International Journal of Nano Studies & Technology, 2012 © 6 Uckun F, Yiv S (2012). Nanoscale Small Interfering RNA Delivery Systems For Personalized Cancer Therapy, Int J Nano Stud Technol, 1(2), 6-11. International Journal of Nano Studies & Technology (IJNST) ISSN 2167-8685 Nanoscale Small Interfering RNA Delivery Systems For Personalized Cancer Therapy Research Article Uckun F 1,2* , Yiv S 1 1 Developmental Therapeutics Program, Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles MS#160, Los Angeles, CA, USA. 2 Division of Hematology-Oncology, Department of Pediatrics, Children’s Center for Cancer and Blood Diseases, University of Southern California Keck School of Medicine and, Los Angeles, CA 90027-0367, USA. *Corresponding Author: Fatih Uckun, Developmental Therapeutics Program, Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles MS#160, Los Angeles, CA, USA. E-mail: fmuckun@chla.usc.edu Received: June 10, 2012 Accepted: August 16, 2012 Published: August 22, 2012 Citation: Uckun F, Yiv S (2012). Nanoscale Small Interfering RNA De- livery Systems For Personalized Cancer Therapy, Int J Nano Stud Tech- nol, 1(2), 6-11. Copyright: Fatih Uckun © 2012 This is an open-access article distribut- ed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. Introduction RNA interference (RNAi) has emerged as an attractive technol- ogy for silencing the expression of speciic genes in human cells (1-6). In the physiological RNA interference pathway of gene silencing, double stranded RNAs are processed into small inter- fering RNAs (siRNA) by the RNase enzyme DICER. These siR- NAs are incorporated into an RNA-induced silencing complex (RISC), that is capable of identifying and degrading mRNA that is complementary to the antisense strand of the siRNA thereby causing “gene silencing” [1-6]. However, sequence-speciic gene knockdown via RNAi can also be triggered by a variety of syn- thetic double-stranded siRNA species that are capable of serv- ing as DICER substrates and are therefore being developed as potential RNAi therapeutics candidates [1-6]. Several formidable obstacles exist for the development of siRNA as RNAi therapeu- tics, including their rapid degradation by nucleases in the blood, poor cellular uptake, and requirements for endosomal escape af- ter cellular uptake, off-target effects due to their microRNA-like activity proile, and their inlammatory effects [7-9]. It remains to be seen if speciic formulation strategies or structural modiica- tions in the synthetic siRNA molecules can effectively overcome these obstacles or prevent inlammatory acute immune respons- es, including activation of innate immune receptors and/or the complement system and release of proinlammatory cytokines. Nanoparticles represent particularly attractive delivery systems for siRNA and may provide the foundation for rational design and formulation of RNAi-triggering nanomedicines. The siRNA delivery systems that have emerged during the last decade revolve around liposomal formulations [1-10], non-bilayer self-assembled polymeric nanoparticles [9],[11-15], and to a lesser extent, tertiary hybrid systems where lipids, polymers or solid cores are utilized [16-18]. The pharmacological effectiveness of oligonucleotide- based therapeutics depends on their cellular uptake, intracelular traficking, endosomal release, and productive delivery to their target subcellular compartments [19,20]. The uptake of siRNA into the target cells is possible only if their highly polyanionic charges are hidden from the hydrophobic cell membrane bilay- ers. This may be achieved by presenting siRNA to the cells in a condensed form where the siRNA charges are neutralized by cationic materials. The condensation of the siRNA can be ena- bled by the formation of polyanion-cation complex, arising from the non-covalent electrostatic interaction between the cationic charges embedded in the nanoparticles and the polyanionic siR- NA. In nearly all of the contemporary siRNA systemic delivery systems in development, the use of siRNA complexation has become almost a universal procedure for packaging siRNA into either lipid-based or polymer-based nanoparticles. siRNA cargo is complexed and compressed, meaning that its polyanionic charges are neutralized and its size made smaller [1-18]. Compression of the siRNA cargo takes place when it forms a complex with cati- onic materials including cationic lipids (lipoplex) and polycationic polymers (polyplex). The design of siRNA packaging has pro- Abstract Nanoparticles represent particularly attractive delivery systems for small interfering RNA (siRNA) and may provide the foundation for ra- tional design and formulation of RNAi-triggering nanomedicines. siRNA can be delivered with a therapeutic intent using lipid-based de- livery platforms such as stable nucleic acid lipid particles (SNALP) with a lipid bilayer containing cationic as well as fusogenic lipids and a diffusible PEG-lipid coat, polymers, cationic complexes, recombinant fusion proteins, conjugates, or polyconjugates. Several investigators have reported preclinical or early clinical proof of concept studies demonstrating that systemic delivery of siRNA nanoparticles targeting speciic gene transcripts can elicit biologic responses. Therapeutic nanoparticles containing siRNA targeting speciic genes that contribute to the aggressiveness and/or radiochemotherapy resistance of cancer cells may facilitate a paradigm shift in modern cancer therapy. Keywords: Personalized Medicine; Cancer; Nanomedicine; Biotherapy; Leukemia; siRNA.