Nanoparticles are tiny containers that scientists create to carry molecules. How tiny? Let us say that a nanoparticle is about 100,000 times smaller than a single M&M candy. Scientists use special nanoparticles to treat specific diseases. For example, the mRNA vaccines that protect people from COVID-19 contain nanoparticles that are packed with mRNA molecules from the virus. In this article, we will answer some interesting questions: What are nanoparticles made of and how do they work? What are the mRNA molecules that are packed inside the nanoparticles of the COVID-19 vaccine? How do scientists create mRNA vaccines, and how do they protect us from COVID-19?
How Vaccines Work
All vaccines work in a similar way. The idea behind any vaccine is to introduce into the body weakened viruses or bacteria (or even just a piece of a disease-causing virus or bacteria), that will be harmless but will still stimulate the body’s immune system. This way, the body can “practice” on a harmless form of the disease-causing organism and become prepared to protect us when the actual, dangerous form of the virus or bacteria arrives. The immune system is very accurate and has a type of memory. For example, if you are vaccinated against a virus, your immune system generally recognizes and protects you against that virus for a long time after vaccination. Mostly, the immune system recognizes proteins on the surface of a bacterium or virus. For the rest of this article, we will focus specifically on viruses, although much of what we will tell you also applies to bacteria.
The immune response is complicated and includes several types of cells, including T cells that can bind to and destroy cells that are infected by viruses, and B cells that can produce proteins called antibodies. Antibodies help protect the body by recognizing and attaching to viruses and marking them for destruction. Once produced, antibodies remain in the body as a type of immune memory, to help the immune system respond quickly if exposed to the virus again.
The first vaccines that were created gave people’s immune systems a chance to react against viral proteins by introducing whole weakened or dead viruses into their bodies. But technology has advanced, so today’s scientists can create vaccines based on the exact proteins they want the immune system to react to, without introducing the entire virus into the body. While there are several methods to do this, we will focus on how scientists use mRNA lipid nanoparticle (mRNA-LNP) vaccines, which have been very effective in the fight against COVID-19 . mRNA-LNP vaccines are made of two main components: the mRNA and the lipid nanoparticle. We will first describe the role of the mRNA molecule.
From DNA to Protein
Both RNA and DNA are molecules called nucleic acids. DNA is a very stable nucleic acid that codes for the production of proteins. However, DNA is located within the nucleus and the production of proteins takes place in the cytoplasm—outside of the nucleus—in a molecular factory called the ribosome. A molecular messenger called messenger RNA (mRNA) carries the code from the DNA in the nucleus to the ribosomes in the cytoplasm. Therefore, each mRNA molecule is a copy of a DNA gene containing the instructions (message) to make a specific protein. How does this code work?
Nucleic acids are made of chains of molecules called nucleotides. DNA is made up of four types of nucleotides: adenine (A), thymine (T), guanine (G), and cytosine (C), linked one to the other to form two long strands. The two DNA strands are connected by a pairing of the nucleotides (A with T, and G with C; for more details about nucleic acids and the process of creating proteins, see this Frontiers for Young Minds article). RNA molecules also have four types of nucleotides, three of which are the same as DNA: A, G, and C; but instead of T, RNA molecules contain uracil (U). Combinations of three nucleotides in a row code for specific amino acids. For example, if RNA contains the code GUU, the ribosome will incorporate an amino acid named valine into the protein chain, while if GCU is coded for, the ribosome will incorporate an amino acid named alanine into the chain. Proteins are long chains of amino acids. Human cells contain 20 different kinds of amino acids that ribosomes can link together in various combinations and lengths, to create unique proteins.
After scientists discovered the genetic code, they could create the instructions for any protein, by making the mRNA molecules that code for that protein. In the case of mRNA-LNP vaccines, the mRNA codes for a surface protein of a virus—the structure on which scientists want the immune system to practice. The challenge with mRNA molecules, however, is that they are fragile and difficult to get inside of cells. For this reason, scientists invented the second component of the mRNA-LNP vaccines—the lipid nanoparticles, which both protect mRNA molecules and transport them into cells.
What Are Lipid Nanoparticles?
Nanoparticles are any tiny particles that range between 1 and 100 nanometers (nm) in size. 1 nm is a million times smaller than 1 mm (1 mm is the average size of a grain of coarse sand). Nanoparticles are so small that they cannot be seen by the human eye or even using a light microscope. They require very advanced microscopes, called electron microscopes, to see of them (Figure 1). Electron microscopes produce images that have much more detail than those produced by standard light microscopes (Figure 2). Over the years, scientists have engineered many types of nanoparticles, made of various materials.
Lipid nanoparticles (LNPs) are made by mixing building blocks that can be found in nature: lipids (fats) and nucleic acids. Both lipids and nucleic acids exist in every cell of the body. Lipids are the main component of the cell membrane. If you look at the LNP structure, you will notice that the RNA molecules are enclosed within the lipid structure (Figure 2).
