Gene Regulation by Intracellular Delivery and Photodegradation of Nanoparticles Containing Small Interfering RNA
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Abstract:
Although the use of small interfering RNA (siRNA) is a promising technique for gene regulation, spatiotemporal control of the effects of siRNA must be achieved if the technique is to be safe and practical. Here, a method for spatiotemporal regulation of genes with nanoparticles containing siRNA is reported. The siRNA is encapsulated in photodegradable nanoparticles that are internalized to SKOV3-Luc cells, where the siRNA is released from the nanoparticles by UV irradiation for 30 s. The encapsulated siRNA only shows no gene-silencing effects, but release of the siRNA upon UV radiation leads to sequence-specific silencing of the luciferase gene in the cells. These results indicate that photodegradable siRNA-containing nanoparticles can be useful for time- and space-dependent regulation of gene expression in cells.Keywords:
Trans-acting siRNA
Small interfering RNA duplexes (siRNA) induce gene silencing in various eukaryotic cells, although usually in an incomplete manner. Using chemically synthesized siRNAs targeting the HIV‐1 co‐receptor CXCR4 or the apoptosis‐inducing Fas‐ligand (FasL), co‐transfection of cells with two or more siRNA duplexes targeting different sites on the same mRNA resulted in an enhanced gene silencing compared with each single siRNA. This was shown in the down‐regulation of protein and mRNA expression, and functionally in the inhibition of CXCR4‐mediated HIV infection and of FasL‐mediated cell apoptosis. Transfection efficiency determined for the FasL‐specific siRNAs was dose‐dependent and varied among the siRNAs tested, but was not the main reason for the enhanced gene silencing.
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A bstract : Transient gene silencing in mammalian cells can be mediated by double stranded RNA (dsRNAs) molecules of ∼20–25 nucleotides termed short interfering (siRNAs). Naturally occurring siRNAs in lower eukaryotes have characteristic structural elements; however, little is known about what features are critical for an exogenous siRNA to mediate RNAi in mammals. We have recently determined some of the critical parameters that influence the efficiency of siRNA‐mediated RNAi in mammalian cells and have been considering the use of RNAi as a functional genomics tool, particularly for high throughput analysis, and the potential use of RNAi as a therapeutic tool.
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The α-synuclein (SNCA) gene is a responsible gene for Parkinson's disease (PD); and not only nucleotide variations but also overexpression of SNCA appears to be involved in the pathogenesis of PD. A specific inhibition against mutant SNCA genes carrying nucleotide variations may be feasible by a specific silencing such as an allele-specific RNA interference (RNAi); however, there is no method for restoring the SNCA overexpression to a normal level. Here, we show that an atypical RNAi using small interfering RNAs (siRNAs) that confer a moderate level of gene silencing is capable of controlling overexpressed SNCA genes to return to a normal level; named "expression-control RNAi" (ExCont-RNAi). ExCont-RNAi exhibited little or no significant off-target effects in its treated PD patient's fibroblasts that carry SNCA triplication. To further assess the therapeutic effect of ExCont-RNAi, PD-model flies that carried the human SNCA gene underwent an ExCont-RNAi treatment. The treated PD-flies demonstrated a significant improvement in their motor function. Our current findings suggested that ExCont-RNAi might be capable of becoming a novel therapeutic procedure for PD with the SNCA overexpression, and that siRNAs conferring a moderate level of gene silencing to target genes, which have been abandoned as useless siRNAs so far, might be available for controlling abnormally expressed disease-causing genes without producing adverse effects.
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In RNA interference (RNAi), double-stranded short interfering RNA (ds-siRNA) inhibits expression from complementary mRNAs. Recently, it was demonstrated that short, single-stranded antisense RNA (ss-siRNA) can also induce RNAi. While ss-siRNA may offer several advantages in both clinical and research applications, its overall poor activity compared with ds-siRNA has prevented its widespread use. In contrast to the poor gene silencing activity of native ss-siRNA, we found that the silencing activity of boranophosphate-modified ss-siRNA is comparable with that of unmodified ds-siRNA. Boranophosphate ss-siRNA has excellent maximum silencing activity and is highly effective at low concentrations. The silencing activity of boranophosphate ss-siRNA is also durable, with significant silencing up to 1 week after transfection. Thus, we have demonstrated that boranophosphate-modified ss-siRNA can silence gene expression as well as native ds-siRNA, suggesting that boranophosphate-modified ss-siRNAs should be investigated as a potential new class of therapeutic agents.
