Biotech Informers

With the approval of mRNA vaccines to treat COVID, mRNA therapeutics are in use to treat a broad range of diseases. This influx of research puts forth the need to create better delivery materials. The formulation in both Moderna’s and Pfizer’s vaccines contains singly charged ionizable lipids. Moderna uses the lipid SM-102, and Pfizer uses the lipid ALC-0315. Since the vaccine approvals in 2020, there have been significant improvements to ionizable lipids including the inception of multi-charged ionizable lipids.

The need for highly efficient mRNA delivery systems is high. The conditions to create an effective delivery system are rigorous. A good delivery material must have high translation efficiency, good immunoadjuvant property, and must be safe. Ionizable lipids play an important role in the formulation of the lipid nanoparticles that have been used for drug delivery. Redesigning their chemical structure can improve ionizable lipids. The structure of these lipids can be divided into subclasses of singly charged and multi-charged lipids. The lipids SM-102 and ALC-0315 both fall under the singly charged lipid category. To improve the efficacy of the therapeutic, scientists have turned to multi-charged ionizable lipids such as C-12-200, G0-C14, cKK-E12, OF-2, and TT3, 3060i10. One of the benefits of multi-charged ionizable lipids is their ability to have a higher N/P ratio. The N/P is the ratio of nanoparticles, in this context it is the ratio of nitrogen atoms “N” of the basic nitrogen containing group of the lipid to the phosphate groups “P”. Low N/P ratios are detrimental to in vivo performance of carrier-cargo complexes. By adding multiple nitrogen containing groups to the structure of the ionizable lipid it improves the N/P ratio that promotes encapsulation, uptake, and mRNA release into the lysosome.

One novel approach to multi-charged ionizable lipids that has shown promise is the lipid 4N4T. This lipid consists of a hydrophilic center with tertiary amines and four hydrophobic tails. The delivery efficiency of 4N4T was greater than that of SM-102 in-vitro and in-vivo. 4N4T also showed greater expression efficiency leading to a robust and long-lasting humoral response in mice; the neutralizing antibody titers generated from 4N4T were higher when compared with SM-102.