Journal
JOURNAL OF CONTROLLED RELEASE
Volume 322, Issue -, Pages 217-226Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2020.03.006
Keywords
Apolipoprotein E; Low density lipoprotein receptor; N-acetyl-D-galactosamine; Asialoglycoprotein receptor; Heparansulfate proteoglycan; Lipid nanoparticles; Hepatic uptake
Funding
- Japan Society for the Promotion of Science (JSPS) KAKENHI, Japan [JP15K20831, JP17H05052]
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Lipid nanoparticles (LNPs) are one of the more promising technologies for efficiently delivering nucleic acids in vivo. Hepatocytes are the primary target cells of LNPs that are delivered via the apolipoprotein E (ApoE)-low density lipoprotein receptor (LDLR) pathway, an endogenous targeting pathway. This robust targeting mechanism results in the specific and efficient delivery of nucleic acids to hepatocytes. Trivalent N-acetyl-D-galactosamine (GalNAc) is known to be a high-affinity exogenous ligand against the asialoglycoprotein receptor (ASGPR), which is highly expressed on hepatocytes. In this study, we report that the kinetics of the hepatic uptake process between the two types of targeting pathways are different. Rapid blood clearance, accumulation to the space of Disse and a subsequent slow cellular uptake was observed in the case of the endogenous ApoELDLR pathway. On the other hand, both blood clearance and cellular uptake were more gradual in the case of the exogenous GalNAc-ASGPR pathway. Interactions between ApoE-bound LNPs and hepatic heparan sulfate proteoglycans (HSPGs) were involved in the rapid blood clearance and accumulation to the space of Disse in the case of the endogenous pathway. The findings presented here contribute to a more precise understanding of the mechanism of hepatic uptake and to the rational design of hepatocyte-targeting nanoparticles.
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