Biotech Informers

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In 2019 one of the greatest challenges in recent history emerged, COVID-19. To manage this new threat to our way of life scientists had to work at unprecedented speeds. During their search for a solution, they turned to mRNA vaccines. Some of the barriers that prevented mRNA vaccines from being efficacious were the inability of mRNA to permeate through cells because of its large size and negative charge. To increase mRNA therapeutic effect, there was a need for a delivery material that promotes endosomal escape and targeted delivery. In their search scientists turned to lipid nanoparticles (LNP).

 These lipids are soluble in organic solvents and insoluble in polar solvents such as water. When suspended in water these lipids form a membrane. This property has enabled scientists to mold these lipids into vesicles to carry mRNA therapeutics. Several lipids that contribute to the LNPs used in mRNA delivery including ionizable lipids, phospholipids, cholesterol, and PEGylated lipids. Ionizable lipids have played a significant role in decreasing the barriers to mRNA therapeutic efficacy. By encapsulating mRNA in ionizable lipids that are positively charged at acidic pH and neutral at physiological pH the mRNA gets condensed into LNPs while minimizing toxicity. When the LNPs interact with acidic endosomes after cellular uptake they become protonated and form cone-shaped ion pairs that drive the transition from a bilayer to an inverted hexagon phase. This phase promotes endosomal escape and the release of the mRNA into the cytosol. These customized ionizable lipids fueled the breakthrough that led to COVID-19 vaccines mRNA-1273 and BNT162b, using ionizable lipids SM-102 and ALC-0315 respectively. Another application for ionizable lipids can be seen in the testing of a vaccine for the dengue virus. Scientists used the ionizable lipid D-Lin-MC3-DMA, DSPC, cholesterol, and PEGylated lipid to encapsulate mRNA. By creating an LNP envelope to contain the mRNA package scientists have been able to induce an antigen-specific immune response in vivo to defend against the dengue virus. The creation of mRNA vaccines in record time is saving millions of lives each year.