Strategies for improving the specificity of siRNAs for enhanced therapeutic potential

References

• Lindquist D, Kvarnbrink S, Henriksson R, et al. LRIG and cancer prognosis. Acta Oncol (Madr). 2014;53(9):1135–1142.
   PubMed Web of Science ®Google Scholar
• Osta WA, Chen Y, Mikhitarian K, et al. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res. 2004;64(16):5818–5824.
   PubMed Web of Science ®Google Scholar
• Napoli C, Lemieux C, Jorgensen R. Introduction of a chimeric chalcone synthase gene into petunia results in reversible co-suppression of homologous genes in trans. Plant Cell. 1990;2(4):279–289.
   PubMed Web of Science ®Google Scholar
• Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391(6669):806–811.
   PubMed Web of Science ®Google Scholar
• Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001;411(6836):494–498.
   PubMed Web of Science ®Google Scholar
• Mello CC, Conte D. Revealing the world of RNA interference. Nature. 2004;431(7006):338–342.
   PubMed Web of Science ®Google Scholar
• Gilmore IR, Fox SP, Hollins AJ, et al. The design and exogenous delivery of siRNA for post-transcriptional gene silencing. J Drug Target. 2004;12(6):315–340.
   PubMed Web of Science ®Google Scholar
• Vermeulen A, Behlen L, Reynolds A, et al. The contributions of dsRNA structure to Dicer specificity and efficiency. Rna. 2005;11(5):674–682.
   PubMed Web of Science ®Google Scholar
• Robb GB, Brown KM, Khurana J, et al. Specific and potent RNAi in the nucleus of human cells. Nat Struct Mol Biol. 2005;12(2):133–137.
   PubMed Web of Science ®Google Scholar
• Agrawal N, Dasaradhi P, Mohmmed A, et al. RNA interference: biology, mechanism, and applications. Microbio Mol Bio Reviews. 2003;67(4):657–685.
   PubMed Web of Science ®Google Scholar
• Song M-S, Rossi JJ. Molecular mechanisms of Dicer: endonuclease and enzymatic activity. Biochem J. 2017;474(10):1603–1618.
   PubMed Web of Science ®Google Scholar
• Birmingham A, Anderson E, Sullivan K, et al. A protocol for designing siRNAs with high functionality and specificity. Nat Protoc. 2007;2(9):2068–2078.
   PubMed Web of Science ®Google Scholar
• Cullen BR. Enhancing and confirming the specificity of RNAi experiments. Nat Methods. 2006;3(9):677–681.
   PubMed Web of Science ®Google Scholar
• Echeverri CJ, Beachy PA, Baum B, et al. Minimizing the risk of reporting false positives in large-scale RNAi screens. Nat Methods. 2006;3(10):777–779.
   PubMed Web of Science ®Google Scholar
• Elbashir SM, Martinez J, Patkaniowska A, et al. Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate. EMBO J. 2001;20(23):6877–6888.
   PubMed Web of Science ®Google Scholar
• Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 21-and 22-nucleotide RNAs. Genes Dev. 2001;15(2):188–200.
   PubMed Web of Science ®Google Scholar
• Elbashir SM, Harborth J, Weber K, et al. Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods. 2002;26(2):199–213.
   PubMed Web of Science ®Google Scholar
• Reynolds A, Leake D, Boese Q, et al. Rational siRNA design for RNA interference. Nat Biotechnol. 2004;22(3):326–330.
   PubMed Web of Science ®Google Scholar
• Amarzguioui M, Prydz H. An algorithm for selection of functional siRNA sequences. Biochem Biophys Res Commun. 2004;316(4):1050–1058.
   PubMed Web of Science ®Google Scholar
• Pei Y, Tuschl T. On the art of identifying effective and specific siRNAs. Nat Methods. 2006;3(9):670–676.
   PubMed Web of Science ®Google Scholar
• Ui‐Tei K, Naito Y, Takahashi F, et al. Guidelines for the selection of highly effective siRNA sequences for mammalian and chick RNA interference. Nucleic Acids Res. 2004;32(3):936–948.
   PubMed Web of Science ®Google Scholar
• Ma J-B, Ye K, Patel DJ. Structural basis for overhang-specific small interfering RNA recognition by the PAZ domain. Nature. 2004;429(6989):318–322.
   PubMed Web of Science ®Google Scholar
• Zhang H, Kolb FA, Brondani V, et al. Human Dicer preferentially cleaves dsRNAs at their termini without a requirement for ATP. EMBO J. 2002;21(21):5875–5885.
   PubMed Web of Science ®Google Scholar
• Tanudji M, Machalek D, Arndt GM, et al. Competition between siRNA duplexes: impact of RNA-induced silencing complex loading efficiency and comparison between conventional-21 bp and dicer-substrate siRNA. Oligonucleotides. 2010;20(1):27–32.
