What are Lipid Nanoparticles?
Malin Edvardsson Sep 24, ’24 ~ 6 min

What are Lipid Nanoparticles?

Lipid nanoparticles (LNP:s) are today well known in the context of for example mRNA therapeutics, but what are LNPs and how do they work? Recently we had the pleasure of having Federica Sebastiani, Tenure Track Assistant Professor at the Department of Pharmacy, University of Copenhagen, giving a talk on the topic of how the binding affinity of serum proteins to mRNA-LNPs could be screened by QCM-D. In this talk, LNP:s were in focus. This is how Assist. Prof. Sebastiani explained what they are.

Lipid nanoparticles for mRNA vaccines and other therapeutics

If we manage to develop good mRNA therapeutics, we can virtually treat any disease, Assist. Prof. Sebastiani says. The great advantage of this approach is that we can produce protein in situ where it is needed without any problem related to the fact of producing it, purifying it, stabilizing it, etc. RNA is a long, negatively charged particle, and it is very difficult to make it cross the cell membrane. Additionally, once it is administered, it is difficult not to get it degraded in the body, because there are plenty of enzymes in the body ready to degrade RNA. So, we need a delivery vehicle that can protect the RNA from this enzymatic degradation and that helps the RNA cross the cell membrane and release it when it is time to release it in the cytosol so it can go to the ribosome and then produce the protein. So, the promise of mRNA therapeutics is great, but there are challenges, Assist. Prof. Sebastiani says.

One of the most advanced delivery vehicles for this kind of therapeutics is lipid nanoparticles, she continues. And it is not by chance, but I find it fascinating that mRNA and lipid-based particles were developed in parallel for a very long time. Already back in the late seventies, they started to meet with simple liposome mRNA formulations. Then slowly, this development brought us to the formulation that we have today. So, this is one of the most advanced, delivery vehicles, used for example for the COVID vaccine, but also for other therapeutics, Assist. Prof. Sebastiani says.

The lipid nanoparticle design – a multicomponent lipid formulation

The lipid NP is made of different lipids, i.e. it is a multi-component lipid formulation, Assist. Prof. Sebastiani explains. The key component is the cationic ionizable lipid. The key feature of this lipid is that the head group becomes positively charged when it is in an acidic environment, while it becomes neutral when it is in a physiological environment. That is important because it helps to complex the mRNA that is negatively charged when you formulate, and you formulate at low pH. When you bring the formulation to a physiological pH, 7.4, the charge becomes close to neutral. That is good because we don't want the body to recognize positively charged particles and degrade them very quickly. Also, they are toxic, so the ionizable lipid is a key component and a key feature of this formulation, Assist. Prof. Sebastiani says.

Then we have the other components. One component could be a phospholipid, such as a DSPC or similar, that helps give stability to the structure together with cholesterol, which is the second most abundant component in this formulation. Then we have a pegylated lipid, which helps to tune the size of the particle and avoid aggregation, Assist. Prof. Sebastiani explains.

The protein corona affects the lipid nanoparticle identity

As soon as you put lipid nanoparticles in the bloodstream a protein corona is formed around it, Assist. Prof. Sebastiani says. The protein corona affects the biological identity of the lipid nanoparticles. So, even if we carefully engineer the surface of our particles, as soon as we put them in a biological fluid, the surface will be coated with biomolecules, proteins, etc. So, this corona is the surface that the cells in the body will see, she says.

One protein that seems to always be present no matter which formulation you use for lipid nanoparticles is the Apolipoprotein E, ApoE. This protein is responsible for the fat metabolism in the body. The ApoE is reversibly bound to HDL, which are the high-density lipoprotein particles in the blood, and transport them to the liver. ApoE can bind any lipid-based particle either endogeneous or external. So, why is this important? This is important because the role of ApoE is proposed to be crucial in the uptake of lipid nanoparticles in hepatocytes. That is because this ApoE bound to the lipid nanoparticle makes the particle enter the cell through the binding to the cell surface receptor, which is the LDL receptor, into the hepatocyte, Assist. Prof. Sebastiani explains.


Learn more about lipid nanoparticles, mRNA therapeutics, and the role of ApoE in Assist. Prof. Sebastiani's talk Screening of the binding affinity of serum proteins to mRNA-LNPs by QCM-D

Using QCM-D in lipid nanoparticle research
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Screening of the binding affinity of serum proteins to mRNA-LNPs by QCM-D

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