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Molecular Mechanisms and Biological Functions of siRNA

Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran, Hassan Dana, Ghanbar Mahmoodi Chalbatani and 19 more

International Journal of Biomedical Science · 2017 · Review

doi:10.59566/ijbs.2017.13048

Abstract

One of the most important advances in biology has been the discovery that siRNA (small interfering RNA) is able to regulate the expression of genes, by a phenomenon known as RNAi (RNA interference). The discovery of RNAi, first in plants and Caenorhabditis elegans and later in mammalian cells, led to the emergence of a transformative view in biomedical research. siRNA has gained attention as a potential therapeutic reagent due to its ability to inhibit specific genes in many genetic diseases. siRNAs can be used as tools to study single gene function both in vivo and in-vitro and are an attractive new class of therapeutics, especially against undruggable targets for the treatment of cancer and other diseases. The siRNA delivery systems are categorized as non-viral and viral delivery systems. The non-viral delivery system includes polymers; Lipids; peptides etc. are the widely studied delivery systems for siRNA. Effective pharmacological use of siRNA requires ‘carriers’ that can deliver the siRNA to its intended site of action. The carriers assemble the siRNA into supramolecular complexes that display functional properties during the delivery process.

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Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

INTRODUCTION

In recent years, few areas of biology have been transformed as thoroughly as RNA molecular biology. This transformation has occurred along many fronts, as detailed in this issue, but one of the most significant advances has been the discovery of small (20–30 nucleotide [nt]) noncoding RNAs that regulate genes and genomes. This regulation can occur at some of the most important levels of genome function, including RNA processing, chromatin structure, RNA stability, chromosome segregation, transcription, and translation.

Despite many classes of small RNAs have emerged, biological roles, associated effector proteins, various aspects of their origins, and structures have led to the general recognition of three main categories: piwi-interacting RNAs (piRNAs), short interfering RNAs (siRNAs), and microRNAs (miRNAs).

RNA interference (RNAi), the biological mechanism by which double-stranded RNA (dsRNA) induces gene silencing by targeting complementary mRNA for degradation, is a tremendous innovation in the universal therapeutic treatment of disease and revolutionizing the way researchers study gene function. RNAi, first discovered in plants, was later demonstrated in the roundworm Caenorhabditis elegans, an organism in which gene expression is downregulated by long dsRNA.

Increasing knowledge on the molecular mechanisms of endogenous RNA interference, siRNAs have been emerging as innovative nucleic acid medicines fo the treatment of incurable diseases such as cancers. Because systemic administration will be required in most cases, there are challenges inherent in the further development of siRNAs for anti-cancer therapeutics, Although several siRNA candidates for the treatment of respiratory and ocular diseases are undergoing clinical trials.

In an attempt to develop siRNA for use in clinical trials as drugs, various chemical modifications are being investigated to improve qualities such as low immunostimulation, target organ/cell delivery, off-target effects, siRNA potency, and serum stability.

Despite the high therapeutic potential of siRNA, its application in clinical settings is still limited mainly due to the lack of efficient delivery systems.

The discovery of RNAi has opened doors that might introduce a novel therapeutic tool to the clinical setting. RNAi is charged with controlling vital processes such as cell growth, tissue differentiation, heterochromatin formation, and cell proliferation. Accordingly, RNAi dysfunction is linked to cardiovascular disease, neurological disorders, and many types of cancer. RNAi pathways transcend mere expansion of the gene regulation toolkit: They confer a qualitative change in the way cellular networks are managed.

MECHANISM OF RNA INTERFERENCE (RNAI)

The first step of RNAi involves processing and cleavage of longer double-stranded RNA into siRNAs, generally bearing a 2 nucleotide overhang on the 3′ end of each strand. The enzyme responsible for this processing is an RNase III-like enzyme termed Dicer. When formed, siRNAs are bound by a multiprotein component complex referred to as RISC (RNAinduced silencing complex). Within the RISC complex, siRNA strands are separated and the strand with the more stable 5′-end is typically integrated to the active RISC complex. The antisense single-stranded siRNA component then guides and aligns the RISC complex on the target mRNA and through the action of catalytic RISC protein, a member of the argonaute family (Ago2), mRNA is cleaved (Figure 1).

ORIGINS siRNAs

Fire and Mello In 1998 uncovered the world of RNAi and revolutionized the contemporary understanding of gene regulation when they made the discovery that the silencing effectors in Caenorh abditis elegans were double stranded RNAs.

In 1999, siRNAs were discovered in plants and similarly demonstrated to guide sequence-dependent endonucleolytic cleavage of the mRNAs that they regulate in mammalian cells. By 2001, miRNAs were found to comprise a broad class of small RNA regulators, with at least dozens of representatives in each of several animal and plant species. With this discovery, in our view of the gene regulatory landscape two categories of small RNAs had become firmly embedded: siRNAs, as defenders of genome integrity in response to foreign or invasive nucleic acids such as transposons, transgenes, and viruses, and miRNAs, as regulators of endogenous genes.