   PubMedGoogle Scholar
• Kim D-H, Behlke MA, Rose SD, et al. Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. Nat Biotechnol. 2005;23(2):222–226.
   PubMed Web of Science ®Google Scholar
• Bégin-Lavallée V, Midavaine É, Dansereau M-A, et al. Functional inhibition of chemokine receptor CCR2 by dicer-substrate-siRNA prevents pain development. Mol Pain. 2016;12:1744806916653969.
   Web of Science ®Google Scholar
• Sano M, Sierant M, Miyagishi M, et al. Effect of asymmetric terminal structures of short RNA duplexes on the RNA interference activity and strand selection. Nucleic Acids Res. 2008;36(18):5812–5821.
   PubMed Web of Science ®Google Scholar
• Rose SD, Kim D-H, Amarzguioui M, et al. Functional polarity is introduced by Dicer processing of short substrate RNAs. Nucleic Acids Res. 2005;33(13):4140–4156.
   PubMed Web of Science ®Google Scholar
• Dudek H, Wong DH, Arvan R, et al. Knockdown of β-catenin with dicer-substrate siRNAs reduces liver tumor burden in vivo. Mol Ther. 2014;22(1):92–101.
   PubMed Web of Science ®Google Scholar
• Tomari Y, Matranga C, Haley B, et al. A protein sensor for siRNA asymmetry. Science. 2004;306(5700):1377–1380.
   PubMed Web of Science ®Google Scholar
• Lee YS, Nakahara K, Pham JW, et al. Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell. 2004;117(1):69–81.
   PubMed Web of Science ®Google Scholar
• Noland CL, Ma E, Doudna JA. siRNA repositioning for guide strand selection by human Dicer complexes. Mol Cell. 2011;43(1):110–121.
   PubMed Web of Science ®Google Scholar
• Sohrab SS, El-Kafrawy SA, Mirza Z, et al. Design and delivery of therapeutic siRNAs: application to MERS-Coronavirus. Curr Pharm Des. 2018;24(1):62–77.
   PubMed Web of Science ®Google Scholar
• Malhotra M, Nambiar S, Rengaswamy V, et al. Small interfering ribonucleic acid design strategies for effective targeting and gene silencing. Expert Opin Drug Discov. 2011;6(3):269–289.
   PubMed Web of Science ®Google Scholar
• Matveeva O, Nechipurenko Y, Rossi L, et al. Comparison of approaches for rational siRNA design leading to a new efficient and transparent method. Nucleic Acids Res. 2007;35(8):e63.
   PubMed Web of Science ®Google Scholar
• Bohula EA, Salisbury AJ, Sohail M, et al. The efficacy of small interfering RNAs targeted to the type 1 insulin-like growth factor receptor (IGF1R) is influenced by secondary structure in the IGF1R transcript. J Biol Chemistry. 2003;278(18):15991–15997.
   PubMed Web of Science ®Google Scholar
• Luo KQ, Chang DC. The gene-silencing efficiency of siRNA is strongly dependent on the local structure of mRNA at the targeted region. Biochem Biophys Res Commun. 2004;318(1):303–310.
   PubMed Web of Science ®Google Scholar
• Zuker M. M fold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 2003;31(13):3406–3415.
   PubMed Web of Science ®Google Scholar
• Ding Y, Chan CY, Lawrence CE. S fold web server for statistical folding and rational design of nucleic acids. Nucleic Acids Res. 2004;32(suppl_2):W135–W141.
   PubMedGoogle Scholar
• Gruber AR, Lorenz R, Bernhart SH, et al. The Vienna RNA websuite. Nucleic Acids Res. 2008;36(suppl_2):W70–W74.
   PubMedGoogle Scholar
• Schmich F, Szczurek E, Kreibich S, et al. gespeR: a statistical model for deconvoluting off-target-confounded RNA interference screens. Genome Biol. 2015;16(1):220.
   PubMedGoogle Scholar
• Buehler E, Khan AA, Marine S, et al. siRNA off-target effects in genome-wide screens identify signaling pathway members. Sci Rep. 2012;2:428.
   PubMed Web of Science ®Google Scholar
• Mysara M, Garibaldi JM, ElHefnawi M. MysiRNA-designer: a workflow for efficient siRNA design. PLoS One. 2011;6(10):e25642.
   PubMed Web of Science ®Google Scholar
• Jackson AL, Burchard J, Schelter J, et al. Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complementarity. RNA. 2006;12(7):1179–1187.
   PubMed Web of Science ®Google Scholar
• Aagaard L, Rossi JJ. RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev. 2007;59(2):75–86.
