Ionizable lipids are a class of lipid molecules that are neutral at physiological pH and protonated (+) at acidic pH. As one major type of lipid in drug delivery nanoparticles, ionizable lipids protect RNA from degradation and facilitate their cytosolic transport. Essentially, ionizable lipids help facilitate effective RNA delivery. This property of these lipids allows them to play an important role in a multitude of disciplines, but most notably in RNA therapeutics.

RNA therapeutics didn't get very popular until the success of Onpattro (MC3) in 2018 (Figure 1, A). The success of this drug re-ignited the enthusiasm for RNA delivery and greatly accelerated the clinical development of other LNP-based RNA therapeutics, particularly mRNA vaccines. Two LNP-based mRNA vaccines (mRNA-1273 and BNT162b2) were quickly developed to combat COVID-19. The mRNA-1273 (Moderna) vaccine uses an ionizable lipid called SM-102 (Figure 1, B) while the BNT162b2 (Pfizer) vaccine uses an ionizable lipid called ALC-0315 (Figure 1, C).

Figure 1: A: Structure of lipid MC3. B: Structure of lipid SM-102. C: Structure of lipid ALC-0315.

When reviewing the approved structures of MC3, SM-102, and ALC-0315 in these drugs/vaccines, it is apparent that an ester-based biodegradable structure appears in all of them; the next most commonly shared features are the multi/branched tail and unsaturated structures. These structures help effectively facilitate RNA delivery by enhancing membrane disruption, endosomal disruption, and RNA potency.

Although the FDA has approved ionizable lipids for RNA delivery applications, there are still several challenges that warrant further investigation and research. Firstly, the ionizable lipid is the key LNP component that causes acute immune responses and long-term toxicity. Although biodegradable ionizable lipids can be used to mitigate this issue, premedication with glucocorticoids and anti-histamines before LNP infusion is still needed. In order to overcome this challenge, optimization of linker chemistry and anti-inflammatory properties through further investigation is needed. Secondly, the preparation of ionizable lipids that have been rationally designed is an extremely laborious synthesis process. To mitigate this issue, investigation into combinatorial chemistry for simplified and accelerated synthesis is needed. Among these two challenges are many more that show that there are still vast opportunities for ionizable lipid optimization and innovation to enable broader translation of RNA therapeutics.

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