To enhance mRNA delivery, Penn engineers have created an ideal “recipe” for ionizable lipids, which are essential components of lipid nanoparticles (LNPs), the molecules that underlie the COVID-19 vaccines and other cutting-edge treatments. The technique, which was published in Nature Biomedical Engineering, is similar to the iterative process of creating a recipe and could result in mRNA vaccines and treatments that are safer and more efficient.
The researchers employed an iterative method, trying variations to determine the right structure for the ionizable lipid, much like how a cook refines a dish by experimenting with flavors and textures. The shape of this lipid affects how well LNPs distribute their contents and promotes mRNA therapies for gene editing and vaccinations.
Because nanoparticles can safely pass through the body, reach target cells, and effectively release their contents, they have revolutionized the delivery of mRNA vaccines and treatments. RNA is brittle on its own and would disintegrate before ever reaching its destination.
Ionizable lipids, unique molecules that can change between charged and neutral states based on their environment, are at the core of these nanoparticles. The journey of the nanoparticle depends on this switch: Ionizable lipids remain neutral in the bloodstream, avoiding toxicity. However, they acquire a positive charge once inside the target cell, which causes the mRNA payload to be released.
By improving the structure of ionizable lipids, the researchers improved this delivery method under the direction of Associate Professor of Bioengineering Michael J. Mitchell. The team created a methodical, “directed chemical evolution” methodology that went beyond current approaches that were constrained by speed and accuracy constraints. They produced dozens of highly effective, biodegradable lipids via five cycles, each of which improved the lipids even more. Some of these lipids even outperformed industry standards.
The Penn Engineers used a novel strategy that combines two widely used techniques to create safer, more efficient ionizable lipids: combinatorial chemistry, which produces a large number of different molecules rapidly through straightforward reactions, and medicinal chemistry, which involves carefully and slowly designing molecules one step at a time. While the latter has low precision and high speed, the former has excellent accuracy but low speed.
We thought it might be possible to achieve the best of both worlds,
High speed and high accuracy, but we had to think outside the traditional confines of the field.
Xuexiang Han
The researchers combined accuracy and speed to create their perfect lipid “recipe” by utilizing the concept of directed evolution, a method that is applied in both biology and chemistry and simulates the process of natural selection.
The method starts by creating a large number of different molecules and screening them to see if they can deliver mRNA. Then, another set of molecular variations is created using the best-performing lipids as starting points, and so on, until only high-performing variants are left.
A3 coupling, a three-component reaction named for its chemical components an amine, an aldehyde, and an alkyne plays a key role in the team’s formula for more ionizable lipids.
The reaction is a cost-effective and environmentally friendly option for quickly creating the vast quantities of ionizable lipid variants required as ingredients for directed evolution. It has never been used to synthesize ionizable lipids for LNPs, but it uses cheap, commercially available ingredients and only yields water as a byproduct.
We found that the A3 reaction was not only efficient, but also flexible enough to allow for precise control over the lipids’ molecular structure,
Michael Mitchell
It is anticipated that this novel approach to creating ionizable lipids will have significant effects on mRNA-based vaccines and treatments, which are positioned to address a variety of illnesses, including infectious diseases and genetic abnormalities.
In this work, the tailored lipids enhanced mRNA transport in preclinical models for two high-priority applications: enhancing the delivery of the COVID-19 mRNA vaccine and altering genes that cause hereditary amyloidosis, a rare illness that causes aberrant protein deposits throughout the body. The modified lipids outperformed the industry-standard lipids in both situations.
Beyond these particular uses, the novel strategy may hasten the advancement of mRNA treatments in general. While creating a useful lipid with conventional techniques can take years.
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Our hope is that this method will accelerate the pipeline for mRNA therapeutics and vaccines, bringing new treatments to patients faster than ever before.
Michael Mitchell
The success of LNPs depends on the characteristics of their ionizable lipids, yet they offer a flexible and safe means of delivering genetic material. The next generation of mRNA treatments is getting closer thanks to the Penn Engineers’ iterative design process, which enables researchers to enhance these lipids with previously unheard-of speed and accuracy.
Penn Engineers have advanced mRNA technology significantly with this novel formula for LNPs, providing optimism for a quicker and more effective route to medicines that could change people’s lives.
Source: Penn Engineering Today
Journal Reference: Han, Xuexiang, et al. “Optimization of the Activity and Biodegradability of Ionizable Lipids for MRNA Delivery via Directed Chemical Evolution.” Nature Biomedical Engineering, vol. 8, no. 11, 2024, pp. 1412-1424, DOI: https://doi.org/10.1038/s41551-024-01267-7.
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