   PubMed Web of Science ®Google Scholar
• Tseng Y-C, Mozumdar S, Huang L. Lipid-based systemic delivery of siRNA. Adv Drug Deliv Rev. 2009;61(9):721–731.
   PubMed Web of Science ®Google Scholar
• Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discovery. 2009;8(2):129–138.
   PubMed Web of Science ®Google Scholar
• Saxena S, Jónsson ZO, Dutta A. Small RNAs with imperfect match to endogenous mRNA repress translation implications for off-target activity of small inhibitory RNA in mammalian cells. J Biol Chem. 2003;278(45):44312–44319.
   PubMed Web of Science ®Google Scholar
• Alemán LM, Doench J, Sharp PA. Comparison of siRNA-induced off-target RNA and protein effects. RNA. 2007;13(3):385–395.
   PubMed Web of Science ®Google Scholar
• Jackson AL, Linsley PS. Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat Rev Drug Discovery. 2010;9(1):57–67.
   PubMed Web of Science ®Google Scholar
• Persengiev SP, Zhu X, Green MR. Nonspecific, concentration-dependent stimulation and repression of mammalian gene expression by small interfering RNAs (siRNAs). Rna. 2004;10(1):12–18.
   PubMed Web of Science ®Google Scholar
• Jackson AL, Bartz SR, Schelter J, et al. Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol. 2003;21(6):635–637.
   PubMed Web of Science ®Google Scholar
• Sigoillot FD, King RW. Vigilance and validation: keys to success in RNAi screening. ACS Chem Biol. 2011;6(1):47.
   PubMed Web of Science ®Google Scholar
• Jackson AL, Burchard J, Leake D, et al. Position-specific chemical modification of siRNAs reduces “off-target” transcript silencing. RNA. 2006;12(7):1197–1205.
   PubMed Web of Science ®Google Scholar
• Robbins M, Judge A, Liang L, et al. 2′-O-methyl-modified RNAs act as TLR7 antagonists. Mol Ther. 2007;15(9):1663–1669.
   PubMed Web of Science ®Google Scholar
• Kamola PJ, Nakano Y, Takahashi T, et al. The siRNA non-seed region and its target sequences are auxiliary determinants of off-target effects. PLoS Comput Biol. 2015;11(12):e1004656.
   PubMed Web of Science ®Google Scholar
• Grimm D, Streetz KL, Jopling CL, et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature. 2006;441(7092):537–541.
   PubMed Web of Science ®Google Scholar
• Hannus M, Beitzinger M, Engelmann JC, et al. siPools: highly complex but accurately defined siRNA pools eliminate off-target effects. Nucleic Acids Res. 2014;42(12):8049–8061.
   PubMed Web of Science ®Google Scholar
• Sakurai K, Amarzguioui M, Kim D-H, et al. A role for human Dicer in pre-RISC loading of siRNAs. Nucleic Acids Res. 2011;39(4):1510–1525.
   PubMed Web of Science ®Google Scholar
• Mansoori B, Shotorbani SS, Baradaran B. RNA interference and its role in cancer therapy. Adv Pharm Bull. 2014;4(4):313–321.
   PubMedGoogle Scholar
• Betancur JG, Tomari Y. Dicer is dispensable for asymmetric RISC loading in mammals. RNA. 2012;18(1):24–30.
   PubMed Web of Science ®Google Scholar
• Khan AA, Betel D, Miller ML, et al. Transfection of small RNAs globally perturbs gene regulation by endogenous microRNAs. Nat Biotechnol. 2009;27(6):549–555.
   PubMed Web of Science ®Google Scholar
• Semizarov D, Frost L, Sarthy A, et al. Specificity of short interfering RNA determined through gene expression signatures. Proc Natl Acad Sci. 2003;100(11):6347–6352.
   PubMed Web of Science ®Google Scholar
• Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801.
   PubMed Web of Science ®Google Scholar
• Simon AK, Hollander GA, McMichael A, editors. Evolution of the immune system in humans from infancy to old age. Proc. R. Soc. B. The Royal Society, London, U.K; 2015.
   Google Scholar
• Judge A, Maclachlan I. Overcoming the innate immune response to small interfering RNA. Hum Gene Ther. 2008;19(2):111–124.
   PubMed Web of Science ®Google Scholar
• Weber C, Müller C, Podszuweit A, et al. Toll‐like receptor (TLR) 3 immune modulation by unformulated small interfering RNA or DNA and the role of CD14 (in TLR‐mediated effects). Immunology. 2012;136(1):64–77.
   PubMed Web of Science ®Google Scholar
• Karikó K, Bhuyan P, Capodici J, et al. Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3. J Immunol. 2004;172(11):6545–6549.
