Milk-borne small extracellular vesicles: kinetics and mechanisms of transport, distribution, and elimination.

Alice Ngu, Javaria Munir, Janos Zempleni
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Abstract

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.

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乳源性细胞外小泡:转运、分布和消除的动力学和机制。
牛奶中的细胞外小泡(sEV)具有向病变组织提供治疗所需的品质。牛奶sEV的生产是可扩展的(每头牛每年1021个),并且它们可以抵抗胃肠道中的降解。迄今为止,研究的大多数细胞通过遵循Michaelis-Menten动力学的可饱和过程内化牛奶sEV。口服乳sEV的生物利用度约为50%。除了穿过肠粘膜,牛奶sEV还穿过胎盘和血脑屏障等屏障,从而能够将治疗药物输送到难以到达的组织。在时间进程研究中,小鼠肠粘膜、血浆和尿液中的乳汁sEV水平在约6小时达到峰值,并在灌胃后24小时恢复到基线水平。在组织中,牛奶sEV水平在灌胃后12小时达到峰值。牛奶sEV似乎在生物学上是安全的。当将牛奶sEV添加到人外周血单核细胞的培养物中或口服给大鼠时,没有观察到细胞因子风暴。大鼠经口灌胃给药15天后,肝、肾功能和红细胞生成没有受损。提供了用治疗货物装载牛奶sEV的协议。目前,牛奶sEV(和其他纳米颗粒)在治疗中的使用受到巨噬细胞内化和靶细胞溶酶体降解快速消除的限制。这篇小型综述讨论了sEV组织分布、粪便和尿液中的排泄、巨噬细胞的内化和溶酶体中的降解的当前知识库。
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