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

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.

A pharmacological toolkit for human microglia identifies Topoisomerase I inhibitors as immunomodulators for Alzheimer’s disease

“…Camptothecin : we identified Topotecan as a clear driver of the CD74 high /MHC high signature ( Figure 2C ; CXCR4 and SRGN expression was upregulated 24hrs following treatment), in particular with the higher dosage of 1µM tested. These results of Topotecan inducing the CD74 high /MHC high microglial subtype are of particular interest as Topotecan is a more effective and safer version of Camptothecin that is FDA approved for the treatment of small-cell lung cancer 16 .…”

“…We identified Topotecan as a structural and functional analog of Camptothecin that robustly induces the CD74 high /MHC high signature and functionally mimics Camptothecin’s downregulation of pro-inflammatory cytokine secretion in HMC3 cells. These results are of particular interest as Topotecan is an FDA-approved drug, originally authorized for the treatment of small-cell lung cancer and cervical cancer 16 . Topotecan is clinically more effective and safer than Camptothecin 55 and in the light of our findings, Topotecan might represent an entry point for therapeutic development of a microglia-targeted AD-therapy with the potential to shift microglial subpopulations towards the reduced CD74 high /MHC high phenotype that enhances Aβ uptake.…”

Framework nucleic acids as promising reactive oxygen species scavengers for anti-inflammatory therapy

“…This special complex also effectively downregulated around 50% gene expression of TNF-α, 93% IL-1β, and 86% IL-6, therefore providing a new therapeutic strategy for resolving inflammatory diseases in the neural system. 90 The most widely studied DNA origami nanostructures are rectangular and triangular nanostructures, which exhibited similar ROS-scavenging capacity in the aforementioned articles. However, since the sizes and shapes of DNA origami are highly changeable, we believe that it will arouse profound interest to investigate the structural stability of different origami geometrical shapes.…”

“…This special complex also effectively downregulated around 50% gene expression of TNF-α, 93% IL-1β, and 86% IL-6, therefore providing a new therapeutic strategy for resolving inflammatory diseases in the neural system. 90…”

Microglial aryl hydrocarbon receptor enhances phagocytic function via SYK and promotes remyelination in the cuprizone mouse model of demyelination

“…The heterogeneity of microglia in the transcriptome and protein expression is likely to affect their ability to modulate remyelination. In addition, microglia go through changes in gene expression and function during the remyelination process [ 5 , 39 , 40 ]. Comprehending the different functional properties of microglia subsets and effector molecules may be conducive to developing effective therapies.…”