Shanghai Institute of Materia Medica , Chinese Academy of Sciences , Shanghai 201203 , China.
University of Chinese Academy of Sciences , Beijing 100049 , China.
Nano Lett. 2018 Apr 11;18(4):2411-2419. doi: 10.1021/acs.nanolett.7b05430. Epub 2018 Mar 23.
RNA interference (RNAi) technology has shown great promise for the treatment of cancer and other genetic disorders. Despite the efforts to increase the target tissue distribution, the safe and effective delivery of siRNA to the diseased cells with sufficient cytosolic transport is another critical factor for successful RNAi clinical application. Here, the constructed lipid-based liquid crystalline nanoparticles, called nano-Transformers, can transform thestructure in the intracellular acidic environment and perform high-efficient siRNA delivery for cancer treatment. The developed nano-Transformers have satisfactory siRNA loading efficiency and low cytotoxicity. Different from the traditional cationic nanocarriers, the endosomal membrane fusion induced by the conformational transition of lipids contributes to the easy dissociation of siRNA from nanocarriers and direct release of free siRNA into cytoplasm. We show that transfection with cyclin-dependent kinase 1 (CDK1)-siRNA-loaded nano-Transformers causes up to 95% reduction of relevant mRNA in vitro and greatly inhibits the tumor growth without causing any immunogenic response in vivo. This work highlights that the lipid-based nano-Transformers may become the next generation of siRNA delivery system with higher efficacy and improved safety profiles.
RNA 干扰 (RNAi) 技术在癌症和其他遗传疾病的治疗方面显示出巨大的应用潜力。尽管人们努力提高靶向组织的分布，但安全有效地将 siRNA 递送至患病细胞并实现足够的细胞质内转运是 RNAi 临床应用成功的另一个关键因素。本文构建了一种基于脂质的液晶纳米颗粒，称为纳米变形金刚，可在细胞内酸性环境中改变结构，并高效递送至癌细胞以治疗癌症。所开发的纳米变形金刚具有令人满意的 siRNA 负载效率和低细胞毒性。与传统的阳离子纳米载体不同，脂质构象转变诱导的内涵体膜融合有助于 siRNA 从纳米载体中容易解离，并将游离的 siRNA 直接释放到细胞质中。我们发现，用细胞周期蛋白依赖性激酶 1 (CDK1)-siRNA 负载的纳米变形金刚进行转染，可使体外相关 mRNA 减少高达 95%，并在体内大大抑制肿瘤生长而不会引起任何免疫反应。这项工作强调了基于脂质的纳米变形金刚可能成为下一代具有更高疗效和改善安全性的 siRNA 递药系统。
