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Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity
- Source :
- Nature communications
- Publication Year :
- 2014
- Publisher :
- Springer Science and Business Media LLC, 2014.
-
Abstract
- 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.
- Subjects :
- Cell
General Physics and Astronomy
02 engineering and technology
Biology
Pharmacology
Transfection
Article
General Biochemistry, Genetics and Molecular Biology
Mice
03 medical and health sciences
In vivo
RNA interference
Leukocytes
medicine
Animals
Gene silencing
RNA, Small Interfering
030304 developmental biology
Drug Carriers
0303 health sciences
Gene knockdown
Multidisciplinary
General Chemistry
021001 nanoscience & nanotechnology
Lipids
medicine.anatomical_structure
Gene Knockdown Techniques
Hepatocytes
Nanoparticles
0210 nano-technology
Drug carrier
Cell culture assays
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....132e41f6ffe2eb272711f9243b490fa0