patients with non‐alcoholic fatty liver disease, obesity, diabetes and cardiovascular disease suffer from a leaky gut and dysbiosis. In this review, we provide an overview of the recent progress in FEVs and discuss their biomedical applications as therapeutic agents and drug delivery systems, highlighting the pivotal role of the gut‐liver axis in the mechanisms of action of FEVs for the treatment of gut disorders and metabolic diseases.

Pre-inflammatory bowel disease (pre-IBD) represents a transitional state between irritable bowel syndrome and IBD, characterized by heightened susceptibility to mucosal inflammation driven by chronic high-fat diet intake and antibiotic exposure. However, effective intervention strategies remain poorly defined. Here, we identify milk-derived extracellular vesicles (mEVs) as a potent nanotherapeutic capable of attenuating pre-IBD pathology. Pre-IBD mice displayed marked gut microbiota dysbiosis and mucosal inflammation, both of which were substantially ameliorated by oral mEVs administration. Mechanistically, mEVs restored microbial homeostasis by enriching Lactobacillus murinus (L. murinus), which in turn reduced lysophosphatidylcholine (LPC) accumulation, two factors that exerted opposing and functionally instructive effects on intestinal inflammation. LPC activated the TLR2/MAPK axis to promote M1 polarization, whereas L. murinus engaged the TLR2/STAT3 pathway to drive M2 polarization. Collectively, these findings demonstrate that mEVs reprogram TLR2-dependent macrophage responses by modulating LPC and L. murinus, thereby mitigating mucosal inflammation and preventing the progression of pre-IBD.

The early and accurate diagnosis of acute myocardial infarction (AMI) remains a significant clinical challenge. To this end, we profiled the surface proteo

Milk-derived extracellular vesicles (mEVs) derived from bovine colostrum (C-mEVs) and mature milk (M-mEVs) are known to carry bioactive molecules with significant immunomodulatory properties and biological effects. However, most research on mEVs has focused on their proteomics, lipidomics, and transcriptome, while metabolome analysis are still lacking. This study aims to explore the metabolomic profiles of C-mEVs and M-mEVs to uncover their molecular characteristics and potential biological functions. The mEVs were purified from both bovine colostrum and mature milk using ultracentrifugation combined with size exclusion chromatography. Through untargeted metabolomic analysis employing liquid chromatography-tandem mass spectrometry (LC-MS/MS), 76 differential metabolites, such as leucylproline, levonordefrin, adenine, polyglycerol esters of fatty acids, and hypoxanthine were identified. Among them, lipid-related metabolites were the most prominent. Hierarchical cluster analysis and principal component analysis revealed distinct metabolic signatures between C-mEVs and M-mEVs. Pathway enrichment analysis indicated that the metabolites were involved in purine metabolism and ABC transporter pathways, which was closely related to cancer, inflammation, gastrointestinal disorders, and metabolic diseases. The findings highlight the potential of metabolomics to provide a temporally precise and detailed snapshot of the molecular properties of mEVs, contributing valuable insights into mEVs-mediated molecular mechanisms and offering new avenues for research into their biological effects and therapeutic applications.