Zinc cyclic di-AMP nanoparticles target and suppress tumours via endothelial STING activation and tumour-associated macrophage reinvigoration

Nat Nanotechnol. 2022 Dec;17(12):1322-1331. doi: 10.1038/s41565-022-01225-x. Epub 2022 Oct 27.


The clinical utility of stimulator of interferon genes (STING) agonists has been limited due to poor tumour-targeting and unwanted toxicity following systemic delivery. Here we describe a robust tumour-targeted STING agonist, ZnCDA, formed by the encapsulation of bacterial-derived cyclic dimeric adenosine monophosphate (CDA) in nanoscale coordination polymers. Intravenously injected ZnCDA prolongs CDA circulation and efficiently targets tumours, mediating robust anti-tumour effects in a diverse set of preclinical cancer models at a single dose. Our findings reveal that ZnCDA enhances tumour accumulation by disrupting endothelial cells in the tumour vasculature. ZnCDA preferentially targets tumour-associated macrophages to modulate antigen processing and presentation and subsequent priming of an anti-tumour T-cell response. ZnCDA reinvigorates the anti-tumour activity of both radiotherapy and immune checkpoint inhibitors in immunologically 'cold' pancreatic and glioma tumour models, offering a promising combination strategy for the treatment of intractable human cancers.

Publication types

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

MeSH terms

  • Adenosine Monophosphate
  • Cyclic AMP
  • Endothelial Cells
  • Humans
  • Membrane Proteins
  • Nanoparticles* / therapeutic use
  • Neoplasms* / drug therapy
  • Tumor-Associated Macrophages
  • Zinc / pharmacology


  • Cyclic AMP
  • Zinc
  • Membrane Proteins
  • Adenosine Monophosphate