Lipid-based Nanoparticles in the Systemic Delivery of siRNA

Qiaoya Lin; Juan Chen; Zhihong Zhang; Gang Zheng


Nanomedicine. 2014;9(1):105-120. 

In This Article

Abstract and Introduction


RNAi therapeutics are believed to be the future of personalized medicine and have shown promise in early clinical trials. However, many physiological barriers exist in the systemic delivery of siRNAs to the cytoplasm of targeted cells to perform their function. To overcome these barriers, many siRNA delivery systems have been developed. Among these, lipid-based nanoparticles have great potential owing to their biocompatibility and low toxicity in comparison with inorganic nanoparticles and viral systems. This review discusses the hurdles of systemic siRNA delivery and highlights the recent progress made in lipid-based nanoparticles, which are categorized based on their key lipid components, including cationic lipid, lipoprotein, lipidoid, neutral lipid and anionic lipid-based nanoparticles. It is expected that these lipid nanoparticle-based siRNA delivery systems will have an enabling role for personalized cancer medicine, where siRNA delivery will join forces with genetic profiling of individual patients to achieve the best treatment outcome.


Since the discovery of the RNAi in 1998 by Fire et al.,[1] the first validation of specific gene knockdown in mammalian cells[2] and the first clinical trial of siRNA for age-related macular degeneration in 2004,[3] RNAi therapeutics gained the world's attention and became an attractive and promising technique in personalized treatment of a broad range of diseases, including cancer, liver and immune-related diseases.

RNAi is found in the cytoplasm.[4] As illustrated in Figure 1, siRNA, a double strand of RNA, incorporates into the RNA-induced silencing complex (RISC), causing unwinding of its double strand. The sense strand of siRNA is then removed from RISC, and the activated RISC with the antisense strand serves as a template for the binding of complementary mRNA, inducing mRNA degradation. As siRNA only functions when it reaches the cytoplasm of cells that produce the targeted gene, systemic siRNA delivery encounters many barriers from its administration all the way to reaching the target gene to be fully functional.

Figure 1.

In vivo siRNA systemic delivery barriers and the mechanism of RNAi. (A) Stability in the blood stream; (B) transport across the vascular endothelial barrier; (C) diffusion through the extracellular matrix; (D) delivery into the cytoplasm by (Di) endosomal escape and (Dii) direct cytosolic delivery. (Dia) The siRNAs or siRNA nanoparticles were trapped in the endosome and (Dib) the siRNAs were released from the endosome into the cytoplasm.