Reviewed by Lexie CornerOct 3 2024
Engineers from the University of Pennsylvania have opened new possibilities in gene therapy and personalized medicine by using lipid nanoparticles (LNPs) to target specific tissues. These molecules, which played a crucial role in delivering COVID-19 vaccines, are now being explored for broader medical applications. The study was published in Nature Nanotechnology.
By adjusting the chemical structure of lipid nanoparticles, the researchers were able to target different organs, presaging a new era in precision medicine. Image Credit: Lulu Xue and Michael J. Mitchell
Previous studies, including those from Penn Engineering, have relied on a trial-and-error approach to screen "libraries" of LNPs to find variants that target specific organs like the lungs.
We have never understood how the structure of one key component of the LNP, the ionizable lipid, determines the ultimate destination of LNPs to organs beyond the liver.
Michael J. Mitchell, Associate Professor, Department of Bioengineering, University of Pennsylvania
Mitchell's research highlights how slight changes to the chemical structure of the ionizable lipid, a key component of LNPs, can enable precise tissue-specific distribution, particularly to the lungs, spleen, and liver.
The Power of Siloxane
The researchers achieved a significant breakthrough by incorporating siloxane composites—silicon- and oxygen-based compounds commonly found in medical devices, cosmetics, and drug delivery—into the ionizable lipids characteristic of LNPs.
Siloxane composites, known for their stability and low toxicity, have been likened to silicon housewares, which are renowned for being long-lasting and simple to clean.
“We sought to explore if these attributes could be exploited to engineer highly stable and minimally toxic LNPs for mRNA delivery,” the researchers reported.
After testing hundreds of versions of these newly developed siloxane-incorporating lipid nanoparticles (SiLNPs), the team identified the precise chemical properties that enhance mRNA delivery.
“Identifying their in vivo delivery was a huge challenge,” said Lulu Xue, Postdoctoral Fellow in the Mitchell Lab and Study Co-First Author.
Finding The Right Formula
The researchers initially tested SiLNPs in an animal model by delivering mRNA encoding firefly luciferase—the gene responsible for a firefly's glow—to malignant liver cells. The glowing cells confirmed that SiLNPs had successfully delivered the mRNA to the target.
Although LNPs often accumulate in the liver due to its extensive blood vessel network, the researchers observed an unexpected and promising result: some SiLNP variants directed the molecules beyond the liver, a major goal in LNP research. Glowing cells also appeared in the lungs, indicating successful mRNA delivery there.
The team further discovered that even small modifications, such as replacing an amide group with an ester, could significantly alter SiLNP behavior, achieving up to a 90 % success rate in targeting lung tissue.
We just changed the structure of the lipids, but this small change in the lipid chemistry substantially increased extrahepatic delivery.
Lulu Xue, Postdoctoral Fellow and Study Co-First Author, University of Pennsylvania
New Effects, New Applications
The researchers found that various chemical factors, such as the structure, length, and number of silicon groups in the lipids, significantly influenced the overall effectiveness of the SiLNPs. They also observed that SiLNPs showed a strong preference for targeting endothelial cells, which make up the blood vessels, suggesting potential applications in regenerative medicine for repairing damaged blood vessels, especially in the lungs.
In animal models with viral infections that damaged lung blood vessels, SiLNPs carrying agents that promote blood vessel formation led to improved blood oxygen levels and lung function.
The scientists hypothesized that the larger size of silicon atoms compared to carbon atoms could be a factor in SiLNP efficiency. This size difference makes the atoms less tightly packed, likely increasing membrane fluidity when SiLNPs fuse with target cells, making it easier for mRNA to enter cells and produce proteins more effectively. Additionally, proteins binding to the surface of SiLNPs in the bloodstream help direct them to the appropriate tissues.
Ultimately, SiLNPs delivered mRNA up to six times more efficiently than current standard LNPs, demonstrating the significant clinical potential of siloxane composites in enhancing delivery performance.
“These SiLNPs show promise for protein replacement therapies, regenerative medicine, and CRISPR-Cas-based gene editing,” said Xue.
We hope that this paper can lead to new clinical applications for lipid nanoparticles by showing how simple alterations to their chemical structure can enable highly specific mRNA delivery to the organ of interest.
Michael J. Mitchell, Associate Professor, Department of Bioengineering, University of Pennsylvania
Journal Reference:
Xue, L., et al. (2024) Combinatorial design of siloxane-incorporated lipid nanoparticles augments intracellular processing for tissue-specific mRNA therapeutic delivery. Nature Nanotechnology. doi.org/10.1038/s41565-024-01747-6.