siRNA Design
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LNPs

Lipid nanoparticles are multicomponent lipid formulations which encapsulate their payload.

  • Key components are ionizable lipids.
  • They promote endosomal release and cytoplasmic uptake of payloads.
  • 2006 — an early generation of LNPs called stable nucleic acid–lipid particles (Zimmermann et al.): DLinDMA, PEG-C-DMA, DSPC & cholesterol.
  • Targeted to hepatocytes by recruitment and binding of endogenous apolipoprotein E, promoting uptake into hepatocytes by receptor-mediated endocytosis.
  • DLin-MC3-DMA (MC3) enhanced siRNA delivery potency by ~100-fold. Jayaraman, M. et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. Int. Ed. Engl. 51, 8529–8533 (2012). Cullis, P. R. & Hope, M. J. Lipid nanoparticle systems for enabling gene therapies. Mol. Ther. 25, 1467–1475 (2017).