PDF(Pubmed)
Abstract：
As endogenous courier vesicles, exosomes play crucial roles in macromolecule transmission and intercellular communication. Therefore, exosomes have drawn increasing attention as biomimetic drug-delivery vehicles over the past few years. However, few studies have investigated the encapsulation of peptide/protein drugs into exosomes for oral administration. Additionally, the mechanisms underlying their biomimetic properties as oral delivery vehicles remain unknown. Herein, insulin-loaded milk-derived exosomes (EXO@INS) were fabricated and the in vivo hypoglycemic effect was investigated on type I diabetic rats. Surprisingly, EXO@INS (50 and 30 IU/kg) elicited a more superior and more sustained hypoglycemic effect compared with that obtained with subcutaneously injected insulin. Further mechanism studies indicated that the origin of excellent oral-performance of milk-derived exosomes combined active multi-targeting uptake, pH adaptation during gastrointestinal transit, nutrient assimilation related ERK1/2 and p38 MAPK signal pathway activation and intestinal mucus penetration. This study provides the first demonstration that multifunctional milk-derived exosomes offer solutions to many of the challenges arising from oral drug delivery and thus provide new insights into developing naturally-equipped nanovehicles for oral drug administration.
摘要：
作为内源性信使囊泡，外泌体在大分子传递和细胞间通讯中起着至关重要的作用。因此,在过去的几年中，外泌体作为仿生药物递送载体引起了越来越多的关注。然而,很少有研究研究将肽/蛋白质药物封装到外泌体中用于口服给药。此外,它们作为口服给药载体的仿生特性的潜在机制仍然未知.在这里，制备了负载胰岛素的乳源外泌体（EXO@INS），并研究了I型糖尿病大鼠的体内降血糖作用。令人惊讶的是,与皮下注射胰岛素相比，EXO@INS（50和30IU/kg）引起的降血糖效果更好，更持久。进一步的机制研究表明，优秀的口服性能的乳源外泌体结合主动多靶向摄取，胃肠道运输过程中的pH适应，养分同化与ERK1/2和p38MAPK旌旗灯号通路激活和肠粘液穿透有关。这项研究首次证明了多功能乳源外泌体为口服药物递送带来的许多挑战提供了解决方案，从而为开发用于口服药物施用的天然装备的纳米载体提供了新的见解。
