Targeted RNA delivery using ribonucleoprotein

摘要 沉默rna(SiRNA)是目前医学上的研究热点，因为它可以诱导出有效的靶向。 几乎任何信使核糖核酸的特异性敲除，创造了一种有用的和经过验证的基因替代工具。三个siRNA- 基于药物的治疗已经得到FDA的批准，另外七种候选药物正在进行第三阶段的试验。一把钥匙 然而，限制siRNA临床应用范围的障碍是体内靶向传递，这是一个长期存在的问题 一直困扰着几乎所有反义疗法的发展。纳米技术的最新进展 生产了许多纳米载体，如阳离子脂类、聚合物、无机纳米颗粒和多肽。虽然 阳离子电荷在siRNA缩合和内体逃逸中起重要作用，它干扰特异性 通过与大多数蛋白质和细胞非特异性结合来靶向。要解决这一根本性和长期性问题 问题，在这里，我们建议进一步开发一种用于递送siRNA鸡尾酒的独一无二的RNA纳米载体 建立在我们最近在人类RNA结合蛋白(Corey&Gao Natural BME，PCT)上取得的突破的基础上 已提交，美国阶段批准)。经过数百万年的进化，这些蛋白质是中性的或轻微的 带负电荷，但仍与货物RNA紧密结合，有效载荷非常高。不存在 过多的阳离子电荷与传统的输送技术形成了直接的对比。直通定向 通过siRNA靶向配体嵌合体的受控自组装，该复合体同时实现了所有 高效的siRNA传递和癌症治疗所需的特性。

ABSTRACT Silencing RNA (siRNA) is of considerable current interest in medicine because it can elicit potent, target specific knockdown of virtually any mRNA, creating a useful and proven genetic surrogate tool. Three siRNA- based therapies have been FDA-approved, while another seven candidates are in phase 3 trials. A key obstacle limiting the scope of siRNA clinical uses, however, is in vivo targeted delivery, a `chronic' problem that has plagued the development of virtually all antisense therapies. Recent advances in nanotechnology have produced many nanocarriers such as cationic lipids, polymers, inorganic nanoparticles, and peptides. Although the cationic charge is important for siRNA condensation and endosomal escape, it interferes with specific targeting by non-specifically binding to most proteins and cells. To address this fundamental and chronic problem, here we propose to further develop a one-of-its-kind RNA nanocarrier for delivery of siRNA cocktails building on a recent breakthrough we made on human RNA-binding proteins (Corey & Gao Nature BME, PCT filed, US phase granted). Optimized through millions of years of evolution, these proteins are neutral or slightly negatively charged yet still binding to cargo RNA tightly and with a very high payload. The absence of excessive cationic charges is in direct contrast to conventional delivery technologies. Through orientation controlled self-assembly with siRNA-targeting ligand chimeras, the complex simultaneously achieves all the desired properties for efficient siRNA delivery and cancer treatment.