The main component in LNPs is a type of lipid called an ionizable lipid. Ions are charged molecules—they can have positive (+) or negative (–) charges. In nature, positively charged molecules are attracted to negatively charged molecules and they stick together. To form LNPs, ionizable lipids are rapidly mixed with mRNA molecules. In this mixture, the ionizable lipids have a positive charge while the mRNA molecules are negatively charged; therefore, a combination of these two components is formed. Each molecule of mRNA is attracted to several ionizable lipid molecules. In this way, tiny clumps of mRNA molecules become surrounded by lipids. The other lipids in the mixture (called structural lipids) organize these structures and create a capsule (outer coating) around them . When we look at LNPs with an electron microscope, we can see that LNPs have a circular structure with a size of about 60–100 nm, and they are filled with masses of lipids and nucleic acids (Figure 2).
RNA Molecules as Medicines
Combining mRNA and LNPs in this way, scientists can now efficiently create any protein they want inside cells. LNPs can also be used to transport other types of nucleic acid molecules. For example, the first LNP drug, approved in 2018, delivered interfering RNA (RNAi) molecules that as opposed to mRNA, prevent the formation of proteins in the liver cells of patients who suffer from a liver disease called amyloidosis. Recently, two mRNA-LNP vaccines have been approved to protect the population from COVID-19. These vaccines use LNPs to deliver mRNA molecules coding for a specific protein found on the surface of the COVID-19 virus, called the spike protein, for the immune system to practice on .
How Does the mRNA Vaccine Against COVID-19 Work?
mRNA-LNP vaccines are injected into the muscle, where they are swallowed by muscle and immune cells. After entering the cells, the mRNA-LNPs release their mRNA molecules into the cells’ cytoplasm. In the cytoplasm, ribosomes “read” the code on the mRNA, using it to create the viral spike protein.
When the spike protein breaks down inside cells, small pieces of it are moved to the cell membrane, where they are “shown” to T cells and B cells. These immune cells recognize the spike protein as foreign (not from a human) and create an immune response, including antibodies against it. Eventually, the mRNA from the vaccine breaks down and all that remains is the immune system’s memory (Figure 3) .
Why Are mRNA-LNP Vaccines a Breakthrough?
mRNA-LNP vaccines are relatively safe, very effective, and can be produced quickly. Scientists can simply make any desired mRNA that codes for a specific protein, and pack it within the LNPs. That makes LNPs a very useful tool. Also, since the mRNA molecules are destroyed in the cytoplasm, do not enter the nucleus, and do not affect the DNA, these vaccines are safe. This type of vaccine is the result of many years of research invested by great scientists who were very helpful in the fight against the COVID-19 pandemic.
Antibodies: ↑ Proteins produced by B cells of the immune system to fight invading viruses and bacteria.
mRNA Lipid Nanoparticle (mRNA-LNP) Vaccines: ↑ Vaccines made of lipid nanoparticles containing mRNA that codes for a viral protein.
Nucleic Acids: ↑ Molecules made out of units called nucleotides, come in two naturally occurring varieties: deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
Ribosome: ↑ A cellular “factory” that makes proteins.
Messenger RNA (mRNA): ↑ An RNA molecule that carries a gene’s code from the DNA in the nucleus to the ribosome in the cytoplasm, to produce a protein.
Nucleotides: ↑ Building blocks that form nucleic acids.
Amino Acids: ↑ Building blocks that form a protein.
Nanoparticles: ↑ Small particles that range from 1 to 100 nm in size; a nm is one-millionth of a mm.
Lipid Nanoparticles: ↑ Nanoparticles made of lipids and nucleic acids.
Ionizable Lipid: ↑ A class of lipid molecules that has the ability to gain a positive charge or remain neutral.
Spike Protein: ↑ Protein that expresses on the surface of SARS-COV2 viruses and allows them to penetrate host cells.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
 ↑ Tregoning, J. S., Flight, K. E., Higham, S. L., Wang, Z., and Pierce, B. F. 2021. Progress of the COVID-19 vaccine effort: Viruses, vaccines and variants vs. efficacy, effectiveness and escape. Nat. Rev. Immunol. 21:626–36. doi: 10.1038/s41577-021-00592-1
 ↑ Kon, E., Elia, U., and Peer, D. 2022. Principles for designing an optimal mRNA lipid nanoparticle vaccine. Curr. Opin. Biotechnol. 73:329–36. doi: 10.1016/J.COPBIO.2021.09.016
 ↑ Dammes, N., and Peer, D. 2020. Paving the road for RNA therapeutics. Trends Pharmacol. Sci. 41:755–75. doi: 10.1016/j.tips.2020.08.004
 ↑ Alameh, M. G., Tombácz, I., Bettini, E., Lederer, K., Sittplangkoon, C., Wilmore, J. R., et al. 2021. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses. Immunity 54:2877–92.e7. doi: 10.1016/J.IMMUNI.2021.11.001