High-density lipoprotein facilitates in vivo delivery of α-tocopherol-conjugated short-interfering RNA to the brain

Hum Gene Ther. 2011 Jun;22(6):711-9. doi: 10.1089/hum.2010.083. Epub 2011 Mar 21.


We originally reported the use of vitamin E (α-tocopherol) as an in vivo vector of short-interfering RNA (siRNA) to the liver. Here, we apply our strategy to the brain. By combining high-density lipoprotein (HDL) as a second carrier with α-tocopherol-conjugated siRNA (Toc-siRNA) in the brain, we achieved dramatic improvement of siRNA delivery to neurons. After direct intracerebroventricular (ICV) infusion of Toc-siRNA/HDL for 7 days, extensive and specific knock-down of a target gene, β-site amyloid precursor protein cleaving enzyme 1 (BACE1), was observed in both mRNA and protein levels, especially in the cerebral cortex and hippocampus. This new delivery method achieved a much more prominent down-regulation effect than conventional silencing methods of the brain gene, i.e., ICV infusion of nonconjugated siRNA or oligonucleotides. With only 3 nmol Toc-siRNA with HDL, BACE1 mRNA in the parietal cortex could be reduced by ∼ 70%. We suppose that this dramatic improvement of siRNA delivery to the brain is due to the use of lipoprotein receptor-mediated endocytosis because the silencing efficiency was significantly increased by binding of Toc-siRNA to the lipoprotein, and in contrast, was clearly decreased in lipoprotein-receptor knockout mice. These results suggest exogenous siRNA could be used clinically for otherwise incurable neurological diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / genetics*
  • Animals
  • Aspartic Acid Endopeptidases / genetics*
  • Brain / metabolism*
  • Endocytosis
  • Gene Silencing
  • Gene Transfer Techniques*
  • HEK293 Cells
  • Humans
  • Infusions, Intraventricular
  • Lipoproteins, HDL / chemistry*
  • Mice
  • Neurons / metabolism
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / chemistry
  • RNA, Small Interfering / genetics
  • alpha-Tocopherol / chemistry
  • alpha-Tocopherol / metabolism*


  • Lipoproteins, HDL
  • RNA, Small Interfering
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse
  • alpha-Tocopherol