Bend Lipids will revolutionize the delivery of MRNA and the edition of the genes

Every time the pendulums dock with an international space station (ISS), a gentle dance between the ferry docking system and its counterpart at the station are shared. Thanks to international standards, these mechanisms are widely compatible, providing astronauts and load can enter the station safely and smoothly.

A similar challenge appears at the microscopic level, when lipid nanoparticles (LNP) – revolutionary vehicles for the supply of drugs behind Covid -19 vaccines – try to deliver MRNA to cells. Optimization of design and LNP delivery can significantly increase their ability to effectively supply mRNA, strengthening cells to fight the disease with the disease needed to transform medicine.

Endosome escape

Unfortunately, even when LNP reaches their target cells, nanoparticles are usually caught by endosomes – small protective bags in the cell. If LNP cannot escape, it is like this ferry in the docking process, station safety just out of reach.

If the endosomal escape process does not occur, LNP will be imprisoned and cannot provide a therapeutic charge. They can do it from a needle to the cell, but if they do not open this final barrier, they are useless. “

Michael J. Mitchell, associate professor in bioengineering (BE), University of Pennsylvania School of Engineering and Applied Science (Penn Engineering)

New approach

A few years ago, scientists from Carnegie Mellon University made an intriguing discovery: adding branches to the end of normally linear LNP lipid tails significantly improved MRNA supply. This discovery prompted Marshall Padilla, doctoral students in the Mitchell laboratory, to ask if it can be used as the key to developing more effective lipids for mrna.

“Every day, scientists create new lipids to improve effectiveness and LNP safety – says Padilla. “But we lack a bright set of design rules for better lipids.”

Most research in this field is like a guessing game. Scientists test large libraries of lipid changes, without fully understanding why some work better than others. Padilla, who has a doctorate in chemistry from the University of Wisconsin-Madison, believed that it could be possible to go beyond the sampling and designing lipids with branched tails from the very beginning to improve their ability to escape endosomes.

Introduction of a bend lipid

One of the main challenges related to improved lipids was the difficulty in creating branched lipids – key LNP elements that change the load to help them escape from the endosome. These lipids are not available in trade in a branched form, so Padilla had to create them himself.

“The key issue was the creation of coal carbon bonds that are extremely difficult,” says Padilla. “I used a complex mix of lithium, copper and magnesium to make the reaction work.”

The result is a new lipid class called lipids disconnected with endosomal (Bend). These unique, branched molecules help LNP break through the endosomal membrane, which makes them more effective in providing MRNA and gene editing tools.

Improvement of MRNA delivery

In the last study at Mitchell Padilla and their colleagues show that the bend lipids improve the supply of MRNA and gene edition LNP, in some cases even ten times.

After testing the lipids of the bend in various experiments – from editing genes in liver cells to starting complex biochemical simulations – scientists came to the conclusion that the bend lipids reliably exceed the LNP used by Moderna and Pfizer/Biontech, creators of Covid vaccines -19.

“We found that our branched groups allow lipids to facilitate the escape of our load from the endosome, where most of the load is destroyed, in cytosol, where it can perform the intended therapeutic effect,” says Padilla.

Designing better therapeutic

Scientists hope that Lipids Bend will not only improve LNP delivery, but also inspire a new approach to lipid design, departing from trial and error methods. With a better understanding of lipids, scientists could better develop new vans for the latest treatments.

“Testing hundreds of thousands of LNP and checking which of them can be an important time, at the cost and workers’ burden – many laboratories are unable to do it,” says Mitchell. “You want to know the rules so that you can design solutions effectively and profitable.”