Exosomes are natural nanoparticles that originate in the endocytic system. Exosomes play an important role in cell-to-cell communication by transferring RNAs, lipids and proteins from donor cells to recipient cells or by binding to receptors on the recipient cell surface. The concentration of exosomes and the diversity of cargos is high in milk, and they resist degradation in the gastrointestinal tract and during processing of milk in dairy plants, are absorbed and accumulate in tissues following oral administrations, cross the blood-brain barrier, and dietary depletion and supplementation elicit phenotypes. These features have sparked the interest of the nutrition and pharmacology communities for exploring milk exosomes as novel bioactive food compounds and for delivering drugs to diseased tissues. This review discusses the current knowledgebase, uncertainties, and controversies in these lines of scholarly endeavor and health research.
Background Milk exosomes and their microRNA (miR) cargos are bioavailable. The content of exosomes and miRs is negligible in infant formulas compared to human milk, and dietary depletion of exosomes led to changes in bacterial communities and impaired gut health in juvenile mice. Adverse effects of formula feeding may be compounded by using soy formulas due to exosome binding by abundant lectins in that matrix. The purpose of this study was to assess the bioavailability of milk exosomes and their miR cargos added to soy formula in adults, as well as the potential role of soy lectins in exosome bioavailability. Methods Eleven healthy adults (6 men, 5 women) enrolled in this randomized crossover study. Participants consumed 1.0 l of soy formula without (SF) or with (SFE) bovine milk exosomes added. Concentration-time curves of six plasma miRs were analyzed using reverse transcription quantitative PCR. Lectin affinity chromatography was used to assess the binding of exosomes by soy lectins. Data were analyzed by using paired t test. P < 0.05 was considered statistically significant. Results Consumption of SF and SFE did not elicit postprandial increases in plasma miRs. Approximately 39% of bovine milk exosome particles were retained by lectin columns. Conclusions We conclude that fortification of soy formulas with milk exosomes, in the absence of removing lectins, is not a viable strategy for delivering bioavailable exosomes and their miR cargos. Lectins in soy formulas bind glycoprotein on the surfaces of milk exosomes, thereby preventing exosome absorption. Trial registration ISRCTN registry ID: 16329971. Retrospectively registered on February 7th, 2019.
Small extracellular vesicles (sEVs) in milk have the qualities desired for delivering therapeutics to diseased tissues. The production of bovine milk sEVs is scalable (1021 annually per cow), and they resist degradation in the gastrointestinal tract. Most cells studied to date internalize milk sEVs by a saturable process that follows Michaelis-Menten kinetics. The bioavailability of oral milk sEVs is approximately 50%. In addition to crossing the intestinal mucosa, milk sEVs also cross barriers such as the placenta and blood-brain barrier, thereby enabling the delivery of therapeutics to hard-to-reach tissues. In time course studies, levels of milk sEVs peaked in the intestinal mucosa, plasma, and urine approximately 6 h and returned to baseline 24 h after oral gavage in mice. In tissues, milk sEV levels peaked 12 h after gavage. Milk sEVs appear to be biologically safe. No cytokine storm was observed when milk sEVs were added to cultures of human peripheral blood mononuclear cells or administered orally to rats. Liver and kidney function and erythropoiesis were not impaired when milk sEVs were administered to rats by oral gavage for up to 15 days. Protocols for loading milk sEVs with therapeutic cargo are available. Currently, the use of milk sEVs (and other nanoparticles) in the delivery of therapeutics is limited by their rapid elimination through internalization by macrophages and lysosomal degradation in target cells. This mini review discusses the current knowledge base of sEV tissue distribution, excretion in feces and urine, internalization by macrophages, and degradation in lysosomes.
Background: Milk exosomes and their microRNA (miR) cargos are bioavailable. The content of exosomes and miRs is negligible in infant formulas compared to human milk, and dietary depletion of exosomes led to changes in bacterial communities and impaired gut health in juvenile mice. Adverse effects of formula feeding may be compounded by using soy formulas due to exosome binding by abundant lectins in that matrix. The purpose of this study was to assess the bioavailability of milk exosomes and their miR cargos added to soy formula in adults, as well as the potential role of soy lectins in exosome bioavailability.Methods: Eleven healthy adults (6 men, 5 women) enrolled in this randomized crossover study. Participants consumed 1.0 liter of soy formula without (SF) or with (SFE) bovine milk exosomes added. Concentration-time curves of six plasma miRs were analyzed using reverse transcription quantitative PCR. Lectin affinity chromatography was used to assess the binding of exosomes by soy lectins. Data were analyzed by using paired t test. P < 0.05 was considered statistically significant.Results: Consumption of SF and SFE did not elicit postprandial increases in plasma miRs. Approximately 39% of bovine milk exosome particles were retained by lectin columns.Conclusions: We conclude that fortification of soy formulas with milk exosomes, in the absence of removing lectins, is not a viable strategy for delivering bioavailable exosomes and their miR cargos. Lectins in soy formulas bind glycoprotein on the surfaces of milk exosomes, thereby preventing exosome absorption.Trial RegistrationISRCTN registry ID: 16329971. Retrospectively registered on February 7th, 2019.
Objectives To develop BMEs that evade elimination by BMDMs. Methods Bovine mammary alveolar MAC-T cells secrete MEs and were used to engineer MEs that express proprietary protein features suspected to decrease elimination by BMDMs, denoted UNL1 and UNL2. MAC-T cells were transformed by using lentiviral vectors. BMEs featuring UNL1 or UNL2 were isolated from MAC-T cell culture media supernatant using polyethylene glycol (PEG) precipitation after removing cell debris by using a 0.22-μm filter. The BMEs were labeled using a carbonyl-reactive fluorescent dye and purified by ultracentrifugation. Primary BMDMs was isolated from mouse hind legs (C57BL/6J, aged 8–10 weeks) and seeded in 96-well plates for assessing BME uptake at a physiological concentration (1010 BMEs/mL). Uptake was compared to unmodified BMEs and normalized for BMDM density. Time points were compared pairwise by using t-test, and P < 0.05 was considered significant. Results The uptake of BME UNL1 by BMDMs was reduced by 37%, 42%, 48% and 47% as compared to unmodified BMEs after 12 h, 24 h, 36 h and 48h, respectively in culture dishes (P < .05; n = 5). Data are preliminary (n = 3), yet encouraging, for BME UNL2: The uptake of BME UNL2 was reduced by 41%, 44%, 46% and 46% compared to unmodified BMEs after 12 h, 24 h, 36 h and 48 h, respectively. Conclusions The elimination of BMEs UNL1 and UNL2 is significantly reduced compared unmodified BMEs in BMDM cultures. This is of great importance when using BMEs for delivering therapeutics. Funding Sources NIH P20GM104320, NIFA2016-67,001-25,301 and 2022–67,021-36,407), USDA Hatch and W-4002, and the SynGAP Research Fund (all to J. Z.). J.Z. serves as consultant for PureTech Health, Inc.
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