Molecular Genetics, Technical University Darmstadt, Schnittspahnstr. 10, 64287, Darmstadt, Germany.
Chembiochem. 2022 Oct 19;23(20):e202200410. doi: 10.1002/cbic.202200410. Epub 2022 Sep 20.
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.
布氏锥虫是人类感染非洲锥虫病和家畜感染那加那病的病原体。这两种疾病目前都采用少数几种化学疗法治疗，但由于各种限制，包括疗效和毒性并发症以及耐药性问题，这些疗法受到了阻碍。在这里，我们探索了基于纳米结构核壳 DNA-脂质体的新型合成杀锥虫剂的正向设计。在水溶液中，这些颗粒自组装成胶束型结构，由暴露于溶剂的亲水性 DNA 壳和疏水性脂质核组成。DNA-脂质纳米颗粒具有膜黏附特性，可以使脂膜通透性增加。我们报告了 DNA-胆固醇纳米颗粒的合成，该颗粒特异性地破坏了 T. brucei 溶酶体的膜完整性，以纳摩尔级的效力杀死寄生虫。此外，我们提供了纳米颗粒可编程性的一个例子。通过用拼接前导 (SL)-RNA 特异性 DNA 酶功能化 DNA 壳，我们针对第二个锥虫特异性途径（双靶方法）。该 DNA 酶提供了备份以抵消受损寄生虫的恢复，从而降低了产生耐药性的风险。
