Core-Shell DNA-Cholesterol Nanoparticles Exert Lysosomolytic Activity in African Trypanosomes

Area of Science:

• Nanotechnology
• Parasitology
• Drug Discovery

Background:

• African trypanosomiasis (sleeping sickness) and Nagana are caused by Trypanosoma brucei.
• Current treatments face challenges including toxicity, efficacy, and drug resistance.
• Novel therapeutic strategies are urgently needed to combat these diseases.

Purpose of the Study:

• To design and synthesize a new class of synthetic trypanocides using nanostructured DNA-lipid particles.
• To investigate the mechanism of action and efficacy of these nanoparticles against Trypanosoma brucei.
• To explore the potential for dual-targeting strategies to mitigate drug resistance.

Main Methods:

• Self-assembly of core-shell DNA-lipid nanoparticles with hydrophilic DNA shells and hydrophobic lipid cores.
• Synthesis of DNA-cholesterol nanoparticles for targeted disruption of T. brucei lysosomal membrane integrity.
• Functionalization of nanoparticle DNA shells with SL-RNA-specific DNAzymes for a dual-targeting approach.

Main Results:

• DNA-cholesterol nanoparticles demonstrated potent trypanocidal activity, killing T. brucei with nanomolar efficacy.
• The nanoparticles effectively subverted the membrane integrity of the T. brucei lysosome.
• A dual-targeting approach using DNAzymes showed potential to reduce the risk of developing drug resistance.

Conclusions:

• Nanostructured DNA-lipid particles represent a novel and effective class of synthetic trypanocides.
• Targeting the T. brucei lysosome with DNA-cholesterol nanoparticles offers a promising therapeutic avenue.
• Programmable nanoparticles with dual-targeting capabilities can enhance efficacy and combat drug resistance in trypanosomiasis treatment.