Comparison of partially and fully chemically-modified siRNA in conjugate-mediated delivery in vivo

Nucleic Acids Res. 2018 Mar 16;46(5):2185-2196. doi: 10.1093/nar/gky037.


Small interfering RNA (siRNA)-based drugs require chemical modifications or formulation to promote stability, minimize innate immunity, and enable delivery to target tissues. Partially modified siRNAs (up to 70% of the nucleotides) provide significant stabilization in vitro and are commercially available; thus are commonly used to evaluate efficacy of bio-conjugates for in vivo delivery. In contrast, most clinically-advanced non-formulated compounds, using conjugation as a delivery strategy, are fully chemically modified (100% of nucleotides). Here, we compare partially and fully chemically modified siRNAs in conjugate mediated delivery. We show that fully modified siRNAs are retained at 100x greater levels in various tissues, independently of the nature of the conjugate or siRNA sequence, and support productive mRNA silencing. Thus, fully chemically stabilized siRNAs may provide a better platform to identify novel moieties (peptides, aptamers, small molecules) for targeted RNAi delivery.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aptamers, Nucleotide / chemistry
  • Cells, Cultured
  • Drug Delivery Systems / methods*
  • Female
  • Genetic Vectors / genetics
  • HeLa Cells
  • Humans
  • Lipids / chemistry
  • Mice, Inbred C57BL
  • Peptides / chemistry
  • RNA Interference*
  • RNA Processing, Post-Transcriptional*
  • RNA, Small Interfering / chemistry
  • RNA, Small Interfering / genetics*
  • RNA, Small Interfering / pharmacokinetics
  • Tissue Distribution


  • Aptamers, Nucleotide
  • Lipids
  • Peptides
  • RNA, Small Interfering