In vivo messenger RNA introduction into the central nervous system using polyplex nanomicelle.
In vivo messenger RNA introduction into the central nervous system using polyplex nanomicelle.
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DOI：
10.1371/journal.pone.0056220
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kataoka K
中科院分区：
文献类型：
--
作者：
Uchida S;Itaka K;Uchida H;Hayakawa K;Ogata T;Ishii T;Fukushima S;Osada K;Kataoka K
信使RNA(信使RNA)的导入是一种很有前途的产生治疗性蛋白质和多肽的方法，而不会有任何插入突变到宿主基因组的风险。但由于其在生理条件下的不稳定性以及Toll样受体(Toll-like Receptor，TLRs)对其较强的免疫原性，很难在体内导入。我们使用了一种基于聚乙二醇-多氨基酸嵌段共聚物自组装的新型载体--多链纳米胶束，将mRNA导入中枢神经系统(CNS)。直径为50 nm的纳米胶束具有核壳结构，含有信使核糖核酸的内核被聚乙二醇层包裹，为纳米胶束提供了高度的稳定性和隐蔽性。具有pH响应性膜失稳能力的功能性多氨基酸允许纳米胶束顺利地逃逸到细胞质中。纳米胶束导入中枢神经系统后，成功地在脑脊液中持续表达了近一周的蛋白质。与裸基因导入相比，纳米胶束能有效地抑制基因导入中枢神经系统后的免疫反应。用表达TLR的特定HEK293细胞进行的体外分析证实，纳米胶束包合物阻止了TLRs对mRNA的识别。因此，复合纳米胶束是一种很有前途的系统，它同时解决了体内mRNA导入的两大问题，即不稳定性和免疫原性，为利用mRNA进行各种新的治疗策略打开了大门。
Messenger RNA (mRNA) introduction is a promising approach to produce therapeutic proteins and peptides without any risk of insertion mutagenesis into the host genome. However, it is difficult to introduce mRNA in vivo mainly because of the instability of mRNA under physiological conditions and its strong immunogenicity through the recognition by Toll-like receptors (TLRs). We used a novel carrier based on self-assembly of a polyethylene glycol (PEG)-polyamino acid block copolymer, polyplex nanomicelle, to administer mRNA into the central nervous system (CNS). The nanomicelle with 50 nm in diameter has a core-shell structure with mRNA-containing inner core surrounded by PEG layer, providing the high stability and stealth property to the nanomicelle. The functional polyamino acids possessing the capacity of pH-responsive membrane destabilization allows smooth endosomal escape of the nanomicelle into the cytoplasm. After introduction into CNS, the nanomicelle successfully provided the sustained protein expression in the cerebrospinal fluid for almost a week. Immune responses after mRNA administration into CNS were effectively suppressed by the use of the nanomicelle compared with naked mRNA introduction. In vitro analyses using specific TLR-expressing HEK293 cells confirmed that the nanomicelle inclusion prevented mRNA from the recognition by TLRs. Thus, the polyplex nanomicelle is a promising system that simultaneously resolved the two major problems of in vivo mRNA introduction, the instability and immunogenicity, opening the door to various new therapeutic strategies using mRNA.
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影响因子：
12.4
作者：
Kariko, Katalin;Muramatsu, Hiromi;Welsh, Frank A.;Ludwig, Janos;Kato, Hiroki;Akira, Shizuo;Weissman, Drew
通讯作者：
Weissman, Drew
影响因子：
14
作者：
Masago, Kayo;Itaka, Keiji;Kataoka, Kazunori
通讯作者：
Kataoka, Kazunori
影响因子：
3.7
作者：
Plews JR;Li J;Jones M;Moore HD;Mason C;Andrews PW;Na J
通讯作者：
Na J
DOI：
10.1038/mt.2012.7
发表时间：
2012-05
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
影响因子：
14.9
作者：
Anderson BR;Muramatsu H;Nallagatla SR;Bevilacqua PC;Sansing LH;Weissman D;Karikó K
通讯作者：
Karikó K