   PubMed Web of Science ®Google Scholar
• Kanasty RL, Whitehead KA, Vegas AJ, et al. Action and reaction: the biological response to siRNA and its delivery vehicles. Mol Ther. 2012;20(3):513–524.
   PubMed Web of Science ®Google Scholar
• Judge AD, Sood V, Shaw JR, et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol. 2005;23(4):457–462.
   PubMed Web of Science ®Google Scholar
• Hornung V, Guenthner-Biller M, Bourquin C, et al. Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med. 2005;11(3):263–270.
   PubMed Web of Science ®Google Scholar
• Diebold SS, Massacrier C, Akira S, et al. Nucleic acid agonists for Toll‐like receptor 7 are defined by the presence of uridine ribonucleotides. Eur J Immunol. 2006;36(12):3256–3267.
   PubMed Web of Science ®Google Scholar
• Pastan I, Willingham MC. The pathway of endocytosis. Springer, Boston, USA; 1985. p. 1–44.
   Google Scholar
• Ming X. Cellular delivery of siRNA and antisense oligonucleotides via receptor-mediated endocytosis. Expert Opin Drug Deliv. 2011;8(4):435–449.
   PubMed Web of Science ®Google Scholar
• El-Sayed A, Harashima H. Endocytosis of gene delivery vectors: from clathrin-dependent to lipid raft-mediated endocytosis. Mol Ther. 2013;21(6):1118–1130.
   PubMed Web of Science ®Google Scholar
• Liang W, Lam JK. Endosomal escape pathways for non-viral nucleic acid delivery systems. INTECH Open Access Publisher, London, U.K; 2012.
   Google Scholar
• Akinc A, Thomas M, Klibanov AM, et al. Exploring polyethylenimine‐mediated DNA transfection and the proton sponge hypothesis. J Gene Med. 2005;7(5):657–663.
   PubMed Web of Science ®Google Scholar
• Sawant RR, Patel NR, Torchilin VP. Therapeutic delivery using cell-penetrating peptides. Eur J Nanomedicine. 2013;5(3):141–158.
   Google Scholar
• Shukla RS, Qin B, Cheng K. Peptides used in the delivery of small noncoding RNA. Mol Pharm. 2014;11(10):3395.
   PubMedGoogle Scholar
• Xu C-F, Wang J. Delivery systems for siRNA drug development in cancer therapy. Asian J Pharm Sci. 2015;10(1):1–12.
   Web of Science ®Google Scholar
• Schroeder A, Levins CG, Cortez C, et al. Lipid‐based nanotherapeutics for siRNA delivery. J Intern Med. 2010;267(1):9–21.
   PubMed Web of Science ®Google Scholar
• Selbo PK, Weyergang A, Høgset A, et al. Photochemical internalization provides time- and space-controlled endolysosomal escape of therapeutic molecules. J Controlled Release. 2010;148(1):2–12.
   PubMed Web of Science ®Google Scholar
• Lennox K, Behlke M. Chemical modification and design of anti-miRNA oligonucleotides. Gene Ther. 2011;18(12):1111–1120.
   PubMed Web of Science ®Google Scholar
• Watts JK, Deleavey GF, Damha MJ. Chemically modified siRNA: tools and applications. Drug Discov Today. 2008;13(19):842–855.
   PubMed Web of Science ®Google Scholar
• Kraynack BA, Baker BF. Small interfering RNAs containing full 2′-O-methylribonucleotide-modified sense strands display Argonaute2/eIF2C2-dependent activity. Rna. 2006;12(1):163–176.
   PubMed Web of Science ®Google Scholar
• Chiu Y-L, Rana TM. siRNA function in RNAi: a chemical modification analysis. Rna. 2003;9(9):1034–1048.
   PubMed Web of Science ®Google Scholar
• Choung S, Kim YJ, Kim S, et al. Chemical modification of siRNAs to improve serum stability without loss of efficacy. Biochem Biophys Res Commun. 2006;342(3):919–927.
   PubMed Web of Science ®Google Scholar
• Elmén J, Thonberg H, Ljungberg K, et al. Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality. Nucleic Acids Res. 2005;33(1):439–447.
   PubMed Web of Science ®Google Scholar
• Li Z-Y, Mao H, Kallick DA, et al. The effects of thiophosphate substitutions on native siRNA gene silencing. Biochem Biophys Res Commun. 2005;329(3):1026–1030.
   PubMed Web of Science ®Google Scholar
• Ku SH, Jo SD, Lee YK, et al. Chemical and structural modifications of RNAi therapeutics. Adv Drug Deliv Rev. 2016;104:16–28.
