Ionizable Lipids

mRNA delivery, and more broadly nucleic acid delivery, is a hot research topic. The
preferred method of delivery for nucleic acid cargo are lipid nanoparticles (LNPs).
LNPs are great delivery tools for mRNA, siRNA, and other nucleic acid cargo due to
their ability to effectively protect and deliver the cargo. LNPs are primarily formulated
with four components (other than the nucleic acid cargo): cationic ionizable lipids,
polymer lipids, phospholipids, and cholesterol.

Cationic ionizable lipids play a major role in the LNP formulation and its ability to
transfect target cells with its cargo. The ionizable lipids are used to complex
negatively charged nucleic acid cargo. The mRNA-cationic lipid complex fuses with
the cell membrane and is then delivered into the cytosol. To be able to play these
roles efficiently, a cationic ionizable lipid must be engineered with a suitable apparent
acid dissociation constant (pKa). 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.