Novel lipid nanoparticles enhance tissue-specific drug delivery

While past research -; including at Penn Engineering -; has screened "libraries" of LNPs to find specific variants that target organs like the lungs, this approach is akin to trial and error.

Michael J. Mitchell, Associate Professor in BioengineeringWe've 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."

By carefully testing hundreds of variants of the newly christened siloxane-incorporating lipid nanoparticles (SiLNPs), the researchers determined which chemical features had an effect on mRNA delivery. "Identifying their in vivo delivery was a huge challenge," says Lulu Xue, a postdoctoral fellow in the Mitchell Lab and one of the paper's co-first authors.

When glowing cells also appeared in the animal models' lungs, the researchers realized that certain SiLNPs variants were guiding the molecules outside the liver -; the holy grail of LNP research, since LNPs tend to congregate in the liver, due to that organ's convoluted network of blood vessels.

The group also determined that a wide variety of chemical factors affected the SiLNPs' overall efficacy, including the number of silicon groups in the lipids, the length of the lipids' tails and the structure of the lipids themselves.

In addition, the SiLNPs had a marked affinity for endothelial cells; since blood vessels are made of endothelial cells, SiLNPs may have clinical applications in regenerative medicine that targets damaged blood vessels, in particular in the lungs. Indeed, the researchers found that SiLNPs delivering substances that promote new blood vessel growth dramatically improved blood oxygen levels and lung function in animal models suffering from a viral infection that damaged their lungs' blood vessels.

The researchers theorized that one reason for SiLNPs' effectiveness could be that silicon atoms are larger than carbon atoms. Because the atoms are less tightly packed, when SiLNPs fuse with target cell membranes, the former likely increases the fluidity of the latter. That extra flexibility in turn helps the mRNA carried by SiLNPs enter the target cell, so the mRNA can be used to produce proteins more readily. As the SiLNPs travel through the bloodstream, proteins that attach to their surface also help guide them to the right tissue.

"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," adds Mitchell.

Source:

University of Pennsylvania School of Engineering and Applied Science

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