   PubMed Web of Science ®Google Scholar
• Morrissey DV, Blanchard K, Shaw L, et al. Activity of stabilized short interfering RNA in a mouse model of hepatitis B virus replication. Hepatology. 2005;41(6):1349–1356.
   PubMed Web of Science ®Google Scholar
• Dowler T, Bergeron D, Tedeschi A-L, et al. Improvements in siRNA properties mediated by 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (FANA). Nucleic Acids Res. 2006;34(6):1669–1675.
   PubMed Web of Science ®Google Scholar
• Judge AD, Bola G, Lee AC, et al. Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol Ther. 2006;13(3):494–505.
   PubMed Web of Science ®Google Scholar
• Nallagatla SR, Bevilacqua PC. Nucleoside modifications modulate activation of the protein kinase PKR in an RNA structure-specific manner. RNA. 2008;14(6):1201–1213.
   PubMed Web of Science ®Google Scholar
• Watts JK, Yu D, Charisse K, et al. Effect of chemical modifications on modulation of gene expression by duplex antigene RNAs that are complementary to non-coding transcripts at gene promoters. Nucleic Acids Res. 2010;38(15):5242–5259.
   PubMed Web of Science ®Google Scholar
• Schirle NT, Kinberger GA, Murray HF, et al. Structural analysis of human Argonaute-2 bound to a modified siRNA guide. J Am Chem Soc. 2016;138(28):8694–8697.
   PubMed Web of Science ®Google Scholar
• Prakash TP, Allerson CR, Dande P, et al. Positional effect of chemical modifications on short interference RNA activity in mammalian cells. J Med Chem. 2005;48(13):4247–4253.
   PubMed Web of Science ®Google Scholar
• Prakash TP. An overview of sugar‐modified oligonucleotides for antisense therapeutics. Chem Biodivers. 2011;8(9):1616–1641.
   PubMed Web of Science ®Google Scholar
• Bramsen JB, Kjems J. Development of therapeutic-grade small interfering RNAs by chemical engineering. Front Genet. 2012;3:154.
   PubMedGoogle Scholar
• Behlke MA. Chemical modification of siRNAs for in vivo use. Oligonucleotides. 2008;18(4):305–320.
   PubMed Web of Science ®Google Scholar
• Wada S, Obika S, Shibata M-A, et al. Development of a 2′, 4′-BNA/LNA-based siRNA for dyslipidemia and assessment of the effects of its chemical modifications in vivo. Mol Ther-Nucleic Acids. 2012;1:e45.
   PubMedGoogle Scholar
• Vaish N, Chen F, Seth S, et al. Improved specificity of gene silencing by siRNAs containing unlocked nucleobase analogs. Nucleic Acids Res. 2011;39(5):1823–1832.
   PubMed Web of Science ®Google Scholar
• Piascik P. Fomiversen sodium approved to treat CMV retinitis. J Am Pharm Assoc (Washington, DC: 1996). 1998;39(1):84–85.
   Google Scholar
• Lundin KE, Gissberg O, Smith CE. Oligonucleotide therapies: the past and the present. Hum Gene Ther. 2015;26(8):475–485.
   PubMed Web of Science ®Google Scholar
• Watts JK, Corey DR. Silencing disease genes in the laboratory and the clinic. J Pathol. 2012;226(2):365–379.
   PubMed Web of Science ®Google Scholar
• Sipa K, Sochacka E, Kazmierczak-Baranska J, et al. Effect of base modifications on structure, thermodynamic stability, and gene silencing activity of short interfering RNA. RNA. 2007;13(8):1301–1316.
   PubMed Web of Science ®Google Scholar
• Dar SA, Thakur A, Qureshi A, et al. siRNAmod: a database of experimentally validated chemically modified siRNAs. Sci Rep. 2016;6.
   PubMed Web of Science ®Google Scholar
• Akhtar S, Benter IF. Nonviral delivery of synthetic siRNAs in vivo. J Clin Invest. 2007;117(12):3623–3632.
   PubMed Web of Science ®Google Scholar
• Hollins AJ, Omidi Y, Benter IF, et al. Toxicogenomics of drug delivery systems: exploiting delivery system-induced changes in target gene expression to enhance siRNA activity. J Drug Target. 2007;15(1):83–88.
   PubMed Web of Science ®Google Scholar
• Nogueira E, Freitas J, Loureiro A, et al. Neutral PEGylated liposomal formulation for efficient folate-mediated delivery of MCL1 siRNA to activated macrophages. Colloids and Surf B: Biointerfaces. 2017;155:459–465.
   PubMed Web of Science ®Google Scholar
• Liang Y, Liu Z, Shuai X, et al. Delivery of cationic polymer-siRNA nanoparticles for gene therapies in neural regeneration. Biochem Biophys Res Commun. 2012;421(4):690–695.
