The Delivery of Small Interfering RNA to Hepatic Stellate Cells Using a Lipid Nanoparticle Composed of a Vitamin A-Scaffold Lipid-Like Material.

Hepatic stellate cells (HSCs) are responsible for hepatic fibrosis and liver cirrhosis via their ability to produce extracellular matrices such as collagens and elastin. However, a strategy for delivering cargoes to HSCs has not been established yet. We herein report on attempts to deliver small interfering RNA (siRNA) to HSCs using several types of SS-cleavable proton-activated lipid-like materials (ssPalms) that contained myristic acid (ssPalmM) or hydrophobic vitamin A (ssPalmA) and E (ssPalmE) as hydrophobic scaffolds. We initially verified that hepatic fibrosis could induce the treatment with tetrachloromethane in terms of collagen fibrils and the expression of marker genes, type I collagen α-1, transforming growth factor β, heat shock protein 47, and α-smooth muscle actin. The siRNA silencing efficiency of the 3 LNPs was then compared using fibrosis-induced mice. Of the materials tested, LNPssPalmA showed the highest efficiency, with an effective (ED)50 of approximately 0.25 mg siRNA/kg. The LNPssPalmA showed a significant inhibitory effect on collagen production at a dose of 3.0 mg siRNA/kg with no evidence of any severe adverse effects. In conclusion, LNPssPalmA holds considerable potential for use in the treatment of HSCs-mediated diseases.