Guanidine-phosphate interactions stabilize polyion complex micelles based on flexible catiomers to improve mRNA delivery
Guanidine-phosphate interactions stabilize polyion complex micelles based on flexible catiomers to improve mRNA delivery
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DOI：
10.1016/j.eurpolymj.2020.110028
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发表时间：
2020-11-05
影响因子：
6
通讯作者：
Cabral, Horacio
中科院分区：
文献类型：
--
作者：
Miyazaki, Takuya;Uchida, Satoshi;Cabral, Horacio
信使RNA（mRNA）作为治疗剂具有巨大的潜力，尽管其广泛的适用性受到核酸酶攻击的快速降解和难以进入细胞的阻碍。由嵌段阳离子聚合物组成的聚离子复合物（PIC）胶束是一种很有前途的mRNA载体，因为它们能有效地保护PIC核心中的mRNA，并能促进mRNA的细胞摄取。我们最近已经表明，柔性聚阳离子可以促进阳离子和mRNA之间的相互作用，以提高递送效率，这表明，通过改造PIC的形成，可以提高负载mRNA的PIC胶束（mRNA/m）的功效。在本文中，我们专注于聚阳离子片段和mRNA之间的价态，并研究其与柔性阳离子聚合物合作促进mRNA稳定性和递送效率以产生有效纳米载体的能力。通过制备聚乙二醇-聚缩水甘油甲基胍（PEG-PGMG）和聚乙二醇-聚缩水甘油甲基胺（PEG-PGMA）两种不同嵌段共聚物，比较了胍和伯胺的官能度。与由PEG-PGMA制备的mRNA/m（mRNA/mPGMA）相比，来自PEG-PGMG的mRNA/m（mRNA/mPGMG）显示出对生物分子（包括聚阴离子、尿素和核酸酶）的增强的稳定性，从而导致高的细胞摄取和蛋白质翻译效率。我们的研究结果表明，在聚阳离子嵌段共聚物和mRNA中的磷酸基团的胍部分之间的多价相互作用是一个关键因素，稳定mRNA/m提高mRNA的递送效率。
Messenger RNA (mRNA) holds great potential as therapeutic agent, though its broad applicability is hampered by its rapid degradation by nuclease attacks and poor access to cells. Polyion complex (PIC) micelles comprising block catiomers are promising mRNA carriers, because of their effective mRNA protection in the PIC core and the capability to promote mRNA cellular uptake. We have recently shown that flexible polycations can promote the interaction between catiomers and mRNA toward improving delivery efficiency, demonstrating that, by engineering the PIC formation, the efficacy of mRNA-loaded PIC micelles (mRNA/m) can be improved. Herein, we focused on the valency between the polycation segment and mRNA, and studied its ability to promote, in collaboration with the flexible catiomers, mRNA stability and delivery efficiency for producing potent nanocarriers. The functionalities of guanidine and primary amine were compared through preparation of two different block copolymers, namely, poly(ethylene glycol)-poly(glycidyl methyl guanidine) (PEG-PGMG) and PEG-poly(glycidyl methyl amine (PEG-PGMA)). mRNA/m from PEG-PGMG (mRNA/mPGMG) showed enhanced stability against biological molecules, including polyanions, urea and nucleases compared to mRNA/m prepared from PEG-PGMA (mRNA/mPGMA), resulting in high efficiency of cellular uptake and protein translation. Our results indicate that multivalent interactions between the guanidine moieties in the polycation segments of block copolymers and the phosphate groups in mRNA are a key factor for stabilizing mRNA/m toward improving mRNA delivery efficiency.