Meade Bryan R, Dowdy Steven F
Department of Cellular & Molecular Medicine, UCSD School of Medicine, University of California at San Diego, CA 92093, USA.
Discov Med. 2009 Dec;8(43):253-6.
If those of us privileged enough to have the opportunity to work towards curing human diseases had the power to design the ideal therapeutic molecule, the question would be what selection criteria would we choose? Arguably, at the top of the list would be four mandatory properties: specificity, potency, tolerability, and universality. So it should come as no surprise the momentum associated with the field of small interfering RNA (siRNA)-induced RNA Interference (RNAi) therapeutics has gained strength, as these molecules have shown exceptional promise in fulfilling all of these requirements. Unfortunately, siRNAs are too large, too charged, and too rigid to passively diffuse across the cellular membrane and thereby require a delivery system to enter cells. Thus, since its conception of working in human cells, siRNA delivery remains The 800 Pound Gorilla in the room. The main complication yet to overcome is engineering delivery systems that are safe and efficient in systemically delivering siRNA molecules to the diseased tissue and across the cellular membrane of target cells. Currently, encapsulating the siRNA in nanoparticle and liposomal systems has risen to become the standard of delivery approaches. While generally speaking these delivery platforms offer significant advancements, our laboratory is committed to generating alternative siRNA delivery technologies that avoid nanoparticle packaging and allow siRNA molecules to be delivered as single, soluble entities. This brief review discusses the first of these technologies, a Peptide Transduction Domain-dsRNA Binding Domain (PTD-DRBD) fusion protein that avidly binds to the siRNA backbone to mask the negative charge and uses the PTD for macromolecular cellular delivery.
如果我们这些有幸有机会致力于治愈人类疾病的人有能力设计出理想的治疗分子，那么问题将是我们会选择哪些筛选标准呢？可以说，排在首位的将是四个必备特性：特异性、效力、耐受性和通用性。因此，小干扰RNA（siRNA）诱导的RNA干扰（RNAi）治疗领域所具有的发展势头日益强劲也就不足为奇了，因为这些分子在满足所有这些要求方面已展现出非凡的前景。不幸的是，siRNA太大、带电荷太多且过于刚性，无法被动扩散穿过细胞膜，因此需要一种递送系统才能进入细胞。所以，自siRNA在人类细胞中发挥作用的概念提出以来，siRNA递送仍然是该领域中一个难以解决的大问题。尚未克服的主要难题是设计出在将siRNA分子全身递送至患病组织并穿过靶细胞的细胞膜时既安全又高效的递送系统。目前，将siRNA封装在纳米颗粒和脂质体系统中已成为递送方法的标准。一般来说，这些递送平台有了显著进展，但我们实验室致力于开发替代的siRNA递送技术，这些技术无需纳米颗粒包装，能使siRNA分子以单一的可溶性实体形式进行递送。这篇简短的综述讨论了这些技术中的第一种，即一种肽转导域 - dsRNA结合域（PTD - DRBD）融合蛋白，它能 avidly 结合到siRNA主链上以掩盖负电荷，并利用PTD进行大分子细胞递送。 （注：avidly这个词在原文语境中不太明确准确意思，可能影响翻译精准度，这里保留英文未翻译）
