Abstract
AbstractThe successful use of small interfering RNAs (siRNAs) for therapeutic purposes requires safe and efficient delivery to specific cells and tissues. Here we demonstrate cell type-specific delivery of anti-HIV siRNAs via fusion to an anti-gp120 aptamer. The envelope glycoprotein is expressed on the surface of HIV-1 infected cells, allowing binding and interalization of the aptamer-siRNA chimeric molecules. We demonstrate that the anti-gp120 aptamer-siRNA chimera is specifically taken up by cells expressing HIV-1 gp120, and the appended siRNA is processed by Dicer, releasing an anti-tat/rev siRNA which in turn inhibits HIV replication. We show for the first time a dual functioning aptamer-siRNA chimera in which both the aptamer and the siRNA portions have potent anti-HIV activities and that gp120 expressed on the surface of HIV infected cells can be used for aptamer mediated delivery of anti-HIV siRNAs.
Highlights
Successful therapeutic applications of RNA interference (RNAi) are critically dependent upon efficient intracellular delivery of siRNAs3
The envelope glycoprotein is expressed on the surface of HIV-1 infected cells, allowing binding and interalization of the aptamer-small interfering RNAs (siRNAs) chimeric molecules
We demonstrate that the anti-gp[120] aptamer-siRNA chimera is taken up by cells expressing HIV-1 gp[120], and the appended siRNA is processed by Dicer, releasing an anti-tat/rev siRNA which in turn inhibits HIV replication
Summary
Successful therapeutic applications of RNAi are critically dependent upon efficient intracellular delivery of siRNAs3. The cell type-specific delivery of siRNAs has been achieved using aptamer-siRNA chimeras[25] In this system, the aptamer portion mediated binding to the prostate-specific membrane antigen (PSAM), a cell-surface receptor and the siRNAs linked to the aptamer was selectively delivered into PSMA expressing cells resulting in silencing of target transcripts both in cell culture and in vivo following intratumoral delivery. In a similar study[26] a modular streptavidin bridge was used to connect lamin A/C or GAPDH siRNAs to the PSMA aptamer. This system induced silencing of the targeted genes only in cells expressing the PSMA receptor
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