Abstract
RNA interference (RNAi) technology has become a powerful tool in application of unraveling the mechanism of disease and may hold the potential to be developed for clinical uses. Small interfering RNA (siRNA) can bind to target mRNA with high specificity and efficacy and thus inhibit the expression of related protein for the purpose of treatment of diseases. The major challenge for RNAi application is how to improve its stability and bioactivity and therefore deliver therapeutic agents to the target sites with high efficiency and accuracy. PEGylated lipid-based delivery system has been widely used for development of various medicines due to its long circulating half-life time, low toxicity, biocompatibility, and easiness to be scaled up. The PEGylated lipid-based delivery system may also provide platform for targeting delivery of nucleic acids, and some of the research works have moved to the phases for clinical trials. In this review, we introduced the mechanism, major challenges, and strategies to overcome technical barriers of PEGylated lipid-based delivery systems for advanced target delivery of siRNA in vivo. We also summarized recent advance of PEGylated lipid-based siRNA delivery systems and included some successful research works in this field.
Highlights
Since antisense oligonucleotides (ASOs) have proven to be efficient drugs for treatment of certain diseases by complementary base pairing to target mRNA to inhibit protein expression or splicing pre-mRNA to mature mRNA (Stephenson and Zamecnik, 1978; Altman, 2012), till some of the oligonucleotide drugs were approved for clinical uses, such as Vitravene for the treatment of cytomegalovirus retinitis and Kynamro for the treatment of familial hypercholesterolemia, and the results are encouraging (Swayze, 2010; Castanotto, 2017; Geary, 2017)
Mechanisms of RNA interference pathway begin with the processing of double-stranded RNA into short RNA duplexes as shown in Figure 1. Small interfering RNA (siRNA) was derived from longer precursor RNA, which may be processed in the cytoplasm by one of the RNase III named Dicer with R2D2 dsRNA binding protein
Lipid-based nanoparticles are widely used in targeting delivery of nucleic acids and function as a promising platform in the generation of more siRNA drugs
Summary
Since antisense oligonucleotides (ASOs) have proven to be efficient drugs for treatment of certain diseases by complementary base pairing to target mRNA to inhibit protein expression or splicing pre-mRNA to mature mRNA (Stephenson and Zamecnik, 1978; Altman, 2012), till some of the oligonucleotide drugs were approved for clinical uses, such as Vitravene (fomivirsen) for the treatment of cytomegalovirus retinitis and Kynamro (mipomersen) for the treatment of familial hypercholesterolemia, and the results are encouraging (Swayze, 2010; Castanotto, 2017; Geary, 2017). These oligonucleotides may target mRNA with high specificity and induce degradation of the targeted mRNA to regulate the expression of related protein by RNA interfering (Reynolds et al, 2004; Bruno, 2012; Wittrup and Lieberman, 2015) These oligonucleotides are unstable and easy to be cleared when exposed to body fluid after administration, and the efficacy and accuracy of delivering siRNA to target site is another challenge for its application. Lipid-based delivery system has proven to be effective in delivering various kinds of drugs such as chemical drugs, proteins, and oligonucleotides It holds the advantages of good biocompatibility, low toxicity, and easiness to be modified by chemical reaction to immobilize functional components. Some lipid-based delivery systems for siRNA involve in usage of cationic lipids, which may help with
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