TY - JOUR
T1 - siRNA delivery to lymphatic endothelial cells via ApoE-mediated uptake by lipid nanoparticles
AU - Sakurai, Yu
AU - Yoshikawa, Keito
AU - Arai, Kenta
AU - Kazaoka, Akira
AU - Aoki, Shigeki
AU - Ito, Kousei
AU - Nakai, Yuta
AU - Tange, Kota
AU - Furihata, Tomomi
AU - Tanaka, Hiroki
AU - Akita, Hidetaka
N1 - Funding Information:
This work was supported by JST CREST grant (grant number JPMJCR17H1 ), JSPS KAKENHI (grant numbers 20H00657 , 21K18320 and 20K20195 ), and The Canon Foundation. We also wish to thank Dr. Milton S. Feather for helpful advice in the preparation of this manuscript.
Publisher Copyright:
© 2022
PY - 2023/1
Y1 - 2023/1
N2 - Systemically administered lipid nanoparticles (LNPs) are complexed with Apolipoprotein E (ApoE) in the bloodstream, and the complex is subsequently largely taken up by hepatocytes. Based on a previous report showing that, like blood, lymph fluid also contains ApoE, and that LECs, in turn, expresses a low density-lipoprotein receptor (LDLR), which is the receptor responsible for the ApoE-bound LNP, we hypothesized that subcutaneously administered LNPs would be taken up by LECs via an ApoE-LDLR pathway. Our in vitro studies using immortal LECs that we established in a previous study showed that LEC indeed took up LNPs in an ApoE-dependent manner. We then reported on the development of LNPs that target the lymphatic endothelium for in vivo siRNA delivery after subcutaneous administration. The key to success for in vivo LEC targeting is that the surface needs to be modified with a high density of polyethylene glycol (PEG)-conjugated lipids with short acyl chains (C14). The LNPs were drained into the lymphatic system, and then accumulated in lymphatic endothelial cells in an ApoE-dependent manner, most likely after the release of the PEG-lipid. Subcutaneous administration of optimized LNPs containing encapsulated siRNA against VEGFR3, a marker of LECs, significantly inhibited the expression of VEGFR3. These findings are the first report of a simple straightforward strategy for targeting lymphatic endothelial cells by using ionizable lipid-formulated LNPs.
AB - Systemically administered lipid nanoparticles (LNPs) are complexed with Apolipoprotein E (ApoE) in the bloodstream, and the complex is subsequently largely taken up by hepatocytes. Based on a previous report showing that, like blood, lymph fluid also contains ApoE, and that LECs, in turn, expresses a low density-lipoprotein receptor (LDLR), which is the receptor responsible for the ApoE-bound LNP, we hypothesized that subcutaneously administered LNPs would be taken up by LECs via an ApoE-LDLR pathway. Our in vitro studies using immortal LECs that we established in a previous study showed that LEC indeed took up LNPs in an ApoE-dependent manner. We then reported on the development of LNPs that target the lymphatic endothelium for in vivo siRNA delivery after subcutaneous administration. The key to success for in vivo LEC targeting is that the surface needs to be modified with a high density of polyethylene glycol (PEG)-conjugated lipids with short acyl chains (C14). The LNPs were drained into the lymphatic system, and then accumulated in lymphatic endothelial cells in an ApoE-dependent manner, most likely after the release of the PEG-lipid. Subcutaneous administration of optimized LNPs containing encapsulated siRNA against VEGFR3, a marker of LECs, significantly inhibited the expression of VEGFR3. These findings are the first report of a simple straightforward strategy for targeting lymphatic endothelial cells by using ionizable lipid-formulated LNPs.
KW - Apolipoprotein E
KW - Lipid nanoparticle
KW - Lymphatic endothelial cells
KW - siRNA
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U2 - 10.1016/j.jconrel.2022.11.036
DO - 10.1016/j.jconrel.2022.11.036
M3 - Article
C2 - 36414194
AN - SCOPUS:85142361910
SN - 0168-3659
VL - 353
SP - 125
EP - 133
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -