Hurdles in cell-specific delivery of small interfering RNA (siRNA) in vivo hinder the clinical translation of RNA interference (RNAi). A fundamental problem concerns conflicting requirements for the design of the delivery vehicles: cationic materials facilitate cargo condensation and endosomolysis, yet hinder in vivo targeting and colloidal stability. Here, we describe a self-assembled, compact (~30 nm) and biocompatible ribonucleoprotein-octamer nanoparticle that achieves endosomal destabilization and targeted delivery. The protein octamer consists of a poly(ethylene glycol) scaffold, a sterically masked endosomolytic peptide, and a double-stranded RNA-binding domain, provides a discrete number of siRNA loading sites and a high siRNA payload (> 30 wt%), and offers flexibility in both siRNA and targeting-ligand selection. We show that a ribonucleoprotein octamer against the polo-like kinase 1 (Plk1) gene and bearing a ligand that binds to prostate specific membrane antigen (PSMA) leads to efficient gene silencing in prostate tumour cells in vitro and when intravenously injected in mouse models of prostate cancer. The octamer's versatile nanocarrier design should offer opportunities for the clinical translation of therapies based on intracellularly acting biologics.

中文翻译：

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用于靶向siRNA递送的核糖核蛋白八聚体。

小干扰RNA（siRNA）在体内的细胞特异性传递中的障碍阻碍了RNA干扰（RNAi）的临床翻译。一个基本问题涉及对运输工具的设计提出的相互矛盾的要求：阳离子材料促进货物凝结和内溶，但阻碍了体内靶向和胶体稳定性。在这里，我们描述了一种自组装的，紧凑的（〜30 nm）且具有生物相容性的核糖核蛋白-八聚体纳米颗粒，可实现内体去稳定化和靶向递送。蛋白质八聚体由聚（乙二醇）支架，空间屏蔽的内溶肽和双链RNA结合结构域组成，提供离散数量的siRNA加载位点和高siRNA负载量（> 30 wt％），并且在siRNA和靶向配体选择方面都提供了灵活性。我们显示，针对polo样激酶1（Plk1）基因并带有与前列腺特异性膜抗原（PSMA）结合的配体的核糖核蛋白八聚体导致前列腺肿瘤细胞在体外和在小鼠模型中静脉注射时有效的基因沉默前列腺癌。octamer的多功能纳米载体设计应为基于细胞内作用生物制剂的临床治疗翻译提供机会。