Myeloid cell-specific topoisomerase 1 inhibition using DNA origami mitigates neuroinflammation

EMBO Rep. 2022 Jul 5;23(7):e54499. doi: 10.15252/embr.202154499. Epub 2022 May 20.


Targeting myeloid cells, especially microglia, for the treatment of neuroinflammatory diseases such as multiple sclerosis (MS), is underappreciated. Our in silico drug screening reveals topoisomerase 1 (TOP1) inhibitors as promising drug candidates for microglial modulation. We show that TOP1 is highly expressed in neuroinflammatory conditions, and TOP1 inhibition using camptothecin (CPT) and its FDA-approved analog topotecan (TPT) reduces inflammatory responses in microglia/macrophages and ameliorates neuroinflammation in vivo. Transcriptomic analyses of sorted microglia from LPS-challenged mice reveal an altered transcriptional phenotype following TPT treatment. To target myeloid cells, we design a nanosystem using β-glucan-coated DNA origami (MyloGami) loaded with TPT (TopoGami). MyloGami shows enhanced specificity to myeloid cells while preventing the degradation of the DNA origami scaffold. Myeloid-specific TOP1 inhibition using TopoGami significantly suppresses the inflammatory response in microglia and mitigates MS-like disease progression. Our findings suggest that TOP1 inhibition in myeloid cells represents a therapeutic strategy for neuroinflammatory diseases and that the myeloid-specific nanosystems we designed may also benefit the treatment of other diseases with dysfunctional myeloid cells.

Keywords: DNA nanostructure; inflammation; macrophage; microglia; topoisomerase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA
  • Macrophages
  • Mice
  • Neuroinflammatory Diseases*
  • Topoisomerase I Inhibitors* / pharmacology
  • Topotecan / pharmacology


  • Topoisomerase I Inhibitors
  • Topotecan
  • DNA