Innovating LNP design to improve mRNA therapeutics

A new method to improve mRNA delivery has been developed by US researchers, which could enhance the safety and efficacy of mRNA vaccines and therapies. Ionisable lipid molecules are at the centre of lipid nanoparticles (LNPs) and can switch between charged and neutral states, ultimately releasing the mRNA payload when positively charged in the target cell.

The team’s approach combined precision with rapid output to achieve an optimal lipid outcome.

Modernising LNP design

They refined this delivery process by optimising the structure of ionisable lipids. A step-by-step, “directed chemical evolution” process was produced.

It took five cycles of refining the lipids to produce “dozens of biodegradable and asymmetric A³-lipids with delivery activity comparable to or better than a benchmark ionisable lipid”, Han et al. wrote in their paper, published in Nature Biomedical Engineering.

The A³ coupling reaction is cost-effective and environmentally friendly as inexpensive ingredients are used, with water as the only byproduct, they revealed. This could “accelerate the structural optimisation of propargylamine-based ionisable lipids”, Han et al. explained in the paper.

Developing safer mRNA delivery

“We found that the A³ reaction was not only efficient, but also flexible enough to allow for precise control over the lipids’ molecular structure,” stated Michael Mitchell, Associate Professor in Bioengineering, Penn Engineering, US. This resulted in ionisable lipid properties safe and effective for mRNA delivery.

Han et al. shared that the optimised lipids improved mRNA delivery in preclinical models: one for the rare disease amyloidosis and better delivery of the COVID-19 mRNA vaccine. The engineered lipids demonstrated improved performance compared to current industry-standard lipids.

Conventional approaches of developing an effective lipid can take years. Notably, this new technique could be completed in months or even weeks, according to Han et al.

“Our hope is that this method will accelerate the pipeline for mRNA therapeutics and vaccines, bringing new treatments to patients faster than ever before,” commented Mitchell.