Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates

Nat Biomed Eng. 2018 May;2(5):279-292. doi: 10.1038/s41551-018-0221-2. Epub 2018 Apr 16.


Macrophage accumulation in atherosclerosis is directly linked to the destabilization and rupture of plaque, causing acute atherothrombotic events. Circulating monocytes enter the plaque and differentiate into macrophages, where they are activated by CD4+ T lymphocytes through CD40-CD40 ligand signalling. Here, we report the development and multiparametric evaluation of a nanoimmunotherapy that moderates CD40-CD40 ligand signalling in monocytes and macrophages by blocking the interaction between CD40 and tumour necrosis factor receptor-associated factor 6 (TRAF6). We evaluated the biodistribution characteristics of the nanoimmunotherapy in apolipoprotein E-deficient (Apoe-/-) mice and in non-human primates by in vivo positron-emission tomography imaging. In Apoe-/- mice, a 1-week nanoimmunotherapy treatment regimen achieved significant anti-inflammatory effects, which was due to the impaired migration capacity of monocytes, as established by a transcriptome analysis. The rapid reduction of plaque inflammation by the TRAF6-targeted nanoimmunotherapy and its favourable toxicity profiles in both mice and non-human primates highlights the translational potential of this strategy for the treatment of atherosclerosis.

Publication types

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

MeSH terms

  • Animals
  • Atherosclerosis / diagnostic imaging
  • Atherosclerosis / pathology
  • Atherosclerosis / therapy*
  • CD40 Antigens / metabolism
  • CD40 Ligand / metabolism
  • Disease Models, Animal
  • Female
  • Immunotherapy / methods*
  • Macaca fascicularis
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Transgenic
  • Monocytes / immunology
  • Nanomedicine / methods*
  • TNF Receptor-Associated Factor 6 / chemistry
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Tissue Distribution


  • CD40 Antigens
  • TNF Receptor-Associated Factor 6
  • CD40 Ligand