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Polysarcosine-Functionalized Lipid Nanoparticles for Therapeutic mRNA Delivery
ACS Applied Nano Materials ( IF 5.3 ) Pub Date : 2020-09-25 , DOI: 10.1021/acsanm.0c01834 Sara S. Nogueira 1 , Anne Schlegel 1 , Konrad Maxeiner 1 , Benjamin Weber 2 , Matthias Barz 3 , Martin A. Schroer 4 , Clement E. Blanchet 4 , Dmitri I. Svergun 4 , Srinivas Ramishetti 5 , Dan Peer 5 , Peter Langguth 6 , Ugur Sahin 1, 7, 8 , Heinrich Haas 1
ACS Applied Nano Materials ( IF 5.3 ) Pub Date : 2020-09-25 , DOI: 10.1021/acsanm.0c01834 Sara S. Nogueira 1 , Anne Schlegel 1 , Konrad Maxeiner 1 , Benjamin Weber 2 , Matthias Barz 3 , Martin A. Schroer 4 , Clement E. Blanchet 4 , Dmitri I. Svergun 4 , Srinivas Ramishetti 5 , Dan Peer 5 , Peter Langguth 6 , Ugur Sahin 1, 7, 8 , Heinrich Haas 1
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Polysarcosine (pSar) is a polypeptoid based on the endogenous amino acid sarcosine (N-methylated glycine), which has previously shown potent stealth properties. Here, lipid nanoparticles (LNPs) for therapeutic application of messenger RNA were assembled using pSarcosinylated lipids as a tool for particle engineering. Using pSar lipids with different polymeric chain lengths and molar fractions enabled the control of the physicochemical characteristics of the LNPs, such as particle size, morphology, and internal structure. In combination with a suited ionizable lipid, LNPs were assembled, which displayed high RNA transfection potency with an improved safety profile after intravenous injection. Notably, a higher protein secretion with a reduced immunostimulatory response was observed when compared to systems based on polyethylene glycol (PEG) lipids. pSarcosinylated nanocarriers showed a lower proinflammatory cytokine secretion and reduced complement activation compared to PEGylated LNPs. In summary, the described pSar-based LNPs enable safe and potent delivery of mRNA, thus signifying an excellent basis for the development of PEG-free RNA therapeutics.
中文翻译：
聚肌氨酸功能化脂质纳米颗粒用于治疗性mRNA的传递。
聚肌氨酸（pSar）是一种基于内源性氨基酸肌氨酸（N-甲基化甘氨酸）的类肽，该蛋白先前已显示出强大的隐身特性。在这里，使用pSarcosinylated脂质作为粒子工程工具，组装用于信使RNA治疗性应用的脂质纳米颗粒（LNP）。使用具有不同聚合物链长和摩尔分数的pSar脂质可以控制LNP的物理化学特征，例如粒径，形态和内部结构。结合合适的可电离脂质，组装了LNP，这些LNP在静脉注射后显示出高RNA转染潜能，并具有改进的安全性。值得注意的是，与基于聚乙二醇（PEG）脂质的系统相比，可以观察到更高的蛋白质分泌和更低的免疫刺激反应。与PEG化的LNPs相比，pSarcosinylated的纳米载体显示出较低的促炎细胞因子分泌和减少的补体激活。总之，所描述的基于pSar的LNP使得能够安全且有效地递送mRNA，从而为开发无PEG的RNA治疗剂提供了极好的基础。
更新日期：2020-11-25
中文翻译：
聚肌氨酸功能化脂质纳米颗粒用于治疗性mRNA的传递。
聚肌氨酸（pSar）是一种基于内源性氨基酸肌氨酸（N-甲基化甘氨酸）的类肽，该蛋白先前已显示出强大的隐身特性。在这里，使用pSarcosinylated脂质作为粒子工程工具，组装用于信使RNA治疗性应用的脂质纳米颗粒（LNP）。使用具有不同聚合物链长和摩尔分数的pSar脂质可以控制LNP的物理化学特征，例如粒径，形态和内部结构。结合合适的可电离脂质，组装了LNP，这些LNP在静脉注射后显示出高RNA转染潜能，并具有改进的安全性。值得注意的是，与基于聚乙二醇（PEG）脂质的系统相比，可以观察到更高的蛋白质分泌和更低的免疫刺激反应。与PEG化的LNPs相比，pSarcosinylated的纳米载体显示出较低的促炎细胞因子分泌和减少的补体激活。总之，所描述的基于pSar的LNP使得能够安全且有效地递送mRNA，从而为开发无PEG的RNA治疗剂提供了极好的基础。
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