Dermal delivery of HSP47 siRNA with NOX4-modulating mesoporous silica-based nanoparticles for treating fibrosis

Jingga Morry, Worapol Ngamcherdtrakul, Shenda Gu, Shaun M. Goodyear, David J. Castro, Moataz M. Reda, Thanapon Sangvanich, Wassana Yantasee

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Fibrotic diseases such as scleroderma have been linked to increased oxidative stress and upregulation of pro-fibrotic genes. Recent work suggests a role of NADPH oxidase 4 (NOX4) and heat shock protein 47 (HSP47) in inducing excessive collagen synthesis, leading to fibrotic diseases. Herein, we elucidate the relationship between NOX4 and HSP47 in fibrogenesis and propose to modulate them altogether as a new strategy to treat fibrosis. We developed a nanoparticle platform consisting of polyethylenimine (PEI) and polyethylene glycol (PEG) coating on a 50-nm mesoporous silica nanoparticle (MSNP) core. The nanoparticles effectively delivered small interfering RNA (siRNA) targeting HSP47 (siHSP47) in an invitro model of fibrosis based on TGF-β stimulated fibroblasts. The MSNP core also imparted an antioxidant property by scavenging reactive oxygen species (ROS) and subsequently reducing NOX4 levels in the invitro fibrogenesis model. The nanoparticle was far superior to n-acetyl cysteine (NAC) at modulating pro-fibrotic markers. Invivo evaluation was performed in a bleomycin-induced scleroderma mouse model, which shares many similarities to human scleroderma disease. Intradermal administration of siHSP47-nanoparticles effectively reduced HSP47 protein expression in skin to normal level. In addition, the antioxidant MSNP also played a prominent role in reducing the pro-fibrotic markers, NOX4, alpha smooth muscle actin (α-SMA), and collagen type I (COL I), as well as skin thickness of the mice.

Original languageEnglish (US)
Pages (from-to)41-52
Number of pages12
JournalBiomaterials
Volume66
DOIs
StatePublished - Oct 1 2015

Keywords

  • Dermal delivery
  • Fibrosis
  • HSP47
  • MSNP
  • NOX4
  • SiRNA

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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