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

Area of Science:

• Neuroimmunology
• Pharmacology
• Nanomedicine

Background:

• Neuroinflammatory diseases like multiple sclerosis (MS) involve myeloid cell dysfunction.
• Targeting microglia, the brain's resident myeloid cells, is an underappreciated therapeutic avenue.
• Topoisomerase 1 (TOP1) is implicated in inflammatory responses within myeloid cells.

Purpose of the Study:

• To investigate topoisomerase 1 (TOP1) inhibitors as potential treatments for neuroinflammation.
• To develop a myeloid-specific delivery system for TOP1 inhibitors.
• To evaluate the efficacy of targeted TOP1 inhibition in a multiple sclerosis model.

Main Methods:

• In silico drug screening identified TOP1 inhibitors.
• In vitro studies using microglia/macrophages treated with camptothecin (CPT) and topotecan (TPT).
• Development of a β-glucan-coated DNA origami nanosystem (MyloGami) loaded with TPT (TopoGami) for myeloid targeting.
• In vivo studies using LPS-challenged mice and experimental autoimmune encephalomyelitis (EAE) models.

Main Results:

• TOP1 expression is elevated in neuroinflammatory conditions.
• TOP1 inhibition by CPT and TPT reduced microglial inflammatory responses and ameliorated neuroinflammation in vivo.
• Transcriptomic analysis revealed TPT alters microglial transcriptional phenotype.
• TopoGami demonstrated enhanced myeloid cell specificity and suppressed inflammation, mitigating MS-like disease progression.

Conclusions:

• Topoisomerase 1 (TOP1) inhibition in myeloid cells is a promising therapeutic strategy for neuroinflammatory diseases.
• The developed myeloid-specific nanosystem (TopoGami) effectively targets and inhibits TOP1 in microglia.
• This approach holds potential for treating MS and other diseases involving myeloid cell dysfunction.