2. Academic Validation
  3. Customizable Lipid Nanoparticle Materials for the Delivery of siRNAs and mRNAs

Customizable Lipid Nanoparticle Materials for the Delivery of siRNAs and mRNAs

  • Angew Chem Int Ed Engl. 2018 Oct 8;57(41):13582-13586. doi: 10.1002/anie.201809056.
Owen S Fenton 1 2,  Kevin J Kauffman 1 3,  Rebecca L McClellan 1,  James C Kaczmarek 1 3,  Manhao D Zeng 1,  Jason L Andresen 1 2,  Luke H Rhym 1 3,  Michael W Heartlein 4,  Frank DeRosa 4,  Daniel G Anderson 1 3 5
Affiliations

Affiliations

  • 1 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 2 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 3 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 4 Translate Bio, Lexington, MA, 02421, USA.
  • 5 Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
PMID: 30112821 DOI: 10.1002/anie.201809056
Abstract

RNAs are a promising class of therapeutics given their ability to regulate protein concentrations at the cellular level. Developing safe and effective strategies to deliver RNAs remains important for realizing their full clinical potential. Here, we develop lipid nanoparticle formulations that can deliver short interfering RNAs (for gene silencing) or messenger RNAs (for gene upregulation). Specifically, we study how the tail length, tail geometry, and linker spacing in diketopiperazine lipid Materials influences LNP potency with siRNAs and mRNAs. Eight lipid Materials are synthesized, and 16 total formulations are screened for activity in vitro; the lead material is evaluated with mRNA for in vivo use and demonstrates luciferase protein expression in the spleen. In undertaking this approach, not only do we develop synthetic routes to delivery Materials, but we also reveal structural criteria that could be useful for developing next-generation delivery Materials for RNA therapeutics.

Keywords

ionizable lipids; lipid nanoparticles; mRNA; nanomaterials; siRNA.

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