Stabilin-1 is required for the endothelial clearance of small anionic nanoparticles

Gabriela Arias-Alpizar,Bjørn Koch,Naomi M Hamelmann,Malene A Neustrup,Jos M.J Paulusse,Wim Jiskoot,Alexander Kros,Jeroen Bussmann

doi:10.1016/j.nano.2021.102395

Abstract

Clearance of nanoparticles (NPs) after intravenous injection – mainly by the liver – is a critical barrier for the clinical translation of nanomaterials. Physicochemical properties of NPs are known to influence their distribution through cell-specific interactions; however, the molecular mechanisms responsible for liver cellular NP uptake are poorly understood. Liver sinusoidal endothelial cells and Kupffer cells are critical participants in this clearance process. Here we use a zebrafish model for liver-NP interaction to identify the endothelial scavenger receptor Stabilin-1 as a non-redundant receptor for the clearance of small anionic NPs. Furthermore, we show that physiologically, Stabilin-1 is required for the removal of bacterial lipopolysaccharide (LPS/endotoxin) from circulation and that Stabilin-1 cooperates with its homolog Stabilin-2 in the clearance of larger (~100 nm) anionic NPs. Our findings allow optimization of anionic nanomedicine biodistribution and targeting therapies that use Stabilin-1 and -2 for liver endothelium-specific delivery.

Highlights

Clinical application of nanoparticles (NPs) after intravenous (i.v.) administration and delivery of their cargo is hampered by the rapid sequestration of NPs, mainly by cells in the liver.[1,2] removal of NPs with sizes above the renal filtration limit (~5.5 nm) from blood plasma[3] leads to the accumulation of most NPs in the liver
Given that the clearance of some anionic NPs is not exclusively dependent on the scavenging function of Stabilin[2,15] we hypothesized that one or more other scavenger receptor (s) expressed in liver sinusoidal endothelial cells (LSECs) might be involved in the removal of NPs
We previously reported that the zebrafish orthologues of these genes are highly expressed on scavenging endothelial cells (SECs).[15]

Summary

Introduction

Clinical application of nanoparticles (NPs) after intravenous (i.v.) administration and delivery of their cargo (i.e. drugs, DNA, RNA, etc.) is hampered by the rapid sequestration of NPs, mainly by cells in the liver.[1,2] removal of NPs with sizes above the renal filtration limit (~5.5 nm) from blood plasma[3] leads to the accumulation of most NPs in the liver. Arias-Alpizar et al / Nanomedicine: Nanotechnology, Biology, and Medicine 34 (2021) 102395 sinusoids), recognize and internalize NPs and were long thought to be the only liver cell type responsible for NP clearance in vivo. Recent studies on the cellular distribution of NPs within the liver have revealed important contributions of B-. The relative contribution of KCs and LSECs to the clearance of circulating NPs depends mainly on size. Phagocytosis by KCs is responsible for clearance of particles with a size >500 nm.[5,6]

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Conclusion