Department of Biological Sciences and Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, South Korea.
Nat Mater. 2010 Mar;9(3):272-8. doi: 10.1038/nmat2626. Epub 2010 Jan 24.
Small interfering RNA (siRNA) with 19-21 base pairs has been recently recognized as a new therapeutic agent for effectively silencing a specific gene on a post-transcription level. For siRNA therapeutics, safe and efficient delivery issues are significant hurdles to clinical applications. Here we present a new class of biologically active siRNA structure based on chemically self-crosslinked and multimerized siRNA through cleavable disulphide linkages. The multimerized siRNA can produce more stable and compact polyelectrolyte complexes with less cytotoxic cationic carriers than naked siRNA because of substantially increased charge densities and the presence of flexible chemical linkers in the backbone. The cleavable and multimerized siRNA shows greatly enhanced gene-silencing efficiencies in vitro and in vivo through a target-messenger-RNA-specific RNA interference processing without significantly eliciting immune induction. This study demonstrates that the multimerized siRNA structure complexed with selected cationic condensing agents can serve as potential gene-silencing therapeutics for treating various diseases.
小干扰 RNA（siRNA）具有 19-21 个碱基对，最近被认为是一种新的治疗剂，可在转录后水平有效沉默特定基因。对于 siRNA 治疗，安全有效的递送问题是临床应用的重大障碍。在这里，我们提出了一类新的基于化学自交联和通过可裂解的二硫键连接多聚化的 siRNA 的具有生物活性的 siRNA 结构。由于电荷密度显著增加以及骨架中存在灵活的化学连接物，多聚化的 siRNA 可以与带较少正电荷的细胞毒性阳离子载体产生更稳定和紧凑的聚电解质复合物，比裸露的 siRNA 多。通过靶信使 RNA 特异性 RNA 干扰处理，可裂解和多聚化的 siRNA 在体外和体内显示出大大增强的基因沉默效率，而不会显著引起免疫诱导。这项研究表明，与选定的阳离子缩合剂复合的多聚化 siRNA 结构可作为治疗各种疾病的潜在基因沉默治疗剂。
