Immunomodulatory spherical nucleic acids

Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):3892-7. doi: 10.1073/pnas.1502850112. Epub 2015 Mar 16.

Abstract

Immunomodulatory nucleic acids have extraordinary promise for treating disease, yet clinical progress has been limited by a lack of tools to safely increase activity in patients. Immunomodulatory nucleic acids act by agonizing or antagonizing endosomal toll-like receptors (TLR3, TLR7/8, and TLR9), proteins involved in innate immune signaling. Immunomodulatory spherical nucleic acids (SNAs) that stimulate (immunostimulatory, IS-SNA) or regulate (immunoregulatory, IR-SNA) immunity by engaging TLRs have been designed, synthesized, and characterized. Compared with free oligonucleotides, IS-SNAs exhibit up to 80-fold increases in potency, 700-fold higher antibody titers, 400-fold higher cellular responses to a model antigen, and improved treatment of mice with lymphomas. IR-SNAs exhibit up to eightfold increases in potency and 30% greater reduction in fibrosis score in mice with nonalcoholic steatohepatitis (NASH). Given the clinical potential of SNAs due to their potency, defined chemical nature, and good tolerability, SNAs are attractive new modalities for developing immunotherapies.

Keywords: TLRs; immune regulation; nanotechnology; oligonucleotides; vaccines.

Publication types

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

MeSH terms

  • Animals
  • Antigens / chemistry
  • Cell Line
  • Female
  • Humans
  • Immunity, Innate
  • Liver Cirrhosis / pathology
  • Lymphoma / therapy
  • Mice
  • Mice, Inbred C57BL
  • Nanomedicine / methods
  • Nanoparticles / chemistry
  • Neoplasms, Experimental / therapy*
  • Non-alcoholic Fatty Liver Disease / therapy*
  • Nucleic Acid Conformation
  • Nucleic Acids / chemistry*
  • Nucleic Acids / therapeutic use
  • Oligonucleotides / therapeutic use
  • Toll-Like Receptors / agonists*

Substances

  • Antigens
  • Nucleic Acids
  • Oligonucleotides
  • Toll-Like Receptors