Chen Zhaowei, Wang Jinqiang, Sun Wujin, Archibong Edikan, Kahkoska Anna R, Zhang Xudong, Lu Yue, Ligler Frances S, Buse John B, Gu Zhen
Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, North Carolina, USA.
Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Nat Chem Biol. 2018 Jan;14(1):86-93. doi: 10.1038/nchembio.2511. Epub 2017 Oct 30.
Generating artificial pancreatic beta cells by using synthetic materials to mimic glucose-responsive insulin secretion in a robust manner holds promise for improving clinical outcomes in people with diabetes. Here, we describe the construction of artificial beta cells (AβCs) with a multicompartmental 'vesicles-in-vesicle' superstructure equipped with a glucose-metabolism system and membrane-fusion machinery. Through a sequential cascade of glucose uptake, enzymatic oxidation and proton efflux, the AβCs can effectively distinguish between high and normal glucose levels. Under hyperglycemic conditions, high glucose uptake and oxidation generate a low pH (<5.6), which then induces steric deshielding of peptides tethered to the insulin-loaded inner small liposomal vesicles. The peptides on the small vesicles then form coiled coils with the complementary peptides anchored on the inner surfaces of large vesicles, thus bringing the membranes of the inner and outer vesicles together and triggering their fusion and insulin 'exocytosis'.
利用合成材料以强大的方式模拟葡萄糖响应性胰岛素分泌来生成人工胰腺β细胞，有望改善糖尿病患者的临床治疗效果。在此，我们描述了具有多隔室“囊泡中囊泡”超结构的人工β细胞（AβCs）的构建，该超结构配备了葡萄糖代谢系统和膜融合机制。通过葡萄糖摄取、酶促氧化和质子外流的顺序级联反应，AβCs能够有效区分高血糖水平和正常血糖水平。在高血糖条件下，高葡萄糖摄取和氧化产生低pH值（<5.6），进而诱导与负载胰岛素的内部小脂质体囊泡相连的肽的空间去屏蔽。然后，小囊泡上的肽与锚定在大囊泡内表面的互补肽形成卷曲螺旋，从而使内囊泡和外囊泡的膜聚集在一起并触发它们的融合以及胰岛素“胞吐”。
