Sure, you’ve heard about mRNA vaccines developed against SARS-Cov-2. Both the Pfizer-BionTech and Moderna vaccines authorized for use in the United States are mRNA vaccines. But how exactly does an mRNA vaccine work and what do nanoparticles have to do with it?
mRNA stands for messenger RNA and it serves as a molecular go-between between the DNA in the nucleus and the ribosomes in the cell cytoplasm: copying the genetic code from the DNA strands and carrying it over to the ribosomes. mRNA transcribes a sequence of the DNA bases containing the instructions for making a particular protein which the ribosomes then translate and synthesize this protein.
An mRNA vaccine takes advantage of this process of translation by inserting exogenous mRNA into the cell that encodes a protein belonging to the virus or bacterium in question. This makes the cell produce parts of the pathogen (also known as antigens) and display them on its cell membrane outside, teaching the immune system to better recognize the offender in case of a potential future infection. Both the Pfizer-BionTech and Moderna vaccines, for example, “tell” the ribosomes to reproduce the iconic coronavirus spike—SARS-CoV-2 spike (S) glycoprotein (Polack et al.; Jackson et al.).
Making the body do the work of producing viral antigens sounds like a brilliant idea, and it was in fact proposed decades ago, however there is a caveat (Pardi et al.). As a single-stranded nucleic acid, mRNA is very unstable and gets easily degraded. In the natural setting, it makes total sense.
Think about it—you would not want mRNA to stick around in your cells forever, prompting the ribosomes to make more and more of the same protein. In the case of a vaccine however, the fragility of mRNA becomes a problem.
Not only, therefore, do the researchers have to worry about the degradation of the mRNA, but also about getting it inside the cell. The mRNA molecule is large and bulky and contains many negative charges which means that it would much rather be dissolved in water (which is polar) than go through the lipid-based hydrophobic cell membrane.
In a paper on the advances in mRNA vaccine technology published in 2020, the authors mention approaches such as “ex vivo-loaded dendritic cells (DCs), intranodal delivery of mRNA, and mechanical methods (gene gun, electroporation)...developed to deliver naked mRNA for vaccination,” which highlights just how complicated it is to use “naked mRNA” in immunizations (Pardi et al.).
Lucky for us, a revolutionary method can now be used to deliver mRNA inside the cells while also protecting them from degradation: lipid nanoparticles, or LNPs. These are hollow lipid shells filled with nucleic acids in an acidic buffer.
“LNPs used in the COVID-19 vaccines contain just four ingredients: ionizable lipids whose positive charges bind to the negatively charged backbone of mRNA, pegylated lipids that help stabilize the particle, and phospholipids and cholesterol molecules that contribute to the particle’s structure” (Cross).
“LNPs take advantage of a natural process called receptor-mediated endocytosis to get into cells...Upon binding to a cell, the nanoparticle becomes encapsulated in...an organelle called an endosome. The endosome’s acidic interior protonates the heads of the ionizable lipids, making them positively charged. That positive charge triggers a change in the shape of the nanoparticle, which scientists think helps it break free from the endosome and ultimately release its RNA cargo into the cell’s cytoplasm” (Cross).
A major advantage of LNPs is the versatility that they offer, as different mRNA can be transported. For instance, in response to the South African strain of coronavirus, Moderna was able to quickly develop a new version of their vaccine that they are currently testing (Chow).
And of course, more broadly, now that we have a ‘recipe’ for the magic nanoparticles that effectively deliver mRNA to the cells in our body, we can start thinking about vaccinating people against many other diseases.
CDC. “Different COVID-19 Vaccines.” Centers for Disease Control and Prevention, 4 Mar. 2021, https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines.html.
Chow, Denise. “Moderna Set to Test New Booster Shot That Targets South African Variant.” NBC News, https://www.nbcnews.com/science/science-news/moderna-test-booster-shot-targets-south-african-variant-rcna310. Accessed 13 Mar. 2021.
Cross, Ryan. “Without These Lipid Shells, There Would Be No MRNA Vaccines for COVID-19.” Chemical & Engineering News, 6 Mar. 2021, https://cen.acs.org/pharmaceuticals/drug-delivery/Without-lipid-shells-mRNA-vaccines/99/i8.
Jackson, Lisa A., et al. “An MRNA Vaccine against SARS-CoV-2 — Preliminary Report.” New England Journal of Medicine, vol. 383, no. 20, Massachusetts Medical Society, Nov. 2020, pp. 1920–31. Taylor and Francis+NEJM, doi:10.1056/NEJMoa2022483.
Pardi, Norbert, et al. “Recent Advances in MRNA Vaccine Technology.” Current Opinion in Immunology, vol. 65, Aug. 2020, pp. 14–20. ResearchGate, doi:10.1016/j.coi.2020.01.008.
Polack, Fernando P., et al. “Safety and Efficacy of the BNT162b2 MRNA Covid-19 Vaccine.” New England Journal of Medicine, vol. 383, no. 27, Massachusetts Medical Society, Dec. 2020, pp. 2603–15. Taylor and Francis+NEJM, doi:10.1056/NEJMoa2034577.
Last Fact Checked on June 5th, 2021.