2. Academic Validation
  3. Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity

Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity

  • Nat Commun. 2014 Jun 27;5:4277. doi: 10.1038/ncomms5277.
Kathryn A Whitehead 1,  J Robert Dorkin 2,  Arturo J Vegas 3,  Philip H Chang 3,  Omid Veiseh 3,  Jonathan Matthews 3,  Owen S Fenton 4,  Yunlong Zhang 3,  Karsten T Olejnik 3,  Volkan Yesilyurt 3,  Delai Chen 3,  Scott Barros 5,  Boris Klebanov 5,  Tatiana Novobrantseva 5,  Robert Langer 6,  Daniel G Anderson 6
Affiliations

Affiliations

  • 1 1] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2].
  • 2 Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
  • 3 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
  • 4 Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
  • 5 Alnylam Pharmaceuticals, 300 Third Street, Cambridge, Massachusetts 02142, USA.
  • 6 1] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2] Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [3] The Institute for Medical Engineering and Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139 USA.
PMID: 24969323 DOI: 10.1038/ncomms5277
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. 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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