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

• Published in: Chembiochem : a European journal of chemical biology Vol. 23; no. 20; pp. e202200410 - n/a
• Main Authors: Knieß, Robert, Leeder, Wolf‐Matthias, Reißig, Paul, Geyer, Felix Klaus, Göringer, H. Ulrich
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 19.10.2022; John Wiley and Sons Inc
• Subjects: African trypanosomes; African trypanosomiasis; Animal diseases; Aqueous solutions; chemotherapeutics; Chemotherapy; Cholesterol; Cholesterol - metabolism; Deoxyribonucleic acid; DNA; DNA - metabolism; DNA biosynthesis; DNA nanoparticles; DNA, Catalytic - metabolism; DNAzymes; drug design; Drug development; Drug resistance; Humans; Hydrophobicity; Lipid membranes; Lipids; Livestock; Membranes; Micelles; Nanoparticles; Parasites; RNA, Spliced Leader - metabolism; Solvents - metabolism; Splicing; Toxicity; Trypanocidal Agents - pharmacology; Trypanocides; Trypanosoma brucei brucei - drug effects; Trypanosome; Trypanosomiasis, African - drug therapy; Trypanosomiasis, African - parasitology; Vector-borne diseases; African trypanosomes; DNA nanoparticles; DNAzymes; drug design; chemotherapeutics
• ISSN: 1439-4227; 1439-7633; 1439-7633
• DOI: 10.1002/cbic.202200410

Trypanosoma brucei is the causal infectious agent of African trypanosomiasis in humans and Nagana in livestock. Both diseases are currently treated with a small number of chemotherapeutics, which are hampered by a variety of limitations reaching from efficacy and toxicity complications to drug‐resistance problems. Here, we explore the forward design of a new class of synthetic trypanocides based on nanostructured, core‐shell DNA‐lipid particles. In aqueous solution, the particles self‐assemble into micelle‐type structures consisting of a solvent‐exposed, hydrophilic DNA shell and a hydrophobic lipid core. DNA‐lipid nanoparticles have membrane‐adhesive qualities and can permeabilize lipid membranes. We report the synthesis of DNA‐cholesterol nanoparticles, which specifically subvert the membrane integrity of the T. brucei lysosome, killing the parasite with nanomolar potencies. Furthermore, we provide an example of the programmability of the nanoparticles. By functionalizing the DNA shell with a spliced leader (SL)‐RNA‐specific DNAzyme, we target a second trypanosome‐specific pathway (dual‐target approach). The DNAzyme provides a backup to counteract the recovery of compromised parasites, which reduces the risk of developing drug resistance. The bioengineering of synthetic nanoparticles with therapeutic potential for the treatment of African sleeping sickness is reported. The molecules are DNA‐cholesterol amphiphiles, which self‐assemble into micelle‐type nanoparticles with an exterior DNA shell and a lipid core. The particles are constructed to attack two parasite‐specific targets thereby reducing the risk of developing drug resistance.