Elbashir et al. in 2001 had successfully used synthetic siRNAs for silencing and determined the basic principles of siRNA structure and RNAi mechanics, providing the foundation for developing RNAi applications.

Delivering siRNA

The discovery of RNAi has excited the scientific field due to its potential for wide range of therapeutic applications. Effective pharmacological use of siRNA requires ‘carriers’ that can deliver the siRNA to its intended site of action. The carriers assemble the siRNA into supramolecular complexes that display functional properties during the delivery process. Viral vectors and non-viral vectors are two major categories delivery system for siRNA. The synthesis and industrial scalability are offer advantages of Non-viral delivery systems. Peptides, polymers, and Lipids are the extensively studied non-viral delivery vehicles.

The pharmacological mediator of siRNA, has faced significant obstacles in reaching its target site and effectively exerting its silencing activity.

The fantastic potential of siRNA to silence important genes in disease pathways comes with noteworthy challenges and barriers in its delivery.

Polymer- mediated Delivery Systems

For siRNA delivery, Polymers have emerged as an alternative class of extensively investigated carriers. Polymer-based delivery systems have been extensively used for plasmid DNA and more recently for siRNA. As non-viral siRNA and plasmid vectors, many polymers have been thoroughly investigated because of their physical characteristics and diverse chemistries and well-characterized, and structure flexibilities, which allows for easy modification to fine-tune their physiochemical properties. Chitosan is reported to have low cytotoxicity and which is a cationic polysaccharide having muco adhesive properties. Cyclodextrin is another polymer that has also been studied as siRNA delivery system.

Peptide-Based Delivery Systems

Due to four major reasons, Peptides are viewed as alternative to the cationic polymers for the siRNA delivery: Cell specific delivery, pH based membrane, disruption, Their efficient packaging and Efficient membrane transport. Control over functionalization, ease of synthesis and stability of the peptide oligonucleotide complex make the low molecular weight peptides as the favorable candidates over lipoplexes as siRNA delivery vehicle.

Cell penetrating peptides (CPPs), also referred to as protein transduction domains (PTD), was observed to cross the plasma membrane by itself, which transactivates transcription of the HIV-1 genome, were first discovered a few decades ago when the HIV-1 Tat-protein. CPPs are the widely studied peptides as siRNA delivery system. The CPPs in three classes are classified: 1) synthetic ones, 2) chimeric peptides and 3) naturally derived peptides. MPPs (Membrane perturbing peptides) are also studied as peptide delivery systems. Depending upon the DNA release behavior, The MPPs are studied in two categories: Endoosmolytic peptides and Fusogenic peptides that Fusogenic peptides act by mediating the DNA release at the endosomal pH and Endoosmolytic peptides act by endosomal lysis followed by DNA release.

Lipid -Based Delivery Systems

Various lipid-based delivery systems have been developed for in vivo application of siRNA. Lipid-based systems include liposomes, micelles, emulsions, and solid lipid nanoparticles.

MIT(Massachusetts Institute of Technology) and Alnylam Inc., (Cambridge, Massachusetts) collaborated on a project to synthesize a library of more than thousand different lipid-like molecules and screened them for their efficiency to deliver siRNA. They tested these delivery systems in mice to treat the respiratory ailment and found that some of their molecules are ten times more efficacious in delivering siRNA in comparison to the existing non encapsulated siRNA delivery.

For the delivery of siRNA using lipid-based systems, particle size, lipid composition, drug-to lipid ratio, and the manufacturing process should be optimized.

Liposomes have been utilized as efficient delivery vectors for siRNA for almost 30 years since the successful use of lipofection in 1987 to transfer nucleic acids into animal and human cells. Liposomes are commonly used as delivery vehicles for a broad spectrum of therapeutics including siRNA. Interaction of the lipids with the nucleic acid leads to the formation of either coated vesicles having nucleic acid in the core or the aggregates, both of which are studied as lipoplexes (Figure 2).

siRNA Conjugate Delivery Systems

Combination of two or more types of delivery vehicles have led to the generation of this category. These combinations may be categorized as Peptide-Polymer, Liposome - Peptide, and Liposome-Polymer any other combination thereof.

Polymer and Liposomal-based delivery systems have been advanced the most for siRNA delivery, and have a vast supporting body of literature due to their extensive previous development for the delivery of antisense oligonucleotides, DNAzymes and plasmid DNA.

For targeted delivery of siRNAs to hepatocytes, Rozema et al. have developed a polymer-siRNA conjugate delivery system termed Dynamic PolyConjugates (DPCs).

Recently, siRNA conjugates have shown promise as delivery platforms, leading to the development of well-defined, single-component systems that optimize the usage of minimal amounts of delivery material. Studies have demonstrated invitro effectiveness of LSPCs (Liposome-siRNA-peptide complexes) in delivering PrP siRNA specifically to AchR-expressing cells, leading to suppressed PrPC expression and eliminated PrPRES formation.

