Lipid nanoparticles (LNPs) have been successfully used in drug delivery for decades. FDA-approved therapies use them as vehicles for delivering messenger RNA (mRNA), which prompts the cell to make new proteins, and small interfering RNA (siRNA), which instruct the cell to silence or inhibit the expression of certain proteins. The biggest challenge in developing a successful RNA therapy is its targeted delivery.
Liver fibrosis occurs when the liver is repeatedly damaged and the healing process results in the accumulation of scar tissue, impeding healthy liver function. Liver fibrosis has remained challenging to treat using RNA therapies due to a lack of delivery systems for targeting activated liver-resident fibroblasts. Both the solid fibroblast structure and the lack of specificity or affinity to target these fibroblasts has impeded current LNPs from entering activated liver-resident fibroblasts, and thus they are unable to deliver RNA therapeutics.
Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, and postdoctoral fellows Xuexiang Han and Ningqiang Gong, found a new way to synthesize ligand-tethered LNPs, increasing their selectivity and allowing them to target liver fibroblasts.
Their study, published in Nature Communications, shows how a small-molecule ligand incorporated into the synthesis of the ionizable lipid, a key component of the LNP, creates an affinity to the notoriously hard-to-target activated fibroblasts in the liver responsible for the buildup of collagen.
Once their LNPs arrive at and enter the target cell, siRNA is released, which silences the expression of HSP47, inhibits the production of collagen and stops fibrosis in its tracks. The treatment is a promising treatment for liver fibrosis in humans.
This story is by Melissa Pappas. Read more at Penn Engineering Today.