Oligo(serine ester) Charge-Altering Releasable Transporters: Organocatalytic Ring-Opening Polymerization and their Use for in Vitro and in Vivo mRNA Delivery
Oligo(serine ester) Charge-Altering Releasable Transporters: Organocatalytic Ring-Opening Polymerization and their Use for in Vitro and in Vivo mRNA Delivery
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DOI：
10.1021/jacs.9b03154
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发表时间：
2019-05-29
影响因子：
15
通讯作者：
Wender, Paul A.
中科院分区：
文献类型：
--
作者：
Benner, Nancy L.;McClellan, Rebecca L.;Wender, Paul A.
RNA技术正在改变生命科学研究和医学，但许多应用受到递送系统的可及性、成本、有效性和耐受性的限制。在这里，我们报道了一类新的动态RNA递送载体的第一个成员，基于寡聚(丝氨酸酯)的电荷改变可释放转运体(Ser-Cart)。由含脂低聚碳酸酯和阳离子低聚(丝氨酸酯)组成，Ser-carts很容易通过使用硫脲阴离子的温和开环聚合制备(一个烧瓶)，并且在与mRNA简单混合后，很容易形成降解为中性丝氨酸产品的复合体，有效地释放它们的mRNA货物。体外获得了95%的mRNA/Ser-Cart转染率。肌肉注射或静脉注射(Iv)mRNA/Ser-carts到活体小鼠体内可导致荧光素酶报告蛋白的体内表达，静脉注射后观察到脾的定位。
RNA technology is transforming life science research and medicine, but many applications are limited by the accessibility, cost, efficacy, and tolerability of delivery systems. Here we report the first members of a new class of dynamic RNA delivery vectors, oligo(serine ester)-based charge-altering releasable transporters (Ser-CARTs). Composed of lipid-containing oligocarbonates and cationic oligo(serine esters), Ser-CARTs are readily prepared (one flask) by a mild ring opening polymerization using thiourea anions and, upon simple mixing with mRNA, readily form complexes that degrade to neutral serine-based products, efficiently releasing their mRNA cargo. mRNA/Ser-CART transfection efficiencies of >95% are achieved in vitro. Intramuscular or intravenous (iv) injections of mRNA/Ser-CARTs into living mice result in in vivo expression of a luciferase reporter protein, with spleen localization observed after iv injection.