Delivery of therapeutic siRNA in cancer

The siRNA has provided new opportunities for the development of innovative medicine to treat previously incurable diseases such as cancer. It is of inherent potency because it exploits the endogenous RNAi pathway, allows specific reduction of disease associated genes, and is applicable to any gene with a complementary sequence. For the rationale of siRNA-mediated gene therapy, genetic nature of cancer provides solid support. In fact, a number of siRNAs have been designed to target dominant oncogenes, viral oncogenes involved in carcinogenesis, or mal functionally regulated oncogenes. In addition, therapeutic siRNAs have been investigated for silencing target molecules crucial for tumor–host interactions and tumor resistance to chemo- or radiotherapy. The silencing of critical cancer-associated target proteins by siRNAs has resulted in significant antiproliferative and/or apoptotic effects. However, most approaches to RNAi-mediated gene silencing for cancer therapy have been with cell cultures in the laboratory, and key impediments in the transition to the bedside due to delivery considerations still remain. Delivery systems that can improve siRNA stability and cancer cell-specificity need to be developed, nonspecific immune stimulatory effects and involve the minimizing of off-target. The delivery systems must be optimized for specific cancers, as the route of administration may differ depending on the nature of cancer. The current progress in siRNA delivery systems for liver, Breast, prostate, and lung cancers is discussed (Table 1).

Efficacy

In the recent years, a number of siRNAs have been successfully used in experimental models. Data from preclinical models are now giving rise to the translation of new siRNA-based therapies into clinical trials. The target selection process is extensional, requiring a thorough mining of pathways and databases. Different siRNAs targeting different parts of the same mRNA sequence have varying RNAi efficacies, and only a limited fraction of siRNAs has been shown to be functional in mammalian cells. Among randomly selected siRNAs, 58–78% were observed to induce silencing with greater than 50% efficiency and only 11–18% induced 90–95% silencing.

Off-target silencing effect

An early glimpse into the possible existence of off-target gene regulation by siRNAs came from gene expression profiling of siRNA studies. The specificity of RNAi is not as robust as it was initially thought to be. It is now well established that siRNA off-targets exist for many siRNA and that most siRNA molecules are probably not as specific as once thought. The introduction of siRNA can result in off-target effect, i.e. the suppression of genes other than the desired gene target, leading to dangerous mutations of gene expression and unexpected consequences. The majority of the off-target gene silencing of siRNA is due to the partial sequence homology, especially within the 3’untranslated region (3’UTR), exists with mRNAs other than the intended target mRNA. This mechanism is similar to the microRNA (miRNA) gene silencing effect. The off-target effect can also be a result of the immune response. RNA is recognized by immunoreceptors such as TLRs (Toll-like receptors), leading to the release of cytokines and changes in gene expression. Although the sequence dependence of the immune response is not fully understood, some immunostimulatory motifs have been identified and they should be avoided. Chemical modification of siRNA, such as 2’-O-methylation of the lead siRNA strand can also taper the miRNA-like off-target effects as well as the immunostimulatory activity without losing silencing effect of the target gene. Overall, therapeutic siRNA must be carefully designed. A combination of computer algorithms and empirica testing is also encouraged to allow effective design of potent siRNA sequences and minimize off-target effect (Figure 3).

CONCLUSION

The design and engineering of siRNA carriers gained significant momentum in recent years, as a result of accumulation of predictable and therapeutically promising molecular targets. RNAi technology has progressed rapidly from an academic discovery to a potential new class of treatment for human disease. Initial observations that were useful for studying gene function in worms were quickly translated to other organisms, and in particular to mammals, revealing the potential clinical applications of siRNA, including an ability to induce persistent, potent, and specific silencing of a wide range of genetic targets. For any new therapeutics, safety is still the primary concern. While the off-target effect of siRNA is a major issue that needs to be addressed by improving the knowledge in this area, the long-term safety of siRNA is still not clear.

siRNA therapeutics are now well poised to enter the clinical formulary as a new class of drugs in the near future. siRNA-based therapies are emerging as a promising new anticancer approach, and a small number of Phase I clinical trials involving patients with solid tumours have now been completed. siRNA-based therapeutics hold great potential for cancer therapy and treatment of other diseases. However, many challenges, including rapid degradation, poor cellular uptake, and off-target effects, need to be addressed in order to carry these molecules into clinical trials. siRNA therapeutics have several distinct advantages over traditional pharmaceutical drugs. RNAi is an endogenous biological process, so almost all genes can be potently suppressed by siRNA. The identification of highly selective and inhibitory sequences is much faster than the discovery of new chemicals, and it is relatively easy to synthesize and manufacture siRNA on a large scale. As the treatment of cancers usually requires systemic delivery rather than more easily achievable local delivery, the progress of siRNA treatment for cancer has been relatively slow compared with that of other diseases curable by local siRNA administration.

