Multifunctional Nanoparticles Facilitate Molecular Targeting and miRNA Delivery to Inhibit Atherosclerosis in ApoE-/- Mice

Azadeh Kheirolomoom, Chan Woo Kim, Jai Seo, Sandeep Kumar, Dong Ju Son, M. Karen J Gagnon, Elizabeth S. Ingham, Katherine W. Ferrara, Hanjoong Jo

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

The current study presents an effective and selective multifunctional nanoparticle used to deliver antiatherogenic therapeutics to inflamed pro-atherogenic regions without off-target changes in gene expression or particle-induced toxicities. MicroRNAs (miRNAs) regulate gene expression, playing a critical role in biology and disease including atherosclerosis. While anti-miRNA are emerging as therapeutics, numerous challenges remain due to their potential off-target effects, and therefore the development of carriers for selective delivery to diseased sites is important. Yet, co-optimization of multifunctional nanoparticles with high loading efficiency, a hidden cationic domain to facilitate lysosomal escape and a dense, stable incorporation of targeting moieties is challenging. Here, we create coated, cationic lipoparticles (CCLs), containing anti-miR-712 (∼1400 molecules, >95% loading efficiency) within the core and with a neutral coating, decorated with 5 mol % of peptide (VHPK) to target vascular cell adhesion molecule 1 (VCAM1). Optical imaging validated disease-specific accumulation as anti-miR-712 was efficiently delivered to inflamed mouse aortic endothelial cells in vitro and in vivo. As with the naked anti-miR-712, the delivery of VHPK-CCL-anti-miR-712 effectively downregulated the d-flow induced expression of miR-712 and also rescued the expression of its target genes tissue inhibitor of metalloproteinase 3 (TIMP3) and reversion-inducing-cysteine-rich protein with kazal motifs (RECK) in the endothelium, resulting in inhibition of metalloproteinase activity. Moreover, an 80% lower dose of VHPK-CCL-anti-miR-712 (1 mg/kg dose given twice a week), as compared with naked anti-miR-712, prevented atheroma formation in a mouse model of atherosclerosis. While delivery of naked anti-miR-712 alters expression in multiple organs, miR-712 expression in nontargeted organs was unchanged following VHPK-CCL-anti-miR-712 delivery.

Original languageEnglish (US)
Pages (from-to)8885-8897
Number of pages13
JournalACS Nano
Volume9
Issue number9
DOIs
StatePublished - Sep 22 2015

Keywords

  • anti-miRNA
  • atherosclerosis
  • endothelial inflammation
  • microRNA
  • multifunctional particles
  • targeted delivery

ASJC Scopus subject areas

  • Engineering(all)
  • Materials Science(all)
  • Physics and Astronomy(all)

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  • Cite this

    Kheirolomoom, A., Kim, C. W., Seo, J., Kumar, S., Son, D. J., Gagnon, M. K. J., Ingham, E. S., Ferrara, K. W., & Jo, H. (2015). Multifunctional Nanoparticles Facilitate Molecular Targeting and miRNA Delivery to Inhibit Atherosclerosis in ApoE-/- Mice. ACS Nano, 9(9), 8885-8897. https://doi.org/10.1021/acsnano.5b02611