Therapeutic targeting of STAT3 with small interference RNAs and antisense oligonucleotides embedded exosomes in liver fibrosis

FASEB J. 2021 May;35(5):e21557. doi: 10.1096/fj.202002777RR.

Abstract

Hepatic fibrosis is a wound healing response that results in excessive extracellular matrix (ECM) accumulation in response to chronic hepatic injury. Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor associated with the pathogenesis of liver fibrosis. Though a promising potential therapeutic target, there are no specific drug candidates for STAT3. Exosomes are extracellular vesicles generated by all cell types with a capacity to efficiently enter cells across different biological barriers. Here, we utilize exosomes as delivery conduit to specifically target STAT3 in liver fibrosis. Exosomes derived from clinical grade fibroblast-like mesenchymal stem cells (MSCs) were engineered to carry siRNA or antisense oligonucleotide (ASO) targeting STAT3 (iExosiRNA-STAT3 or iExomASO-STAT3 ). Compared to scrambled siRNA control, siRNA-STAT3, or ASO-STAT3, iExosiRNA-STAT3 or iExomASO-STAT3 showed enhanced STAT3 targeting efficiency. iExosiRNA-STAT3 or iExomASO-STAT3 treatments suppressed STAT3 levels and ECM deposition in established liver fibrosis in mice, and significantly improved liver function. iExomASO-Stat3 restored liver function more efficiently when compared to iExosiRNA-STAT3 . Our results identify a novel anti-fibrotic approach for direct targeting of STAT3 with exosomes with immediate translational potential.

Trial registration: ClinicalTrials.gov NCT03608631.

Keywords: STAT3; engineered exosomes; liver fibrosis; mesenchymal stromal cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Tetrachloride / toxicity
  • Exosomes / genetics*
  • Female
  • Gene Expression Regulation*
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Oligonucleotides, Antisense / pharmacology*
  • RNA, Small Interfering / genetics*
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • Signal Transduction

Substances

  • Oligonucleotides, Antisense
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Carbon Tetrachloride

Associated data

  • ClinicalTrials.gov/NCT03608631