Delivery, especially systemically administered siRNA, is another important barrier to be overcome. Although new materials and delivery systems are being investigated to enhance the delivery efficiency, approval procedures could be hindered by the complicated formulation. On the other hand, eyes and lungs are promising tissues for local delivery of naked siRNA, especially the former, which is reflected by the high number of clinical trial studies targeting this site. It is not surprising to see the first siRNA therapeutics to be approved is for ocular therapy in the very near future.

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    Gomes-da-Silva LC, Fernandez Y, Abasolo I, et al. Efficient intracellular delivery of siRNA with a safe multitargeted lipid-based nanoplatform. Nanomedicine (Lond). 2013;8:1397-1413.

    Not in our library10.2217/nnm.12.174

  68. 68.

    Guo J, Fisher KA, Darcy R, Cryan JF, et al. Therapeutic targeting in the silent era: advances in non-viral siRNA delivery. Mol. Biosyst. 2010;6(7):1143-1161.

    Not in our library10.1039/c001050m

  69. 69.

    Zhang XLi, Huang L. Non-viral nanocarriers for siRNA delivery in breast cancer. J. Control. Release. 2014;190:440-450.

    Not in our library10.1016/j.jconrel.2014.05.037

  70. 70.

    Pulford B, Reim N, Bell A, et al. Liposome-siRNApeptide complexes cross the blood-brain barrier and significantly decrease PrP on neuronal cells and PrP in infected cell cultures. PLoS One. 2010;5:11085.

    Not in our library10.1371/journal.pone.0011085

  71. 71.

    Wu ZW, Chien CT, Liu CY, Yan JY, et al. J. Drug Target. 2012;20:551.

    Not in our library10.3109/1061186x.2012.699057

  72. 72.

    Akhtar S, Benter IF. Clin J. Invest. 2007;117:3623.

    Not in our library10.1172/jci33494

  73. 73.

    Jere D, Jiang HL, Arote R, Kim YK, et al. Expert Opin. Drug Delivery. 2009;6:827.

    Not in our library10.1517/17425240903029183

  74. 74.

    Gary DJ, Puri N, Won YY. Polymer-based siRNA delivery: perspectives on the fundamental and phenomenological distinctions from polymer-based DNA delivery. J. Control. Release. 2007;121:64-73.

    Not in our library10.1016/j.jconrel.2007.05.021

  75. 75.

    Lungwitz U, Breunig M, Blunk T, Gopferich A. Eur. J. Pharm. Biopharm. 2005;60:247.

    Not in our library10.1016/j.ejpb.2004.11.011

  76. 76.

    Kortylewski M, et al. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat. Biotechnol. 2009;27:925-932.

    Not in our library10.1038/nbt.1564

  77. 77.

    Boussif O, Zanta MA, Behr JP. Optimized galenics improve in vitro gene transfer with cationic molecules up to 1000-fold. Gene Ther. 1996;3:1074-1080.

    Not in our library

  78. 78.

    Soutschek J, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature. 2004;432:173-178.

    Not in our library10.1038/nature03121

  79. 79.

    Felber AE, Dufresne MH, Leroux JC. pH-sensitive vesicles, polymeric micelles, and nanospheres prepared with polycarboxylates. Adv Drug Deliv Rev. 2012;64:979-992.

    Not in our library10.1016/j.addr.2011.09.006

  80. 80.

    Rozema DB, et al. Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes. Proc. Natl Acad. Sci. USA. 2007;104:12982-12987.

    Not in our library10.1073/pnas.0703778104

  81. 81.

    Hunter AC. Molecular hurdles in polyfectin design and mechanistic background to polycation induced cytotoxicity. Adv. Drug Deliv. Rev. 2006;58:1523-1531.

    Not in our library10.1016/j.addr.2006.09.008

  82. 82.

    Thurston TL, Wandel M, von Muhlinen MP, Foeglein N, et al. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature. 2012;482:414-418.

    Not in our library10.1038/nature10744

  83. 83.

    Cheung CY, Murthy N, Stayton PS, et al. A pH-sensitive polymer that enhances cationic lipid-mediated gene transfer. Bioconjug Chem. 2001;12:906-910.

    Not in our library10.1021/bc0100408

  84. 84.

    Rajeev KG, et al. Hepatocyte-specific delivery of siRNAs conjugated to novel non-nucleosidic trivalent N-acetylgalactosamine elicits robust gene silencing in vivo. Chem. BioChem. 2015;16:903-908.

    Not in our library10.1002/cbic.201500023

  85. 85.

    Fischer D, von Harpe A, Kunath K, Petersen H, et al. Copolymers of ethylene imine and N-(2-hydroxyethyl)-ethyleneimine as tools to study effects of polymer structure on physicochemical and biological properties of DNA complexes. Bioconjug. Chem. 2002;13:1124-1133.

    Not in our library10.1021/bc025550w

  86. 86.