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RNA interference (RNAi) and specifically the use of small interfering RNAs (siRNAs) represents a potentially new paradigm in gene knockout technology. Clearly siRNAs can be used to knockdown the expression of a targeted transcript in what has been termed posttranscriptional gene silencing (PTGS). While there are a plethora of reports applying siRNA-mediated PTGS the limitation of the duration of the effect remains. Recently, in human cells, siRNAs have been shown, similar to plants and Schizosaccharomyces pombe, to mediate transcriptional gene silencing (TGS). The observation that siRNAs can function in a TGS manner in human cells suggests that, similar to plants, human genes may also be able to be silenced more permanently via epigenetic modifications. The ramifications of siRNA-mediated TGS in humans suggest that longer term suppression of gene function can be obtained via siRNA-directed chromatin modifications. Undoubtedly the potential to employ siRNA technology is broader than once envisioned in human cells and suggests that siRNA-mediated TGS is not simply limited to PTGS. The potential to utilize siRNAs to direct epigenetic changes in local chromatin structure offers a new therapeutic avenue that could prove remarkably robust and of immeasurable therapeutic value in the directed control of target gene expression.
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我们的以前的学习表明了引起 amyotrophic 的变异的基因的调停 siRNA 的、等位基因特定的 silencing。为了改进 siRNA ，为 RNA 干扰的更好治疗学的使用设计，我们系统地在不对称的 siRNA.Methods 的设计测试了基础配对的失配策略:指向人的 Cu 的自然地对称的 siRNA Zn 超级氧化物歧化酶 G85R 变异的等位基因被从在的位置 1～4 把 1 或 2 失配放在 siRNA 的结束修改每次。目标偏爱和修改 siRNA 的 silencing 功效用修改双酶 system.Results 被测量: 单个基础配对的失配的修正成功地完成了原来被赞成到变异的等位基因的反感觉到被赞成到基因的感觉海滨的那的 siRNA 的变换。比作错配单人赛的 siRNA，那些与在一结束的双失配表明了增加的不对称现象，和 thus，基因 silencing 的提高的特性和功效。另外，有在两结束的双失配的 siRNA 留在 symmetry.Conclusion :我们的结果建议由介绍失配进它的结构把对称的 siRNA 变换成不对称的有效性，并且到在生产源于 siRNA 的混乱的选择基因 silencing 的错配单人赛的 siRNA 的 双mismatched siRNA 的优势对称。双失配策略是单个失配的方法的改进并且能在为引起由的疾病的处理的有效 siRNAs 的设计有用主导， gain-of-function 基因变化，例如 ALS。
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Simultaneous suppression of multiple oncogenes is an attractive strategy to treat cancers. Herein we present a series of long double-stranded multiplex small interfering RNAs (multi-siRNAs) that is suitable for dual genes silencing through a sequence-specific RNA interference process without inducing significant immune responses. A gap feature structurally designed in either of the nucleotide strands of the multi-siRNAs was proved to be essential toward silencing target genes and avoiding immune responses. Furthermore, the silencing effect of multi-siRNAs against SURVIVIN and BCL-2 genes was shown to be effective and resulted in up-regulation of caspase-3 related apoptosis and, in turn, inhibition of bladder cancer cell proliferation. Our observation suggested that the rationally designed multi-siRNAs would have great potential for therapeutic siRNA design.
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Gene silencing by RNA interference (RNAi) allows, for the first time, investigation of the balance between the life and death of a cell under stress-free conditions. Thus it is now possible to (i) identify key antiapoptotic genes that constitutively enable, for example, cancer cell survival, and (ii) map the pathways such genes control (using RNAi co-silencing). New gene targets for anticancer therapy are identified and, full circle, RNAi provides the means for their selective therapeutic silencing.
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