Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Biotechnol Adv. 2013 Sep-Oct;31(5):491-503. doi: 10.1016/j.biotechadv.2012.09.002. Epub 2012 Sep 15.
Small interfering RNA (siRNA) holds a great promise for the future of genomic medicine because of its highly sequence-specific gene silencing and universality in therapeutic target. The medical use of siRNA, however, has been severely hampered by the inherent physico-chemical properties of siRNA itself, such as low charge density, high structural stiffness and rapid enzymatic degradation; therefore, the establishment of efficient and safe siRNA delivery methodology is an essential prerequisite, particularly for systemic administration. For an efficient systemic siRNA delivery, it is a critical issue to obtain small and compact siRNA polyplexes with cationic condensing reagents including cationic polymers, because the size and surface properties of the polyplexes are major determinants for achieving desirable in vivo fate. Unfortunately, synthetic siRNA is not easily condensed with cationic polymers due to its intrinsic rigid structure and low spatial charge density. Accordingly, the loose siRNA polyplexes inevitably expose siRNA to the extracellular environment during systemic circulation, resulting in low therapeutic efficiency and poor biodistribution. In this review, we highlight the innovative approaches to increase the size of siRNA via structural modification of the siRNA itself. The attempts include several methodologies such as hybridization, chemical polymerization, and micro- and nano-structurization of siRNA. Due to its increased charge density and flexibility, the structured siRNA can produce highly condensed and homogenous polyplexes compared to the classical monomeric siRNA. As a result, stable and compact siRNA polyplexes can enhance serum stability and target delivery efficiency in vivo with desirable biodistribution. The review specifically aims to provide the recent progress of structural modification of siRNA. In addition, the article also briefly and concisely explains the improved physico-chemical properties of structured siRNA with respect to stability, condensation ability and gene silencing efficiency.
小干扰 RNA（siRNA）因其具有高度序列特异性的基因沉默作用和治疗靶标的通用性，在基因组医学的未来中具有巨大的应用前景。然而，由于 siRNA 本身固有的物理化学性质，如低电荷密度、高结构刚性和快速酶降解，其医学应用受到严重阻碍；因此，建立有效的和安全的 siRNA 递送方法是一个必要的前提，尤其是用于系统给药。为了实现有效的系统 siRNA 递送，获得带有阳离子缩合剂（包括阳离子聚合物）的小而紧凑的 siRNA 多聚物是一个关键问题，因为多聚物的大小和表面性质是实现理想的体内命运的主要决定因素。不幸的是，由于其固有的刚性结构和低空间电荷密度，合成的 siRNA 不易与阳离子聚合物缩合。因此，在系统循环期间，松散的 siRNA 多聚物不可避免地使 siRNA 暴露于细胞外环境中，导致治疗效率低和生物分布差。在这篇综述中，我们重点介绍了通过 siRNA 本身的结构修饰来增加 siRNA 大小的创新方法。这些尝试包括几种方法，如杂交、化学聚合以及 siRNA 的微结构和纳米结构。由于其增加的电荷密度和灵活性，与经典的单体 siRNA 相比，结构化 siRNA 可以产生高度浓缩和均匀的多聚物。因此，稳定和紧凑的 siRNA 多聚物可以增强血清稳定性，并提高体内的靶向递送效率，同时具有理想的生物分布。这篇综述的目的是提供 siRNA 结构修饰的最新进展。此外，本文还简要而扼要地解释了结构化 siRNA 在稳定性、缩合能力和基因沉默效率方面的改进的物理化学性质。
