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

Keying Zhu, Yang Wang, Heela Sarlus, Keyi Geng, Erik Nutma, Jingxian Sun, Shin-Yu Kung, Cindy Bay, Jinming Han, Jin-Hong Min, Irene Benito-Cuesta, Harald Lund, Sandra Amor, Jun Wang, Xing-Mei Zhang, Claudia Kutter, André Ortlieb Guerreiro-Cacais, Björn Högberg, Robert A Harris

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere54499
Pages (from-to)e54499
JournalEMBO reports
Volume23
Issue number7
DOIs
Publication statusPublished - 5 Jul 2022

Keywords

  • DNA nanostructure
  • inflammation
  • macrophage
  • microglia
  • topoisomerase

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