   PubMed Web of Science ®Google Scholar
• Pantazis P, Dimas K, Wyche JH, et al. Preparation of siRNA-encapsulated PLGA nanoparticles for sustained release of siRNA and evaluation of encapsulation efficiency. Nanoparticles in Bio and Med: Methods and Protoc. 2012;906:311–319.
   Google Scholar
• Andón F, Pazinatto D, Fadeel B. DNA origami: self-assembled nucleic acid nanoparticles for siRNA delivery. Nanomedicine (Lond). 2012;7(9):1295.
   Web of Science ®Google Scholar
• Wang J, Lu Z, Wientjes MG, et al. Delivery of siRNA therapeutics: barriers and carriers. AAPS J. 2010;12(4):492–503.
   PubMed Web of Science ®Google Scholar
• Pan M, Ni J, He H, et al. New paradigms on siRNA local application. BMB Rep. 2015;48(3):147.
   PubMed Web of Science ®Google Scholar
• Zatsepin TS, Kotelevtsev YV, Koteliansky V. Lipid nanoparticles for targeted siRNA delivery – going from bench to bedside. Int J Nanomedicine. 2016;11:3077.
   PubMed Web of Science ®Google Scholar
• Davis ME. The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: from concept to clinic. Mol Pharm. 2009;6(3):659–668.
   PubMed Web of Science ®Google Scholar
• Kim N, Jiang D, Jacobi AM, et al. Synthesis and characterization of mannosylated pegylated polyethylenimine as a carrier for siRNA. Int J Pharm. 2012;427(1):123–133.
   PubMedGoogle Scholar
• Akhtar S, Benter I. Toxicogenomics of non-viral drug delivery systems for RNAi: potential impact on siRNA-mediated gene silencing activity and specificity. Adv Drug Deliv Rev. 2007;59(2–3):164–182.
   PubMed Web of Science ®Google Scholar
• Khan A, Benboubetra M, Sayyed PZ, et al. Sustained polymeric delivery of gene silencing antisense ODNs, siRNA, DNAzymes and ribozymes: in vitro and in vivo studies. J Drug Target. 2004;12(6):393–404.
   PubMed Web of Science ®Google Scholar
• Nguyen J, Steele TW, Merkel O, et al. Fast degrading polyesters as siRNA nano-carriers for pulmonary gene therapy. J Controlled Release. 2008;132(3):243–251.
   PubMed Web of Science ®Google Scholar
• Danhier F, Ansorena E, Silva JM, et al. PLGA-based nanoparticles: an overview of biomedical applications. J Controlled Release. 2012;161(2):505–522.
   PubMed Web of Science ®Google Scholar
• Tam DY, Lo PK. Multifunctional DNA nanomaterials for biomedical applications. J Nanomater. 2015;2015:6.
   Google Scholar
• Capel V, Vllasaliu D, Watts P, et al. Insight into the relationship between the cell culture model, cell trafficking and siRNA silencing efficiency. Biochem Biophys Res Commun. 2016;477(2):260–265.
   PubMed Web of Science ®Google Scholar
• Cheng A, Magdaleno S, Vlassov AV. Optimization of transfection conditions and analysis of siRNA potency using real-time PCR. Ther Oligonucleotides: Methods Protoc. 2011;764:199–213.
   Google Scholar
• Holmes K, Williams CM, Chapman EA, et al. Detection of siRNA induced mRNA silencing by RT-qPCR: considerations for experimental design. BMC Res Notes. 2010;3(1):53.
   PubMedGoogle Scholar
• Rantala JK, Mäkelä R, Aaltola A-R, et al. A cell spot microarray method for production of high density siRNA transfection microarrays. BMC Genomics. 2011;12(1):162.
   PubMedGoogle Scholar
• Zhang A, Pastor L, Nguyen Q, et al. Small interfering RNA and gene expression analysis using a multiplex branched DNA assay without RNA purification. J Biomol Screen. 2005;10(6):549–556.
   PubMedGoogle Scholar
• Bader A, Brown D, Stoudemire J, et al. Developing therapeutic microRNAs for cancer. Gene Ther. 2011;18(12):1121–1126.
   PubMed Web of Science ®Google Scholar
• Barros SA, Hinkle G. Discovery and development strategies for small interfering RNAs. In: Y. Will, J. E. McDuffie, A. J. Olaharski, et.al., editors.Drug discovery toxicology: from target assessment to translational biomarkers, Hoboken, New Jersey, United States. 2016. p. 39.
