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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.

A previous version of this manuscript has been deposited on a preprint server (https://doi.org/10.1101/2022.07.18.500428).