Refining lipid nanoparticles for better mRNA therapies

Engineers at Penn's School of Engineering and Applied Science have developed up a new way to improve mRNA delivery, developing an optimal "recipe" for ionizable lipids-key ingredients in lipid nanoparticles (LNPs), the molecules behind the COVID-19 vaccines and other innovative therapies. The method, described in Nature Biomedical Engineering, mirrors the iterative process of developing a culinary dish and may lead to safer, more effective mRNA vaccines and therapeutics.

The researchers used an iterative process, testing variations to find the ideal structure for the ionizable lipid. This lipid's structure influences the ability of LNPs to successfully deliver their contents and advances mRNA therapies for vaccines and gene editing.

Nanoparticles have transformed how mRNA vaccines and therapeutics are delivered by allowing them to travel safely through the body, reach target cells and release their contents efficiently. On its own, RNA is fragile, and would otherwise dissolve without ever reaching its intended target.

At the heart of these nanoparticles are ionizable lipids, special molecules that can switch between charged and neutral states depending on their surroundings. This switch is essential for the nanoparticle's journey: In the bloodstream, ionizable lipids stay neutral, preventing toxicity. But once inside the target cell, they become positively charged, triggering the release of the mRNA payload.

Led by Michael J. Mitchell, associate professor in bioengineering, the researchers refined this delivery process by optimizing the structure of ionizable lipids.

To develop safer, more effective ionizable lipids, the Penn Engineers employed a unique approach that combines two prevailing methods: medicinal chemistry, which involves slowly and laboriously designing molecules one step at a time, and combinatorial chemistry, which involves generating many different molecules quickly through simple reactions. The former has high accuracy but low speed, while the latter has low accuracy and high speed.

"We thought it might be possible to achieve the best of both worlds," says Xuexiang Han, the paper's first author and, until recently, a postdoctoral fellow in the Mitchell Lab. "High speed and high accuracy, but we had to think outside the traditional confines of the field."

This new method for designing ionizable lipids is expected to have broad implications for mRNA-based vaccines and therapeutics, which are poised to treat a range of conditions, from genetic disorders to infectious diseases.

Read more at Penn Engineering Today.