September 02 2017 by Drew Haser
A common example of the use of nanoparticles in drug delivery are lipid-based nanoparticles. Essentially, drugs are safely housed in lipid nanobubbles until they reach their target. This has great potential for reducing side-effects to normal cells as well as creating a carrier for some drugs that otherwise have poor bioavailability. However, despite the growing interest in lipid-based nanoparticle drug delivery vehicles the issue of endosomal escape has been a constant problem limiting cytosolic availability and therapeutic efficacy.
One class of therapeutics that has extensively explored the potential for using lipid-based nanoparticles is mRNA, which needs specific delivery to the cell nucleus to enact its therapeutic effect. Now it appears researchers have shed light on how to boost intracellular mRNA delivery using lipid nanoparticles. This means that perhaps the largest barrier to the effective use of lipid-based nanoparticles is crumbling, which may usher in a new era of nanoparticle based therapeutic delivery.
How Lipid Nanoparticle Function to Deliver mRNA
Systemic injection revealed that the nanoparticles specifically target to cancer cells
(Green: cytoskeleton. Red: Fluorescent pRNA nanoparticle. Blue: Nuclei.)
Now, research published in this month’s issue of Nano Letters may have discovered a way to boost the escape and delivery of therapeutic nucleic acids. According to the authors:
“Using a series of CRISPR-based genetic perturbations of the lysosomal pathway, we have identified that late endosome/lysosome (LE/Ly) formation is essential for functional delivery of exogenously presented mRNA. Lysosomes provide a spatiotemporal hub to orchestrate mTOR signaling and are known to control cell proliferation, nutrient sensing, ribosomal biogenesis, and mRNA translation. Through modulation of the mTOR pathway we were able to enhance or inhibit LNP-mediated mRNA delivery.”
After screening more that 200 lipid-like molecules that modulate cell signaling the study reports that leukotriene-antagonists, clinically approved for treatment of asthma and other lung diseases, enhance intracellular mRNA delivery in vitro (over 3-fold) and in vivo (over 2-fold).
This is highly encouraging for the design and engineering of new nanoparticle systems. Through a better understanding of nanoparticle intracellular delivery the next generation of RNA therapeutics may have significantly higher potencies and reduced toxicity.
More Information: Siddharth Patel, et.al., "Boosting Intracellular Delivery of Lipid Nanoparticle-Encapsulated mRNA" Nano Letters (2017). DOI: 10.1021/acs.nanolett.7b02664