    Biessen EA, et al. Synthesis of cluster galactosides with high affinity for the hepatic asialoglycoprotein receptor. J. Med. Chem. 1995;38:1538-1546.

    Not in our library10.1021/jm00009a014

  87. 87.

    Wong SC, et al. Co-injection of a targeted, reversibly masked endosomolytic polymer dramatically improves the efficacy of cholesterolconjugated small interfering RNAs in vivo. Nucleic Acid Ther. 2012;22:380-390.

    Not in our library10.1089/nat.2012.0389

  88. 88.

    Hou KK, Pan H, Schlesinger PH, Wickline SA. A role for peptides in overcoming endosomal entrapment in siRNA delivery – a focus on melittin. Biotechnol Adv. 2015;33(9 Pt 1):931-940.

    Not in our library10.1016/j.biotechadv.2015.05.005

  89. 89.

    Adami RC, Rice KG. Metabolic stability of glutaraldehyde cross-linked peptide DNA condensates. J. Pharm. Sci. 1999;88(8):739-746.

    Not in our library10.1021/js990042p

  90. 90.

    Choi SW, Lee SH, Mok H, Park TG. Multifunctional siRNA delivery system: polyelectrolyte complex micelles of six-arm PEG conjugate of siRNA and cell penetrating peptide with crosslinked fusogenic peptide. Biotechnol. Prog. 2010;26:57-63.

    Not in our library10.1002/btpr.310

  91. 91.

    Oliveira S, van Rooy I, Kranenburg O, Storm G, et al. Fusogenic peptides enhance endosomal escape improving siRNAinduced silencing of oncogenes. Int. J. Pharm. 2007;331:211-214.

    Not in our library10.1016/j.ijpharm.2006.11.050

  92. 92.

    Song E, et al. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat. Biotechnol. 2005;23:709-717.

    Not in our library10.1038/nbt1101

  93. 93.

    Hatakeyama H, Ito E, Akita H, et al. A pH-sensitive fusogenic peptide facilitates endosomal escape and greatly enhances the gene silencing of siRNA-containing nanoparticles in vitro and in vivo. J Control Release. 2009;139:127-132.

    Not in our library10.1016/j.jconrel.2009.06.008

  94. 94.

    Hou KK, Pan H, Ratner L, Schlesinger PH, et al. Mechanisms of nanoparticle-mediated siRNA transfection by melittin-derived peptides. ACS Nano. 2013;7(10):8605-8615.

    Not in our library10.1021/nn403311c

  95. 95.

    Peer D, Zhu P, Carman CV, Lieberman J, et al. Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1. Proc. Natl Acad. Sci. USA. 2007;104:4095-4100.

    Not in our library10.1073/pnas.0608491104

  96. 96.

    Gallarate M, Battaglia L, Peira E, Trotta M. Peptide-loaded solid lipid nanoparticles prepared through coacervation technique. International Journal of Chemical Engineerin. 2011;1-6.

    Not in our library

  97. 97.

    Kumar P, et al. T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell. 2008;134:577-586.

    Not in our library10.1016/j.cell.2008.06.034

  98. 98.

    Barrett SE, et al. Development of a liver-targeted siRNA delivery platform with a broad therapeutic window utilizing biodegradable polypeptide-based polymer conjugates. J. Control. Release. 2014;183:124-137.

    Not in our library10.1016/j.jconrel.2014.03.028

  99. 99.

    Chiarantini L, Cerasi A, Fraternale A, et al. Comparison of a noveldelivery system for antisense peptide nucleid acids. J. Control Release. 2005;109:24-36.

    Not in our library10.1016/j.jconrel.2005.09.013

  100. 100.

    Yao YD, et al. Targeted delivery of PLK1-siRNA by ScFv suppresses Her2+ breast cancer growth and metastasis. Sci. Transl Med. 2012;4:130-148.

    Not in our library10.1126/scitranslmed.3003601

  101. 101.

    Green M, Loewenstein PM. Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell. 1988;55:1179-1188.

    Not in our library10.1016/0092-8674(88)90262-0

  102. 102.

    Tunnemann G, Martin RM, Haupt S, Patsch C, et al. Cargodependent mode of uptake and bioavailability of TAT-containing proteins and peptides in living cells. FASEB J. 2006;20:1775-1784.

    Not in our library10.1096/fj.05-5523com

  103. 103.

    Chiu YL, Ali A, Chu CY, Cao H, et al. Visualizing a correlation between siRNA localization, cellular uptake, and RNAi in living cells. Chem. Biol. 2004;11:1165-1175.

    Not in our library10.1016/j.chembiol.2004.06.006

  104. 104.

    Moschos SA, Jones SW, Perry MM, Williams AE, et al. Lung delivery studies using siRNA conjugated to TAT(48–60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity. Bioconjug. Chem. 2007;18:1450-1459.

    Not in our library10.1021/bc070077d

  105. 105.

