McKinlay Colin J, Vargas Jessica R, Blake Timothy R, Hardy Jonathan W, Kanada Masamitsu, Contag Christopher H, Wender Paul A, Waymouth Robert M
Department of Chemistry, Stanford University, Stanford, CA 94305.
Department of Pediatrics, Stanford University, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E448-E456. doi: 10.1073/pnas.1614193114. Epub 2017 Jan 9.
Functional delivery of mRNA to tissues in the body is key to implementing fundamentally new and potentially transformative strategies for vaccination, protein replacement therapy, and genome editing, collectively affecting approaches for the prevention, detection, and treatment of disease. Broadly applicable tools for the efficient delivery of mRNA into cultured cells would advance many areas of research, and effective and safe in vivo mRNA delivery could fundamentally transform clinical practice. Here we report the step-economical synthesis and evaluation of a tunable and effective class of synthetic biodegradable materials: charge-altering releasable transporters (CARTs) for mRNA delivery into cells. CARTs are structurally unique and operate through an unprecedented mechanism, serving initially as oligo(α-amino ester) cations that complex, protect, and deliver mRNA and then change physical properties through a degradative, charge-neutralizing intramolecular rearrangement, leading to intracellular release of functional mRNA and highly efficient protein translation. With demonstrated utility in both cultured cells and animals, this mRNA delivery technology should be broadly applicable to numerous research and therapeutic applications.
将信使核糖核酸（mRNA）有效地递送至体内组织是实施疫苗接种、蛋白质替代疗法和基因组编辑等全新且可能具有变革性的策略的关键，这些策略共同影响着疾病的预防、检测和治疗方法。能够将mRNA高效递送至培养细胞的广泛适用工具将推动许多研究领域的发展，而有效且安全的体内mRNA递送可能会从根本上改变临床实践。在此，我们报告了一类可调节且有效的合成可生物降解材料的分步经济合成及评估：用于将mRNA递送至细胞的电荷改变可释放转运体（CARTs）。CARTs结构独特，通过一种前所未有的机制发挥作用，最初作为寡聚（α - 氨基酯）阳离子，可与mRNA结合、保护并递送mRNA，然后通过降解性的电荷中和分子内重排改变物理性质，导致功能性mRNA在细胞内释放并实现高效蛋白质翻译。鉴于其在培养细胞和动物中均已证明的效用，这种mRNA递送技术应广泛适用于众多研究和治疗应用。
