体内
基因敲除
RNA干扰
转染
基因沉默
化学
小干扰RNA
细胞
计算生物学
细胞生物学
纳米技术
体外
生物
核糖核酸
生物化学
材料科学
基因
生物技术
作者
Kathryn A. Whitehead,J. Robert Dorkin,Arturo J. Vegas,Philip Chang,Omid Veiseh,J. Matthews,Owen S. Fenton,Yunlong Zhang,Karsten Olejnik,Volkan Yesilyurt,Delai Chen,Scott Barros,Boris Klebanov,Tatiana I. Novobrantseva,Robert Langer,Daniel G. Anderson
摘要
One of the most significant challenges in the development of clinically viable delivery systems for RNA interference therapeutics is to understand how molecular structures influence delivery efficacy. Here, we have synthesized 1,400 degradable lipidoids and evaluate their transfection ability and structure-function activity. We show that lipidoid nanoparticles mediate potent gene knockdown in hepatocytes and immune cell populations on IV administration to mice (siRNA EC50 values as low as 0.01 mg kg(-1)). We identify four necessary and sufficient structural and pKa criteria that robustly predict the ability of nanoparticles to mediate greater than 95% protein silencing in vivo. Because these efficacy criteria can be dictated through chemical design, this discovery could eliminate our dependence on time-consuming and expensive cell culture assays and animal testing. Herein, we identify promising degradable lipidoids and describe new design criteria that reliably predict in vivo siRNA delivery efficacy without any prior biological testing.
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