    Frankel AD, Pabo CO. Cellular uptake of the Tat protein from human immunodeficiency virus. Cell. 1988;55:1189-1193.

    Not in our library10.1016/0092-8674(88)90263-2

  106. 106.

    Pujals S, Fernandez-Carneado J, Lopez-Iglesias C, Kogan MJ, et al. Mechanistic aspects of CPP-mediated intracellular drug delivery: relevance of CPP self-assembly. Biochim Biophys. Acta. 2006;1759(3):264-279.

    Not in our library10.1016/j.bbamem.2006.01.006

  107. 107.

    Wagner E. Application of membrane-active peptides for nonviral gene delivery. Adv. Drug Deliv. Rev. 1999;38:279-289.

    Not in our library10.1016/s0169-409x(99)00033-2

  108. 108.

    Zuhorn IS, Engberts JB, Hoeckstra D. Gene delivery by cationic lipid vectors: overcoming cellular barriers. Eur. Biophys J. 2007;36:349-362.

    Not in our library10.1007/s00249-006-0092-4

  109. 109.

    Liu Y, Zhu YH, Mao CQ, Dou S, et al. Triple negative breast cancer therapy with CDK1 siRNA delivered by cationic lipid assisted PEG-PLA nanoparticles. J. Control. Release. 2014;192:114-121.

    Not in our library10.1016/j.jconrel.2014.07.001

  110. 110.

    Kim SI, Shin D, Choi TH, Lee JC, et al. Systemic and specific delivery of small interfering RNAs to the liver mediated by apolipoprotein A-I. Mol. Ther. 2007;15:1145-1152.

    Not in our library10.1038/sj.mt.6300168

  111. 111.

    Akinc A, Zumbuehl A, Goldberg M, Leshchiner ES, et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat. Biotechnol. 2008;26:561-569.

    Not in our library10.1038/nbt1402

  112. 112.

    Dreyer JL. Lentiviral vector-mediated gene transfer and RNA silencing technology in neuronal dysfunctions. Mol. Biotechnol. 2011;47(2):169-187.

    Not in our library10.1007/s12033-010-9334-x

  113. 113.

    Yagi N, Manabe I, Tottori T, Ishihara A, et al. A nanoparticle system specifically designed to deliver short interfering RNA inhibits tumor growth in vivo. Cancer Res. 2009;69:6531-6538.

    Not in our library10.1158/0008-5472.can-08-3945

  114. 114.

    Zhang J, et al. Assessing the heterogeneity level in lipid nanoparticles for siRNA delivery: size-based separation, compositional heterogeneity, and impact on bioperformance. Mol. Pharm. 2013;10:397-405.

    Not in our library10.1021/mp3005337

  115. 115.

    Semple SC, Akinc A, Chen J, Sandhu AP, et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 2010;28:172-176.

    Not in our library10.1038/nbt.1602

  116. 116.

    Couto LB, High KA. Viral vector-mediated RNA interference. Curr. Opin. Pharmacol. 2010;10(5):534-542.

    Not in our library10.1016/j.coph.2010.06.007

  117. 117.

    Hobo W, Novobrantseva TI, Fredrix H, Wong J, et al. Improving dendritic cell vaccine immunogenicity by silencing PD-1 ligands using siRNA-lipid nanoparticles combined with antigen mRNA electroporation. Cancer Immunol. Immunother. 2013;62:285-297.

    Not in our library10.1007/s00262-012-1334-1

  118. 118.

    Zimmermann TS, Lee AC, Akinc A, Bramlage B, et al. RNAi-mediated gene silencing in non-human primates. Nature. 2006;441:111-114.

    Not in our library10.1038/nature04688

  119. 119.

    Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat. Cell Biol. 2009;11:1143-1149.

    Not in our library10.1038/ncb1929

  120. 120.

    Castanotto D, Rossi JJ. The promises and pitfalls of RNA-interference-based therapeutics. Nature. 2009;457(7228):426-433.

    Not in our library10.1038/nature07758

  121. 121.

    Lee JB, Zhang K, Tam YY, Tam YK, et al. Lipid nanoparticle siRNA systems for silencing the androgen receptor in human prostate cancer in vivo. Int. J. Cancer. 2012;131:E781-E790.

    Not in our library10.1002/ijc.27361

  122. 122.

    Akinc A, Zumbuehl A, Goldberg M, et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat. Biotechnol. 2008;26:561-569.

    Not in our library10.1038/nbt1402

  123. 123.

    Malone RW, Felgner PL, Verma IM. Proc. Natl. Acad. Sci. USA. 1989;86:6077.

    Not in our library10.1073/pnas.86.16.6077

  124. 124.

    Felgner PL, Gadek TR, Holm M, Roman R, et al. Proc. Natl. Acad. Sci. USA. 1987;84:7413.

    Not in our library10.1073/pnas.84.21.7413

  125. 125.

    Gavrilov K, Saltzman WM. Therapeutic siRna: Principles, challenges, and strategies. Yale Journal of Biology and Medicine. 2012;85:187-200.

