Inspired by space shuttle technology, Penn Engineering researchers have developed a new method to synthesize an essential element, lipid nanoparticles (LNPs). These LNPs are key to the application of mRNA therapies, such as the Pfizer-BioNTech and Moderna vaccines, against COVID-19 by increasing both the ease of production of LNPs and the efficiency of delivering mRNA into cells for medical treatment.

In the article N Nature Communication Michael J. Mitchell, associate professor of bioengineering, describes a new way to synthesize ionized lipidoids, the key chemical components of LNPs that help protect and deliver medical payloads. For this paper, Mitchell and his co-authors tested the delivery of an mRNA drug to treat obesity and gene editing tools to treat genetic diseases.

Optimization of the production process

Previous experiments had shown that lipidoids with branched tails were better at delivering mRNA into cells, but methods to create these molecules were time-consuming and expensive. “We propose a new construction strategy for the rapid and cost-effective synthesis of these lipidoids,” says Xuexiang Han, a postdoctoral researcher in Mitchell’s laboratory and one of the paper’s authors.

The method involves the combination of three chemicals: an amine “head,” two alkylepoxide “tails,” and finally two acyl chloride “branched tails.” It’s no coincidence that the finished lipidoid resembles a space shuttle attached to two launch vehicles: Hahn recalls being watched by a documentary about the space shuttle while in college, where he was impressed by the design of the solid-state rocket boosters that allowed the shuttle to enter orbit. “I thought we could add two branch tails to the lipidoid as ‘enhancers’ to facilitate mRNA delivery,” says Hahn.

Indeed, the addition of branched tails resulted in a dramatic increase in the ability of the new lipidoid-equipped LNPs to deliver mRNA to target cells, just like a rocket whose boosters allow them to more easily enter the atmosphere. “After delivering mRNA along with these lipidoids, we saw a dramatic increase in a hormone that regulates metabolism in target cells, which is really exciting as a way to treat obesity,” says Mitchell.