On the Formation and Morphology of Lipid Nanoparticles Containing Ionizable Cationic Lipids and siRNA
This week we profile a recent publication in ACS Nano from Dr. Pieter Cullis at the UBC Life Sciences Institute.
Can you provide a brief overview of your lab’s current research focus?
The Cullis group’s focus is the development of lipid-based drug delivery systems to enable the therapeutic use of small molecule drugs or “fragile” macromolecules (nucleic acid) which, without a delivery system, are unable exert their function. We work closely with Dr. Jenifer L. Thewalt at SFU; her lab is focused on the biophysical characterization of the nanoparticles to gain a better understanding of the molecular interactions of lipids.
What is the significance of the findings in this publication?
In this publication we focus on lipid nanoparticles containing siRNA (LNP-siRNA) that represent the most advanced non-viral gene delivery system (see Patisiran) in terms of potency for delivery to hepatocytes, and achieving near 100% entrapment of siRNA. We knew very little about their structure other than these particles are electron-dense when imaged by cryogenic-transmission electron microscopy (cryo-TEM). This publication provides evidence of how the nanoparticles form and the resulting structure where all data is consistent with previous observations. What is interesting to note is that previous work had suggested a structure (largely by in silico methods) that is inconsistent with the current dataset. This has major implications for rationalizing the observations regarding potency of LNP for hepatocyte gene silencing, the role of Apolipoprotein E in targeting LNP to hepatocytes, and finally, provides the basis to further improve LNP formulations.
What are the next steps for this research?
These findings provide a platform to design the next generation of LNP. We now know how to improve the composition and potency of LNP-siRNA. There are also implications for design of the ionizable lipids. We have shown that the “sweet-spot” for such lipids is a pKa of 6.2-6.7, yet their geometry and structure could be designed to improve siRNA delivery.
This research was funded by:
Dr. Pieter R. Cullis is funded by a CIHR Foundation Grant (FDN 148469) and a BCIC Ignite grant. Dr. Jenifer L. Thewalt is funded by an NSERC Strategic Project Grant (STPGP/463247-2014)