As crucial components in LNPs, new cationic ionizable lipids for Nucleic Acid Delivery are being investigated to optimize RNA complexation, endosomal membrane fusion and cargo release into the cytosol.
Cationic ionizable lipids must be engineered with a suitable apparent acid dissociation constant (pKa) in order to facilitate fusion of the LNP with the cell membrane. The apparent pKa of a cationic ionizable lipid is the likely pKa at the LNP surface. Currently, the cationic ionizable lipids in FDA-approved therapeutics all have an apparent pKa between 6-7. This is crucial for the cationic ionizable lipid to maintain a neutral charge while in systemic circulation (pH above the pKa of the lipid, pH ~7.5), as well as its ability to become positively charged in the endosome (pH ~6.5) and facilitate membrane fusion and subsequent cytosolic release.
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