Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity.
Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity.
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DOI：
10.1038/ncomms5277
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发表时间：
2014-06-27
影响因子：
16.6
通讯作者：
Anderson, Daniel G.
中科院分区：
文献类型：
--
作者：
Whitehead, Kathryn A.;Dorkin, J. Robert;Vegas, Arturo J.;Chang, Philip H.;Veiseh, Omid;Matthews, Jonathan;Fenton, Owen S.;Zhang, Yunlong;Olejnik, Karsten T.;Yesilyurt, Volkan;Chen, Delai;Barros, Scott;Klebanov, Boris;Novobrantseva, Tatiana;Langer, Robert;Anderson, Daniel G.
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. To this end, we synthesized 1400 degradable lipidoids and evaluated their transfection ability and structure function activity. Here we show that lipidoid nanoparticles mediate potent gene knockdown in hepatocytes and immune cell populations upon IV administration to mice (siRNA EC50 values as low as 0.01 mg/kg). Surprisingly, 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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影响因子：
3.7
作者：
Lee MJ;Veiseh O;Bhattarai N;Sun C;Hansen SJ;Ditzler S;Knoblaugh S;Lee D;Ellenbogen R;Zhang M;Olson JM
通讯作者：
Olson JM
影响因子：
15
作者：
Chen, Delai;Love, Kevin T.;Anderson, Daniel G.
通讯作者：
Anderson, Daniel G.
影响因子：
16.6
作者：
Jayaraman, Muthusamy;Ansell, Steven M.;Mui, Barbara L.;Tam, Ying K.;Chen, Jianxin;Du, Xinyao;Butler, David;Eltepu, Laxman;Matsuda, Shigeo;Narayanannair, Jayaprakash K.;Rajeev, Kallanthottathil G.;Hafez, Ismail M.;Akinc, Akin;Maier, Martin A.;Tracy, Mark A.;Cullis, Pieter R.;Madden, Thomas D.;Manoharan, Muthiah;Hope, Michael J.
通讯作者：
Hope, Michael J.
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
15
作者：
Geng, Y;Discher, DE
通讯作者：
Discher, DE