    Not in our library

  126. 126.

    Lee SK, Siefert A, Beloor J, et al. Cell-specific siRNA delivery by peptides and antibodies. Methods Enzymol. 2012;502:91-122.

    Not in our library10.1016/b978-0-12-416039-2.00005-7

  127. 127.

    Cesarone G, Edupuganti OP, Edupuganti CP, Wickstrom E. Insulin receptor substrate 1 knockdown in human MCF7 ER+ breast cancer cells by nuclease-resistant IRS1 siRNA conjugated to a disulfide-bridged D-peptide analogue of insulinlike growth factor 1. Bioconjugate Chem. 2007;18:1831-1840.

    Not in our library10.1021/bc070135v

  128. 128.

    Lorenz C, Hadwiger P, John M, Vornlocher HP, et al. Steroid and lipid conjugates of siRNAs to enhance cellular uptake and gene silencing. Bioorg Med Chem Lett. 2004;14(19):4975-4977.

    Not in our library10.1016/j.bmcl.2004.07.018

  129. 129.

    Blum JS, Saltzman WM. High loading efficiency and tunable release of plasmid DNA encapsulated in submicron particles fabricated from PLGAconjugated with poly-L-lysine. J. Control Release. 2008;129(1):66-72.

    Not in our library10.1016/j.jconrel.2008.04.002

  130. 130.

    Kataoka K, Harada A, Nagasaki Y. Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv. Drug Deliv Rev. 2001;47(1):113-131.

    Not in our library10.1016/s0169-409x(00)00124-1

  131. 131.

    Rozema DB, Lewis DL, Wakefield DH, Wong SC, et al. Proc. Natl. Acad. Sci. USA. 2007;104:12982.

    Not in our library10.1073/pnas.0703778104

  132. 132.

    Jackson AL, Linsley PS. Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat. Rev. Drug Discov. 2010;9(1):57-67.

    Not in our library10.1038/nrd3010

  133. 133.

    Bobbin ML, Rossi JJ. RNA interference (RNAi)-based therapeutics:delivering on the promise? Annu Rev Pharmacol Toxicol. 2016;56:103-122.

    Not in our library10.1146/annurev-pharmtox-010715-103633

  134. 134.

    Castanotto D, Rossi JJ. The promises and pitfalls of RNA-interferencebased therapeutics. Nature. 2009;457:426-433.

    Not in our library10.1038/nature07758

  135. 135.

    Bora RS, Gupta D, Mukkur TK, Saini KS. RNA interference therapeutics for cancer: challenges and opportunities (review). Mol. Med. Rep. 2012;6:9-15.

    Not in our library10.3892/mmr.2012.871

  136. 136.

    Taratula O, Garbuzenko O, Savla R, Wang YA, et al. Multifunctional nanomedicine platform for cancer specific delivery of siRNAby superparamagnetic iron oxide nanoparticles-dendrimer complexes. Curr Drug Deliv. 2011;8(1):59-69.

    Not in our library10.2174/156720111793663642

  137. 137.

    Hu-Lieskovan S, Heidel JD, Bartlett DW, Davis ME, et al. Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing’s sarcoma. Cancer Res. 2005;65(19):8984-8992.

    Not in our library10.1158/0008-5472.can-05-0565

  138. 138.

    Yano J, Hirabayashi K, Nakagawa S, Yamaguchi T, et al. Antitumor activity of small interfering RNA/cationic liposome complex in mouse models of cancer. Clin. Cancer Res. 2004;10:7721-7726.

    Not in our library10.1158/1078-0432.ccr-04-1049

  139. 139.

    Leung RK, Whittaker PA. RNA interference: from gene silencing to gene-specific therapeutics. Pharmacol. Ther. 2005;107:222-239.

    Not in our library10.1016/j.pharmthera.2005.03.004

  140. 140.

    Pai SI, Lin YY, Macaes P, Meneshian A, et al. Prospects of RNA interference therapy for cancer. Gene Ther. 2006;13:464-477.

    Not in our library10.1038/sj.gt.3302694

  141. 141.

    Lorenz C, Hadwiger P, John M, Vornlocher HP, et al. Steroid and lipid conjugates of siRNAs to enhance cellular uptake and gene silencing in liver cells. Bioorg Med Chem Lett. 2004;14(19):4975-4977.

    Not in our library10.1016/j.bmcl.2004.07.018

  142. 142.

    Pille JY, Li H, Blot E, Bertrand JR, et al. Intravenous delivery of anti-RhoA small interfering RNA loaded in nanoparticles of chitosan in mice: safety and efficacy in xenografted aggressive breast cancer. Hum Gene Ther. 2006;17(10):1019-1026.

    Not in our library10.1089/hum.2006.17.1019

  143. 143.

    Bedi D, Musacchio T, Fagbohun OA, Gillespie JW, et al. Delivery of siRNA into breast cancer cells via phage fusion proteintargeted liposomes. Nanomedicine. 2011;7(3):315-323.

