Big Concepts in Brief: What are Lipid Nanoparticles?

When it comes to developing drugs and vaccines, it’s not just about finding an ​‘active ingredient’ that works. Getting that compound to its intended target, without degrading or causing adverse reactions, is an equally important piece of the puzzle. 

Take COVID-19 mRNA vaccines, as an example. Their success is not only due to the vaccine itself, but also the delivery mechanism: lipid nanoparticles. They provide a protective shield around mRNA vaccines, which would otherwise degrade in the body very easily, and help deliver the vaccine to the right place. 

So, what are lipid nanoparticles and how are they being further developed for new treatments?

What are lipid nanoparticles?

The clue is in the name. Let’s start with lipids. These are a class of organic molecules that includes fats and oils. For example, cells have a ​“lipid bilayer membrane”, which means that the cell surface is made up of two layers of fat molecules. 

Nano is short for nanometres, a very small unit of measurement. How small? 1 million times smaller than a millimetre. 

So, Lipid nanoparticles – or LNPs for short – are particles formed of lipids, engineered in the lab to do a specific job, that are about 100 nanometres in diameter. That’s roughly 1,000 times smaller than the width of a human hair.

What are LNPs used for?

LNPs are used as drug delivery vehicles to help with stability and targeting. You can think of them as smart packaging that protects a drug and helps it get into cells. Once delivered, the LNP biodegrades. 

That makes them excellent for delivering the next generation of RNA medicines. They can also carry larger RNA molecules than viral vectors – up to several million nucleotides, or the size of chromosomes. In addition, similar LNPs can also be used for subsequent vaccine or drug doses, whereas viral vectors cannot because the body eventually develops an immune response to them. 

Beyond COVID, there is a lot of research being done around developing LNPs to deliver RNA therapies or vaccines for influenza, (including combined COVID-flu vaccines), cancer and genetic disorders that produce defective or incorrect proteins, such as cystic fibrosis.

What are LNPs made of?

LNPs are made up of a mix of four different lipids: 

1. Phospholipid – found naturally in the human body surrounding all our own cells. This helps encapsulate the drug, and with uptake and delivery.
2. Pegylated lipid – a lipid with a polymer called polyethylene glycol on it. This helps enhance stability and circulation time in the body.
3. Cholesterol – a natural molecule found in the body that adds structure to the LNP.
4. Ionisable lipid – a lipid that becomes positively or negatively charged depending on the pH or acidity of the environment. This helps it perform two roles: enclosure of the RNA molecule being delivered, and release of it into the cell.

How do LNPs work?

The cationic, or ionisable, lipid can be made to change its charge depending on the environment it is in. So, at a low pH you can make this ionisable lipid positively charged, so that it binds to a negatively charged RNA molecule, forming a complex in the LNP. The other lipids of the LNP will fit around that. 

When you inject the LNP into the body, it encounters a neutral pH, so the ionisable lipid becomes neutrally charged, reducing the risk of adverse effects of toxicity. 

This property could also be crucial during the uptake and release of the drug into the cell where another change in pH breaks up that complex between the lipids and the RNA – so the RNA can go on and do its job. 

This means LNPs offer a two-fold benefit: first making it easier to encapsulate the RNA or drug for delivery, and second, making the drug safer and more stable once it is injected into the body and the RNA is released.

What’s the difference between LNPs and liposomes?

A lot of people ask this and, unfortunately, there isn’t an easy answer. Both are used for delivery and the terms are often used interchangeably. Liposomes have been around since the 1960s and scientists have been gradually adding new components, such as cholesterol and pegylation. 

What makes them a little bit different is that final ionisable lipid, which changes the structure. A liposome has a bubble structure with a lipid bilayer that forms a sphere and an aqueous, or watery, environment inside where you will find the drug. LNPs have a much more complicated structure with some lipids on the inside, the ionisable lipid bound to the drug or mRNA, and some lipid around the outside. Researchers are trying to understand the structure and how it changes with different drug payloads and chemistries.

How do LNPs get into the body?

LNPs can be administered to the body in different ways: 

1. Intramuscularly – injected directly into the muscle, as done for the mRNA COVID vaccines. 
2. Intravenously – administered directly into the bloodstream using an IV catheter. 
3. Intranasally – some new formulations being worked on may be sprayed or inhaled into the nose or lung. 
4. Intratumorally – direct injection into cancer tumours if they are near the surface of the body. 

Each of these delivery methods requires a different tweak to the formulation and the chemistry of the LNP.

How is CPI helping develop next-generation LNP-based drug delivery systems?

There are a huge number of RNA-based therapies in development and in clinical trials, so we’re expecting many new therapies based on this exciting technology to come through in the next few years. 

CPI has a strong research group with expertise in manufacturing LNPs who have been working on them since 2016. Our end-to-end capability includes R&D, scale-up of manufacturing processes and manufacturing for clinical trials to go into patients. We were the first place in the UK to be able to do that for both the RNA drug and the encapsulated LNP product. 

We also launched the Intracellular Drug Delivery Centre with partners across the UK, including The University of Strathclyde, The University of Liverpool, Imperial College London, and The Medicines Discovery Catapult. By bringing together expertise from across the UK into this centre of excellence, we can learn from each other, solve research challenges and bring costs down. The aim is to open up greater potential of this drug delivery technology, by using robotics, automation and advanced modelling to really understand the link between the chemistry and formulation of the LNP and how it performs in humans. We can use this approach to rapidly develop more LNP formulations for drugs to treat new diseases. The drugs can then be made available in clinics to people around the world. 

LNPs are an exciting field that offers new possibilities for medicine innovation. Our unique expertise and capabilities place us at the forefront of these important advances.