Size, Shape, and Sequence-Dependent Immunogenicity of RNA Nanoparticles

Sijin Guo, Hui Li, Mengshi Ma, Jian Fu, Yizhou Dong, Peixuan Guo

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


RNA molecules have emerged as promising therapeutics. Like all other drugs, the safety profile and immune response are important criteria for drug evaluation. However, the literature on RNA immunogenicity has been controversial. Here, we used the approach of RNA nanotechnology to demonstrate that the immune response of RNA nanoparticles is size, shape, and sequence dependent. RNA triangle, square, pentagon, and tetrahedron with same shape but different sizes, or same size but different shapes were used as models to investigate the immune response. The levels of pro-inflammatory cytokines induced by these RNA nanoarchitectures were assessed in macrophage-like cells and animals. It was found that RNA polygons without extension at the vertexes were immune inert. However, when single-stranded RNA with a specific sequence was extended from the vertexes of RNA polygons, strong immune responses were detected. These immunostimulations are sequence specific, because some other extended sequences induced little or no immune response. Additionally, larger-size RNA square induced stronger cytokine secretion. 3D RNA tetrahedron showed stronger immunostimulation than planar RNA triangle. These results suggest that the immunogenicity of RNA nanoparticles is tunable to produce either a minimal immune response that can serve as safe therapeutic vectors, or a strong immune response for cancer immunotherapy or vaccine adjuvants.

Original languageEnglish
Pages (from-to)399-408
Number of pages10
JournalMolecular Therapy Nucleic Acids
StatePublished - Dec 2017

Bibliographical note

Publisher Copyright:
© 2017 The Authors


  • RNA nanoparticle
  • RNA nanotechnology
  • RNA polygon
  • immune response
  • immunogenicity
  • immunomodulation
  • nanobiotechnology
  • pRNA 3WJ

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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