    Not in our library10.1016/j.nano.2010.10.004

  144. 144.

    Kim SH, Lee SH, Tian H, Chen X, et al. Prostate cancer cell-specific VEGF siRNA delivery system using cell targeting peptide conjugated polyplexes. J. Drug Target. 209;17(4):311-317.

    Not in our library10.1080/10611860902767232

  145. 145.

    Zamora MR, Budev M, Rolfe M, Gottlieb J, et al. RNA interference therapy in lung transplant patients infected with respiratory syncytial virus. Am. J. Respir Crit. Care Med. 2011;183(4):531-538.

    Not in our library10.1164/rccm.201003-0422oc

  146. 146.

    Li S, Wu SP, Whitmore M, Loeffert EJ, et al. Effect of immune response on gene transfer to the lung via systemic administration of cationic lipidic vectors. Am. J. Physiol. 1999;276(5Pt 1):L796-804.

    Not in our library10.1152/ajplung.1999.276.5.l796

  147. 147.

    Urban-Klein B, Werth S, Abuharbeid S, Czubayko F, et al. RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo. Gene Ther. 2005;12:461-466.

    Not in our library10.1038/sj.gt.3302425

  148. 148.

    Grzelinski M, Urban-Klein B, Martens T, Lamszus K, et al. RNA interference-mediated gene silencing of pleiotrophin through polyethylenimine-complexed small interfering RNAs in vivo exerts antitumoral effects in glioblastoma xenografts. Hum. Gene Ther. 2006;17:751-766.

    Not in our library10.1089/hum.2006.17.751

  149. 149.

    Xu CX, Jere D, Jin H, Chang SH, et al. Poly (ester amine)-mediated, aerosol-delivered Akt1 small interfering RNA suppresses lung tumorigenesis. Am. J. Respir. Crit. Care Med. 2008;178:60-73.

    Not in our library10.1164/rccm.200707-1022oc

  150. 150.

    Yano J, Hirabayashi K, Nakagawa S, Yamaguchi T, et al. Antitumor activity of small interfering RNA/cationic liposome complex in mouse models of cancer. Clin. Cancer Res. 2004;10:7721-7726.

    Not in our library10.1158/1078-0432.ccr-04-1049

  151. 151.

    Li SD, Chen YC, Hackett MJ, Huang L. Tumor-targeted delivery of siRNA by selfassembled nanoparticles. Mol. Ther. 2008;16:163-169.

    Not in our library10.1038/sj.mt.6300323

  152. 152.

    Hogrefe RI, Lebedev AV, Zon G, Pirollo KF, et al. Chemically modified short interfering hybrids (siHYBRIDS): nanoimmunoliposome delivery in vitro and in vivo for RNAi of HER-2. Nucleosides Nucleotides Nucleic Acids. 2006;25:889-907.

    Not in our library10.1080/15257770600793885

  153. 153.

    Morrissey DV, Lockridge JA, Shaw L, Blanchard K, et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat. Biotechnol. 2005;23:1002-1007.

    Not in our library10.1038/nbt1122

  154. 154.

    Yiu SM, Wong PW, Lam TW, Mui YC, et al. Filtering of ineffective siRNAs and improved siRNA design tool. Bioinformatics. 2005;21(2):144-151.

    Not in our library10.1093/bioinformatics/bth498

  155. 155.

    Naito Y, Ui-Tei K. Designing functional siRNA with reduced off-target effects. Methods Mol. Biol. 2013;942:57-68.

    Not in our library10.1007/978-1-62703-119-6_3

  156. 156.

    Chalk AM, Wahlestedt C, Sonnhammer EI. Improved and automated prediction of effective siRNA. Biochem. Biophys. Res. Commun. 2004;319(1):264-274.

    Not in our library10.1016/j.bbrc.2004.04.181

  157. 157.

    Jenny KW, Lam J, Alan J Worsley. What is the Future of SiRNA Therapeutics? J. Drug Des Res. 2014;1(1):1005.

    Not in our library

  158. 158.

    Birmingham A, Anderson EM, Reynolds A, Ilsley-Tyree D, et al. 3’ UTR seed matches, but not overall identity, are associated with RNAi off-targets. Nat Methods. 2006;3:199-204.

    Not in our library10.1038/nmeth854

  159. 159.

    Watts JK, Deleavey GF, Damha MJ. Chemically modified siRNA: tools and applications. Drug Discov Today. 2008;13:842-855.

    Not in our library10.1016/j.drudis.2008.05.007

  160. 160.

    Judge AD, Sood V, Shaw JR, Fang D, et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol. 2005;23:457-462.

    Not in our library10.1038/nbt1081

  161. 161.

    Jinek M, Doudna JA. A three-dimensional view of the molecular machinery of RNA interference. Nature. 2009;457(7228):405-412.

    Not in our library10.1038/nature07755

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