Using lipid nanoparticles (LNPs) to deliver mRNA has hit the headlines in the last few years. As well as delivering vaccines based on mRNA, this method has other potential medical applications including cancer therapy and gene editing.
LNPs encapsulate mRNA during delivery, preventing it from being broken down. How well it does this depends on the individual lipids making up the nanoparticle, in particular the ionisable lipids whose shape changes on entry to the cell, enabling the release of the mRNA.
Developing a new LNP system requires screening many different lipids for their functionality and safety. To speed up the process of LNP design, the team at AstraZeneca developed an automated, high-throughput platform that was able to generate thousands of different LNPs quickly and cost-effectively. They could then screen the LNPs to see which are suitable for mRNA encapsulation.
Combining these stages into one automated workflow has provided the team at AstraZeneca with a process that enables them to make, characterise and evaluate LNPs for drug delivery simply and quickly. This means they can focus on the most effective for further testing in vivo.
When evaluating the LNPs their platform produced in vitro, they learnt that they were more successful at delivering mRNA than LNPs produced by a standard route. To understand what was causing this improvement, they compared LNPs produced by both methods using a series of characterisation techniques, including small-angle neutron and X-ray scattering (SANS and SAXS).
In their study, published in Small, they also tested the effectiveness of the LNPs at delivering mRNA in vivo, to see how effective they were at drug delivery.
They found that the nanoparticles produced using their new automated system contained more mRNA than those produced through other methods. They were larger and had more of the lipid DSPC present on their surface. This, combined with an improvement in their ability to rupture once inside cells, made them 4.5 times more effective than LNPs made through a standard procedure.
Developing this understanding of how the structure of LNPs influences their ability to deliver drugs is key to the design and development of future medications.
“We are very pleased to have been able to get some insight into the enhanced mRNA functional delivery as part of our exciting LNP frameworks," explains Lili Cui, from AstraZeneca. “LNP, as a clinically advanced non-viral delivery system for nucleic acids, requires more understanding regarding its internal molecular architecture, surface properties and physicochemical and biological properties in order to expand its application and accelerate future mRNA therapeutics."
“We deeply appreciate the support from ISIS facility and scientists for the neutron beam time and the valuable knowledge which help us unveil the internal and surface property of the mRNA LNP nanoparticles."
The full paper can be found at DOI: 10.1002/smll.202105832
More information about the screening platform can be found in the group's recent paper, available at DOI: 10.1039/D1NR06858J