Properties of Native High-Density Lipoproteins Inspire Synthesis of Actively Targeted In Vivo siRNA Delivery Vehicles

Kaylin M. McMahon, Michael P. Plebanek, Colby Shad Thaxton*

*Corresponding author for this work

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Efficient systemic administration of therapeutic short interfering RNA (siRNA) is challenging. High-density lipoproteins (HDLs) are natural in vivo RNA delivery vehicles. Specifically, native HDLs: 1) load single-stranded RNA; 2) are anionic, which requires charge reconciliation between the RNA and HDL, and 3) actively target scavenger receptor type B-1 (SR-B1) to deliver RNA. Emphasizing these particular parameters, templated lipoprotein particles (TLP), mimics of spherical HDLs, are employed and are self-assembled with single-stranded complements of, presumably, any highly unmodified siRNA duplex pair after formulation with a cationic lipid. Resulting siRNA templated lipoprotein particles (siRNA-TLP) are anionic and tunable with regard to RNA assembly and function. Data demonstrate that the siRNA-TLPs actively target SR-B1 to potently reduce androgen receptor and enhancer of zeste homolog 2 proteins in multiple cancer cell lines. Systemic administration of siRNA-TLPs demonstrated no off-target toxicity and significantly reduced the growth of prostate cancer xenografts. Thus, native HDLs inspired the synthesis of a hybrid siRNA delivery vehicle that can modularly load single-stranded RNA complements after charge reconciliation with a cationic lipid, and that function due to active targeting of SR-B1.

Original languageEnglish (US)
Pages (from-to)7824-7835
Number of pages12
JournalAdvanced Functional Materials
Volume26
Issue number43
DOIs
StatePublished - Nov 15 2016

Keywords

  • active delivery
  • lipoproteins
  • nanoparticles
  • short interfering iRNA
  • single-stranded RNA

ASJC Scopus subject areas

  • Chemistry(all)
  • Materials Science(all)
  • Condensed Matter Physics

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