siRNA纳米递送系统研究进展

小干扰RNA (small interfering RNA,siRNA)是RNA干扰的引发物,激发与之互补的目标mRNA沉默,对基因调控及疾病治疗有重要意义。siRNA作为药物需要克服血管屏障、实现细胞内吞及溶酶体逃逸,同时还需要避免核酸酶作用下发生降解。因此,设计合适的纳米载体以帮助siRNA成功递送进细胞并发挥作用是目前siRNA药物发展的重要目标。纳米载体的材料种类、尺寸、结构、表面修饰等精确设计是实现siRNA药物成功递送的重要因素。随着研究的深入和应用的发展,siRNA药物纳米载体的精确控制制备、精准靶向递送及多功能化取得了较好的成果。本文围绕siRNA药物纳米载体,对siRNA药物应用及其递送困难、siRNA药物纳米载体主要设计策略、目前siRNA药物上市情况进行介绍,同时对其未来发展方向进行展望。

Research Progress of siRNA Nano-delivery System

Small interfering RNA (siRNA) is the initiator of RNA interference, which stimulates the silencing of complementary target mRNA. It is of great significance for gene regulation and disease treatment. It is used in viral infections, cancers, family genetic diseases and autoimmune diseases. As a new type of drug, siRNA is gradually being valued by researchers due to its high efficiency, strong specificity, and easy detection of therapeutic effects. siRNA used as a drug alone or co-delivered with anti-tumor drugs such as chemotherapy for cancer treatment shows greater application potential than traditional drugs. siRNA drugs have the advantages of designable targeting, convenient synthesis, instantaneous silencing, and strong target specificity. However, their delivery also faces obstacles that they are easily degraded in the blood circulation, cleared by the kidney, and difficult to break through the vascular endothelium/cell membrane/lysosome. Therefore, designing suitable nanocarriers to help siRNA successfully deliver into cells and play a role is an important goal for the development of siRNA drugs, and the amout of research in this area is also increasing year by year. The precise design of the nanocarrier material type, size, structure, surface modification, etc. are important factors for the successful delivery of siRNA drugs. At present, the design of siRNA drug nanocarriers mainly includes 4 strategies: loading siRNA drugs on the surface of nanocarriers, co-assembly of siRNA drugs and nanocarriers, nanocarriers encapsulating siRNA drugs, and siRNA self-assembly. At this stage, the use of nanocarriers to achieve siRNA drug delivery has made great progress. With the in-depth research and application development, the precise controlled preparation, precise targeted delivery and multifunctionalization of siRNA drug nanocarriers have achieved good results. However, there are still some problems that need to be overcome by researchers. For example, when siRNA drugs are used in the clinic, there are still problems such as inaccurate structure design of targeted drugs, serious off-target effects, difficulty in achieving endosome escape, and difficulties in large-scale preparation of nanocarriers. Because of this, only 3 siRNA drugs have been approved for marketing, namely Onpattro (Patisiran), Givlaari (Givosiran) and Oxlumo (Lumasiran) developed by Alnylam Pharmaceuticals. How to prepare siRNA drugs on a large scale is a major problem facing the clinical application of siRNA drugs, and it will become a research hotspot. At the same time, with the development of computer technology, combined with artificial intelligence, machine learning and other technologies, drug design with the aid of big data analysis is becoming a new research and development trend. Intelligent design and precise regulation of siRNA nanomedicine, and the design of multifunctional siRNA nanomedicine that integrates targeting, tracing, and co-delivery with other drugs to achieve synergy is also one of the future development directions of siRNA nanomedicine.