Bridging mRNA and polycation using RNA oligonucleotide derivatives improves the robustness of polyplex micelle for efficient mRNA delivery.
Bridging mRNA and polycation using RNA oligonucleotide derivatives improves the robustness of polyplex micelle for efficient mRNA delivery.
复制标题
使用 RNA 寡核苷酸衍生物桥接 mRNA 和聚阳离子可提高聚合物胶束的稳健性，以实现有效的 mRNA 递送。
DOI：
10.1002/adhm.202102016
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
K. Kataoka,
中科院分区：
文献类型：
--
作者：
N. Yoshinaga;S. Uchida;A. Dirisala;M. Naito;K. Koji;K. Osada;H. Cabral;K. Kataoka,
信使RNA(信使RNA)递送的Polyplex需要在信使RNA和聚阳离子之间具有强烈的但可逆的关联，以实现细胞外的稳定性和选择性的细胞内解体。在这里，连接mRNA和聚阳离子的RNA寡核苷酸(OrigoRNA)衍生物被开发出来以稳定多链胶束(PM)。一组在其5‘端引入多元醇部分的寡聚RNA被设计用于杂交到沿mRNA链的固定位置。从杂化的mRNA和聚乙二醇阳离子嵌段共聚物制备PM后，PBA部分在PM核心中与寡聚RNA的5‘端的多元醇部分和核糖的3’端的二醇部分形成可逆的苯基硼酸酯键。寡聚RNA作为一个节点连接离子络合的mRNA和聚阳离子，从而提高PM在细胞外环境中抵抗多离子交换反应和核糖核酸酶攻击的稳定性。在细胞摄取后，细胞内高浓度的三磷酸腺苷触发苯基硼酸酯连接的断裂，导致PM释放mRNA最终，PM在气管内给药后，在培养细胞和小鼠肺中提供了有效的mRNA导入，展示了桥接策略在基于多聚体的mRNA传递中的潜力。
Polyplex for messenger RNA (mRNA) delivery requires strong yet reversible association between mRNA and polycation for extracellular robustness and selective intracellular disintegration. Herein, RNA oligonucleotide (OligoRNA) derivatives that bridge mRNA and polycation are developed to stabilize polyplex micelles (PMs). A set of the OligoRNAs introduced with a polyol moiety in their 5′ end is designed to hybridize to fixed positions along mRNA strand. After PM preparation from the hybridized mRNA and poly(ethylene glycol)‐polycation block copolymer derived with phenylboronic acid (PBA) moieties in its cationic segment, PBA moieties form reversible phenylboronate ester linkages with a polyol moiety at 5′ end of OligoRNAs and a diol moiety at their 3′ end ribose, in the PM core. The OligoRNAs work as a node to bridge ionically complexed mRNA and polycation, thereby improving PM stability against polyion exchange reaction and ribonuclease attack in extracellular environment. After cellular uptake, intracellular high concentration of adenosine triphosphate triggers the cleavage of phenylboronate ester linkages, resulting in mRNA release from PM. Ultimately, the PM provides efficient mRNA introduction in cultured cells and mouse lungs after intratracheal administration, demonstrating the potential of the bridging strategy in polyplex‐based mRNA delivery.