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Nanoparticle-Based Delivery of RNAi Therapeutics: Progress and Challenges

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      Abstract

      RNA interference (RNAi) is an evolutionarily conserved, endogenous process for post-transcriptional regulation of gene expression. Although RNAi therapeutics have recently progressed through the pipeline toward clinical trials, the application of these as ideal, clinical therapeutics requires the development of safe and effective delivery systems. Inspired by the immense progress with nanotechnology in drug delivery, efforts have been dedicated to the development of nanoparticle-based RNAi delivery systems. For example, a precisely engineered, multifunctional nanocarrier with combined passive and active targeting capabilities may address the delivery challenges for the widespread use of RNAi as a therapy. Therefore, in this review, we introduce the major hurdles in achieving efficient RNAi delivery and discuss the current advances in applying nanotechnology-based delivery systems to overcome the delivery hurdles of RNAi therapeutics. In particular, some representative examples of nanoparticle-based delivery formulations for targeted RNAi therapeutics are highlighted.

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      Most cited references 135

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      Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans.

       S Kostas,  A Fire,  S Xu (1998)
      Experimental introduction of RNA into cells can be used in certain biological systems to interfere with the function of an endogenous gene. Such effects have been proposed to result from a simple antisense mechanism that depends on hybridization between the injected RNA and endogenous messenger RNA transcripts. RNA interference has been used in the nematode Caenorhabditis elegans to manipulate gene expression. Here we investigate the requirements for structure and delivery of the interfering RNA. To our surprise, we found that double-stranded RNA was substantially more effective at producing interference than was either strand individually. After injection into adult animals, purified single strands had at most a modest effect, whereas double-stranded mixtures caused potent and specific interference. The effects of this interference were evident in both the injected animals and their progeny. Only a few molecules of injected double-stranded RNA were required per affected cell, arguing against stochiometric interference with endogenous mRNA and suggesting that there could be a catalytic or amplification component in the interference process.
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        Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.

        RNA interference (RNAi) is the process of sequence-specific, post-transcriptional gene silencing in animals and plants, initiated by double-stranded RNA (dsRNA) that is homologous in sequence to the silenced gene. The mediators of sequence-specific messenger RNA degradation are 21- and 22-nucleotide small interfering RNAs (siRNAs) generated by ribonuclease III cleavage from longer dsRNAs. Here we show that 21-nucleotide siRNA duplexes specifically suppress expression of endogenous and heterologous genes in different mammalian cell lines, including human embryonic kidney (293) and HeLa cells. Therefore, 21-nucleotide siRNA duplexes provide a new tool for studying gene function in mammalian cells and may eventually be used as gene-specific therapeutics.
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          Nanocarriers as an emerging platform for cancer therapy.

          Nanotechnology has the potential to revolutionize cancer diagnosis and therapy. Advances in protein engineering and materials science have contributed to novel nanoscale targeting approaches that may bring new hope to cancer patients. Several therapeutic nanocarriers have been approved for clinical use. However, to date, there are only a few clinically approved nanocarriers that incorporate molecules to selectively bind and target cancer cells. This review examines some of the approved formulations and discusses the challenges in translating basic research to the clinic. We detail the arsenal of nanocarriers and molecules available for selective tumour targeting, and emphasize the challenges in cancer treatment.
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            Author and article information

            Affiliations
            [1 ]Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, City of Hope, 1500 East Duarte Rd, Duarte, CA 91010, USA; E-Mails: jzhou@ 123456coh.org (J.Z.); kshum@ 123456coh.org (K.S.); jburnett@ 123456coh.org (J.C.B.)
            [2 ]Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, City of Hope, 1500 East Duarte Rd, Duarte, CA 91010, USA
            Author notes
            [† ]

            These two authors contributed equally to this work.

            [* ]Author to whom correspondence should be addressed; E-Mail: jrossi@ 123456coh.org ; Tel.: +1-626-301-8360; Fax: +1-626-301-8271.
            Journal
            Pharmaceuticals (Basel)
            Pharmaceuticals (Basel)
            pharmaceuticals
            Pharmaceuticals
            MDPI
            1424-8247
            16 January 2013
            January 2013
            : 6
            : 1
            : 85-107
            23667320
            3649006
            10.3390/ph6010085
            pharmaceuticals-06-00085
            © 2013 by the authors; licensee MDPI, Basel, Switzerland.

            This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

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