Existing at the crossroads of immunology and molecular biology, the mRNA vaccine against SARS-CoV-2, the virus that causes COVID-19, is the ultimate example of how decades of basic biomedical research can culminate as a global response to an infectious disease. It might be obvious that the “mRNA” part of the “mRNA vaccine” is what is technically responsible for building our immunity, but likely less appreciated is how the mRNA is able to get into our cells in the first place. The US-based pharmaceutical companies, Moderna and Pfizer-BioNTech, both created a vaccine that delivers specific mRNA molecules into our cells using lipid biochemistry, specifically focusing on emulsions. Representing a medical application of emulsion science, Lipid Nanoparticles (LNPs) are designed as a highly specialized transport system for protecting mRNA molecules. These tiny and highly specialized lipid spheres get vaccine-specific mRNA into our cells so they do their immunological thing.
mRNA-LNPs have been called a “true platform technology.” Once scientists understood the rules of how cellular molecules such as lipids, proteins, and nucleotides can interact, the creation of LNPs for mRNA vaccine delivery became streamlined, translating into a relatively quick turnaround for specific mRNA vaccines. LNPs contain 4 major lipid molecules, each serving important purposes (Table 1):
Table 1: LNP lipid components and their function
||Structural elements of LNPs that dictate LNP membrane architecture and biocompatibility, including characteristics like size, curvature, fluidity, and charge. PEG Lipids specifically help prevent particle aggregation during storage
|Polyethylene Glycol (PEG) Lipid
|Ionizable Cationic Lipid
||A lipid that is neutral as it travels through our bloodstream, but can switch to a positive charge when specific conditions are met
To make the COVID-19 mRNA vaccine, the above lipid components are rigorously combined in specific ratios and at a specific rate with modified mRNA strands that map to the spike (S) protein of the SARS-CoV-2 virus. This process ultimately creates densely packed LNPs, with mRNA molecules safely encapsulated in lipids. While the precise architecture of mRNA-LNPs remains unknown (for now), the general principle is represented in Figure 1. Essentially, Ionizable Cationic Lipids surround the negatively charged mRNA molecules. These lipid-mRNA complexes are further encapsulated by a mixed-lipid coat (PEG-Lipid, Ionizable Cationic Lipid, Helper Lipid, and Cholesterol). This particle is taken up by cells, and the mRNA is released into the cytosol where it begins the process of immunological programming.
Figure 1: Schematic of an mRNA-LNP (Illustration by Marc Roseboro/CNSI)
Recall when you got your COVID-19 vaccine or flu shot — the needle went right into your upper arm. This is called Intramuscular (IM) administration, and most vaccines are delivered into our bodies via this route. The IM injection itself causes localized inflammation and the recruitment of immune cells to the injection site. The mRNA-LNPs fuse with the cell membranes of these immune system cellular recruits, ultimately dumping the mRNA into the cytosol, where it can be translated into the S protein. The S proteins are then presented on the surface of these cells as an “antigen,” setting off the process to build up immunity against COVID-19.