siRNA delivery to lymphatic endothelial cells via ApoE-mediated uptake by lipid nanoparticles

Yu Sakurai, Keito Yoshikawa, Kenta Arai, Akira Kazaoka, Shigeki Aoki, Kousei Ito, Yuta Nakai, Kota Tange, Tomomi Furihata, Hiroki Tanaka, Hidetaka Akita

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)125-133
Number of pages9
JournalJournal of Controlled Release
Publication statusPublished - 2023 Jan


  • Apolipoprotein E
  • Lipid nanoparticle
  • Lymphatic endothelial cells
  • siRNA

ASJC Scopus subject areas

  • Pharmaceutical Science


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