Non-canonical inflammasome activation mediates the adjuvanticity of nanoparticles

Natalia Muñoz-Wolf, Ross W. Ward, Claire H. Hearnden, Fiona A. Sharp, Joan Geoghegan, Katie O'Grady, Craig P. McEntee, Katharine A. Shanahan, Coralie Guy, Andrew G. Bowie, Matthew Campbell, Carla B. Roces, Giulia Anderluzzi, Cameron Webb, Yvonne Perrie, Emma Creagh, Ed C. Lavelle

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The non-canonical inflammasome sensor caspase-11 and gasdermin D (GSDMD) drive inflammation and pyroptosis, a type of immunogenic cell death that favors cell-mediated immunity (CMI) in cancer, infection, and autoimmunity. Here we show that caspase-11 and GSDMD are required for CD8+ and Th1 responses induced by nanoparticulate vaccine adjuvants. We demonstrate that nanoparticle-induced reactive oxygen species (ROS) are size dependent and essential for CMI, and we identify 50- to 60-nm nanoparticles as optimal inducers of ROS, GSDMD activation, and Th1 and CD8+ responses. We reveal a division of labor for IL-1 and IL-18, where IL-1 supports Th1 and IL-18 promotes CD8+ responses. Exploiting size as a key attribute, we demonstrate that biodegradable poly-lactic co-glycolic acid nanoparticles are potent CMI-inducing adjuvants. Our work implicates ROS and the non-canonical inflammasome in the mode of action of polymeric nanoparticulate adjuvants and establishes adjuvant size as a key design principle for vaccines against cancer and intracellular pathogens.

Original languageEnglish
Article number100899
Number of pages22
JournalCell Reports Medicine
Issue number1
Publication statusPublished - 17 Jan 2023


  • adjuvant
  • Caspase-1
  • Caspase-11
  • CD4
  • CD8+
  • cell-mediated immunity
  • CTL
  • IL-1
  • non-canonical inflammasome
  • PLGA
  • polymeric nanoparticles
  • T cells
  • Th1
  • vaccine


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