Laboratory of Organic Chemistry , ETH Zurich , 8093 Zurich , Switzerland.
J Am Chem Soc. 2018 Aug 22;140(33):10439-10442. doi: 10.1021/jacs.8b06442. Epub 2018 Aug 9.
Oligonucleotide therapeutics have transformative potential in modern medicine but are poor drug candidates in themselves unless fitted with compensatory carrier systems. We describe a simple approach to transform a designed porous protein cage into a nucleic acid delivery vehicle. By introducing arginine mutations to the lumenal surface, a positively supercharged capsule is created, which can encapsidate oligonucleotides in vitro with high binding affinity. We demonstrate that the siRNA-loaded cage is taken up by mammalian cells and releases its cargo to induce RNAi and knockdown gene expression. These general concepts could also be applied to alternative scaffold designs, expediting the development of artificial protein cages toward delivery applications.
寡核苷酸疗法在现代医学中有变革性的潜力，但本身作为药物候选物的效果较差，除非配备补偿性载体系统。我们描述了一种将设计的多孔蛋白笼转化为核酸传递载体的简单方法。通过在腔表面引入精氨酸突变，创建了一个带正电荷的胶囊，可以在体外与寡核苷酸高亲和力结合。我们证明，装载 siRNA 的笼被哺乳动物细胞摄取，并释放其货物以诱导 RNAi 和基因表达下调。这些通用概念也可以应用于替代支架设计，加速人工蛋白笼向传递应用的发展。