   Google Scholar
• Romano N, Macino G. Quelling: transient inactivation of gene expression in Neurospora crassa by transformation with homologous sequences. Mol Microbiol. 1992;6(22):3343–3353.
   PubMed Web of Science ®Google Scholar
• Ren Y, Gong W, Xu Q, et al. siRecords: an extensive database of mammalian siRNAs with efficacy ratings. Bioinformatics. 2006;22(8):1027–1028.
   PubMed Web of Science ®Google Scholar
• Shabalina SA, Spiridonov AN, Ogurtsov AY. Computational models with thermodynamic and composition features improve siRNA design. BMC Bioinformatics. 2006;7(1):65.
   PubMedGoogle Scholar
• Vert J-P, Foveau N, Lajaunie C, et al. An accurate and interpretable model for siRNA efficacy prediction. BMC Bioinformatics. 2006;7(1):520.
   PubMedGoogle Scholar
• Huesken D, Lange J, Mickanin C, et al. Design of a genome-wide siRNA library using an artificial neural network. Nat Biotechnol. 2005;23(8):995–1001.
   PubMed Web of Science ®Google Scholar
• Ichihara M, Murakumo Y, Masuda A, et al. Thermodynamic instability of siRNA duplex is a prerequisite for dependable prediction of siRNA activities. Nucleic Acids Res. 2007;35(18):e123.
   PubMed Web of Science ®Google Scholar
• Han Y, Liu Y, Zhang H, et al. Utilizing selected di-and trinucleotides of siRNA to predict RNAi activity. Comput Math Methods Med. 2017;2017.
   Google Scholar
• Bramsen JB, Laursen MB, Nielsen AF, et al. A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity. Nucleic Acids Res. 2009;37(9):2867–2881.
   PubMed Web of Science ®Google Scholar
• Jagani H, Rao JV, Palanimuthu VR, et al. A nanoformulation of siRNA and its role in cancer therapy: in vitro and in vivo evaluation. Cell Mol Biol Lett. 2013 Mar 01;18(1):120–136.
   PubMed Web of Science ®Google Scholar
• Sharma M, El-Sayed NS, Do H, et al. Tumor-targeted delivery of siRNA using fatty acyl-CGKRK peptide conjugates. Sci Rep. 2017;7(1):6093.
   PubMedGoogle Scholar
• Jagani Hitesh JVR. RNA interference in therapeutics: issues, solutions and future prospects. 1 ed. Singh B, SPSSC editor. Vol. 5. U.S.A: Studium Press; 2015. Nanobiomedicine; 5.
   Google Scholar
• Koganti S, Jagani HV, Palanimuthu VR, et al. In vitro and in vivo evaluation of the efficacy of nanoformulation of siRNA as an adjuvant to improve the anticancer potential of cisplatin. Exp Mol Pathol. 2013;94(1):137–147.
   PubMed Web of Science ®Google Scholar
• Draz MS, Fang BA, Zhang P, et al. Nanoparticle-mediated systemic delivery of siRNA for treatment of cancers and viral infections. Theranostics. 2014;4(9):872.
   PubMed Web of Science ®Google Scholar
• Miniarikova J, Zanella I, Huseinovic A, et al. Design, characterization, and lead selection of therapeutic miRNAs targeting Huntingtin for development of gene therapy for Huntington’s disease. Mol Ther-Nucleic Acids. 2016;5.
   Google Scholar
• Chen Y, Gu H, Zhang DS-Z, et al. Highly effective inhibition of lung cancer growth and metastasis by systemic delivery of siRNA via multimodal mesoporous silica-based nanocarrier. Biomaterials. 2014;35(38):10058–10069.
   PubMed Web of Science ®Google Scholar
• Thi EP, Mire CE, Lee ACH, et al. Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates. Nature. 2015;521:362.
   PubMed Web of Science ®Google Scholar
• Chakraborty C, Sharma AR, Sharma G, et al. Therapeutic miRNA and siRNA: moving from bench to clinic as next generation medicine. Mol Ther-Nucleic Acids. 2017;8:132–143.
   PubMedGoogle Scholar
• Chalk AM, Wahlestedt C, Sonnhammer EL. Improved and automated prediction of effective siRNA. Biochem Biophys Res Commun. 2004;319(1):264–274.
   PubMed Web of Science ®Google Scholar
• Jiang P, Wu H, Da Y, et al. RFRCDB-siRNA: improved design of siRNAs by random forest regression model coupled with database searching. Comput Methods Programs Biomed. 2007;87(3):230–238.
   PubMed Web of Science ®Google Scholar
• Naito Y, Yamada T, Ui-Tei K, et al. siDirect: highly effective, target-specific siRNA design software for mammalian RNA interference. Nucleic Acids Res. 2004;32(suppl 2):W124–W129.
