PDF(Pubmed)
Abstract：
RNA therapeutics have the potential to resolve a myriad of genetic diseases. Lipid nanoparticles (LNPs) are among the most successful RNA delivery systems. Expanding their use for the treatment of more genetic diseases hinges on our ability to continuously evolve the design of LNPs with high potency, cellular-specific targeting, and low side effects. Overcoming the difficulty of releasing cargo from endocytosed LNPs remains a significant hurdle. Here, we investigate the fundamental properties of nonviral RNA nanoparticles pertaining to the activation of topological transformations of endosomal membranes and RNA translocation into the cytosol. We show that, beyond composition, LNP fusogenicity can be prescribed by designing LNP nanostructures that lower the energetic cost of fusion and fusion-pore formation with a target membrane. The inclusion of structurally active lipids leads to enhanced LNP endosomal fusion, fast evasion of endosomal entrapment, and efficacious RNA delivery. For example, conserving the lipid make-up, RNA-LNPs having cuboplex nanostructures are significantly more efficacious at endosomal escape than traditional lipoplex constructs.
摘要：
RNA疗法具有解决无数遗传疾病的潜力。脂质纳米颗粒(LNP)是最成功的RNA递送系统之一。扩大其用于治疗更多遗传疾病的用途取决于我们不断发展高效LNP设计的能力，细胞特异性靶向，和低副作用。克服从内吞LNP释放货物的困难仍然是一个重大障碍。这里,我们研究了非病毒RNA纳米颗粒的基本特性，这些特性与激活内体膜的拓扑转化和RNA易位进入细胞质有关。我们证明,超越构图，LNP融合性可以通过设计LNP纳米结构来规定,所述LNP纳米结构降低与目标膜的融合和融合孔形成的能量成本。包含结构活性脂质导致增强的LNP内体融合，快速逃避内体截留，和有效的RNA递送。例如,保存脂质组成，具有立方体复合物纳米结构的RNA-LNP在内体逃逸方面比传统的脂质复合物构建体显著更有效。