   PubMedGoogle Scholar
• Wang L, Mu FYA. Web-based design center for vector-based siRNA and siRNA cassette. Bioinformatics. 2004;20(11):1818–1820.
   PubMed Web of Science ®Google Scholar
• Owczarzy R, Tataurov AV, Wu Y, et al. IDT SciTools: a suite for analysis and design of nucleic acid oligomers. Nucleic Acids Res. 2008;36(suppl 2):W163–W169.
   PubMedGoogle Scholar
• Lu ZJ, Mathews DH. OligoWalk: an online siRNA design tool utilizing hybridization thermodynamics. Nucleic Acids Res. 2008;36(suppl 2):W104–W108.
   PubMed Web of Science ®Google Scholar
• Kang C-S, Pu P-Y, Li Y-H, et al. An in vitro study on the suppressive effect of glioma cell growth induced by plasmid-based small interference RNA (siRNA) targeting human epidermal growth factor receptor. J Neurooncol. 2005;74(3):267–273.
   PubMed Web of Science ®Google Scholar
• Park Y-K, Park S-M, Choi Y-C, et al. AsiDesigner: exon-based siRNA design server considering alternative splicing. Nucleic Acids Res. 2008;36(suppl 2):W97–W103.
   PubMedGoogle Scholar
• Schwarz DS, Hutvágner G, Du T, et al. Asymmetry in the assembly of the RNAi enzyme complex. Cell. 2003;115(2):199–208.
   PubMed Web of Science ®Google Scholar
• Shah JK, Garner HR, White MA, et al. sIR: siRNA information resource, a web-based tool for siRNA sequence design and analysis and an open access siRNA database. BMC Bioinformatics. 2007;8(1):178.
   PubMedGoogle Scholar
• Kittler R, Surendranath V, Heninger A-K, et al. Genome-wide resources of endoribonuclease-prepared short interfering RNAs for specific loss-of-function studies. Nat Methods. 2007;4(4):337–344.
   PubMed Web of Science ®Google Scholar
• Overhoff M, Alken M, Far R-K-K, et al. Local RNA target structure influences siRNA efficacy: a systematic global analysis. J Mol Biol. 2005;348(4):871–881.
   PubMed Web of Science ®Google Scholar
• Ui-Tei K, Naito Y, Nishi K, et al. Thermodynamic stability and Watson–Crick base pairing in the seed duplex are major determinants of the efficiency of the siRNA-based off-target effect. Nucleic Acids Res. 2008;36(22):7100–7109.
   PubMed Web of Science ®Google Scholar
• Eberle F, Gießler K, Deck C, et al. Modifications in small interfering RNA that separate immunostimulation from RNA interference. J Immunol. 2008;180(5):3229–3237.
   PubMed Web of Science ®Google Scholar
• Heil F, Hemmi H, Hochrein H, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303(5663):1526–1529.
   PubMed Web of Science ®Google Scholar
• Forsbach A, Nemorin J-G, Montino C, et al. Identification of RNA sequence motifs stimulating sequence-specific TLR8-dependent immune responses. J Immunol. 2008;180(6):3729–3738.
   PubMed Web of Science ®Google Scholar
• Sui H, Zhou M, Chen Q, et al. siRNA enhances DNA-mediated interferon lambda-1 response through crosstalk between RIG-I and IFI16 signalling pathway. Nucleic Acids Res. 2014;42(1):583–598.
   PubMed Web of Science ®Google Scholar
• Lo SL, Wang S. An endosomolytic Tat peptide produced by incorporation of histidine and cysteine residues as a nonviral vector for DNA transfection. Biomaterials. 2008;29(15):2408–2414.
   PubMed Web of Science ®Google Scholar
• Hassani Z, Lemkine GF, Erbacher P, et al. Lipid‐mediated siRNA delivery down‐regulates exogenous gene expression in the mouse brain at picomolar levels. J Gene Med. 2005;7(2):198–207.
   PubMed Web of Science ®Google Scholar
• Draz MS, Fang BA, Zhang P, et al. Nanoparticle-mediated systemic delivery of siRNA for treatment of cancers and viral infections. Theranostics. 2014;4(9):872–892.
   PubMed Web of Science ®Google Scholar
• Zhou J, Rossi JJ. Aptamer-targeted cell-specific RNA interference. Silence. 2010;1(1):4.
   PubMedGoogle Scholar
• Oliveira S, Fretz MM, Høgset A, et al. Photochemical internalization enhances silencing of epidermal growth factor receptor through improved endosomal escape of siRNA. Biochimica Et Biophysica Acta (Bba)-Biomembranes. 2007;1768(5):1211–1217.
   PubMed Web of Science ®Google Scholar