Home LiteratureArticle Details
PMID: 22252451 Published · ppublish English Journal Article Review

Action and reaction: the biological response to siRNA and its delivery vehicles.

Molecular therapy : the journal of the American Society of Gene Therapy ·Vol. 20 ·No. 3 ·2012-03-00 ·Pages 513-24

Kanasty RL, Whitehead KA, Vegas AJ, Anderson DG

Abstract

RNA interference (RNAi)-based therapeutics have significant potential for the treatment of human disease. Safe and effective delivery of RNA to target tissues remains a major barrier to realizing its clinical potential. Several factors can affect the in vivo performance of short interfering RNA (siRNA) delivery formulations, including siRNA sequence, structure, chemical modification, and delivery formulation. This review provides an introduction to the principles underlying the pharmacokinetics and pharmacodynamics of systemically administered siRNA and its delivery formulations, including the factors that lead to its degradation, clearance, and tissue uptake, as well as its potential for immunogenicity, toxicity, and off-target effects within the body.

MeSH Terms
Animals Drug Delivery Systems Gene Silencing Gene Transfer Techniques Humans RNA Interference RNA, Small Interfering/administration & dosage,chemistry,pharmacology
Chemicals
RNA, Small Interfering
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Kanasty Rosemary L
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Whitehead Kathryn A
Vegas Arturo J
Anderson Daniel G
References (170)
170 references, click to expand
  1. Combinatorial microRNA target predictions.
    Nat Genet. 2005 May;37(5):495-500 PMID: 15806104
  2. In vivo activity of nuclease-resistant siRNAs.
    RNA. 2004 May;10(5):766-71 PMID: 15100431
  3. UNA (unlocked nucleic acid): a flexible RNA mimic that allows engineering of nucleic acid duplex stability.
    Bioorg Med Chem. 2009 Aug 1;17(15):5420-5 PMID: 19604699
  4. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms.
    Mol Ther. 2010 Jul;18(7):1357-64 PMID: 20461061
  5. The role of interleukins in insulin resistance and type 2 diabetes mellitus.
    Nat Rev Endocrinol. 2009 Jun;5(6):305-11 PMID: 19399017
  6. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review.
    J Control Release. 2000 Mar 1;65(1-2):271-84 PMID: 10699287
  7. Lymphatic metastasis in the absence of functional intratumor lymphatics.
    Science. 2002 Jun 7;296(5574):1883-6 PMID: 11976409
  8. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs.
    Nature. 2005 Feb 17;433(7027):769-73 PMID: 15685193
  9. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation.
    Cancer Res. 2000 Aug 15;60(16):4324-7 PMID: 10969769
  10. Pathways of clathrin-independent endocytosis.
    Nat Rev Mol Cell Biol. 2007 Aug;8(8):603-12 PMID: 17609668
  11. Molecular make-up of the glomerular filtration barrier.
    Biochem Biophys Res Commun. 2010 May 21;396(1):164-9 PMID: 20494132
  12. Development of lipidoid-siRNA formulations for systemic delivery to the liver.
    Mol Ther. 2009 May;17(5):872-9 PMID: 19259063
  13. Sheddable coatings for long-circulating nanoparticles.
    Pharm Res. 2008 Jan;25(1):55-71 PMID: 17551809
  14. Mechanistic insights aid computational short interfering RNA design.
    Methods Enzymol. 2005;392:73-96 PMID: 15644176
  15. Nanocarriers' entry into the cell: relevance to drug delivery.
    Cell Mol Life Sci. 2009 Sep;66(17):2873-96 PMID: 19499185
  16. Vesicle formation and trafficking in endothelial cells and regulation of endothelial barrier function.
    Histochem Cell Biol. 2002 Feb;117(2):105-12 PMID: 11935286
  17. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms.
    Circ Res. 2007 Feb 2;100(2):158-73 PMID: 17272818
  18. Elimination pathways of systemically delivered siRNA.
    Mol Ther. 2011 Feb;19(2):381-5 PMID: 21119623
  19. Openings between defective endothelial cells explain tumor vessel leakiness.
    Am J Pathol. 2000 Apr;156(4):1363-80 PMID: 10751361
  20. Target accessibility dictates the potency of human RISC.
    Nat Struct Mol Biol. 2005 May;12(5):469-70 PMID: 15852021
  21. Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows.
    Cancer Res. 1994 Sep 1;54(17):4564-8 PMID: 8062241
  22. Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application.
    Nat Rev Drug Discov. 2010 Jan;9(1):57-67 PMID: 20043028
  23. MALDI-TOF mass spectral analysis of siRNA degradation in serum confirms an RNAse A-like activity.
    Mol Biosyst. 2007 Jan;3(1):43-50 PMID: 17216055
  24. Rational siRNA design for RNA interference.
    Nat Biotechnol. 2004 Mar;22(3):326-30 PMID: 14758366
  25. Factors affecting the clearance and biodistribution of polymeric nanoparticles.
    Mol Pharm. 2008 Jul-Aug;5(4):505-15 PMID: 18672949
  26. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA.
    Nat Biotechnol. 2005 Apr;23(4):457-62 PMID: 15778705
  27. A novel series of amphiphilic imidazolinium compounds for in vitro and in vivo gene delivery.
    Biochemistry. 1995 Oct 17;34(41):13537-44 PMID: 7577942
  28. Molecular mechanisms of phagocytic uptake in mammalian cells.
    Cell Mol Life Sci. 2008 Jul;65(13):1957-76 PMID: 18322649
  29. Cell type-specific involvement of RIG-I in antiviral response.
    Immunity. 2005 Jul;23(1):19-28 PMID: 16039576
  30. OligoWalk: an online siRNA design tool utilizing hybridization thermodynamics.
    Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W104-8 PMID: 18490376
  31. siRNA and innate immunity.
    Oligonucleotides. 2009 Jun;19(2):89-102 PMID: 19441890
  32. Polymer-related off-target effects in non-viral siRNA delivery.
    Biomaterials. 2011 Mar;32(9):2388-98 PMID: 21183213
  33. Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging.
    Nat Med. 2009 Oct;15(10):1219-23 PMID: 19749772
  34. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics.
    Nat Biotechnol. 2008 May;26(5):561-9 PMID: 18438401
  35. Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models.
    Microcirculation. 2010 Apr;17(3):206-25 PMID: 20374484
  36. Pattern recognition receptors and inflammation.
    Cell. 2010 Mar 19;140(6):805-20 PMID: 20303872
  37. Role of podocyte slit diaphragm as a filtration barrier.
    Nephrology (Carlton). 2006 Aug;11(4):274-81 PMID: 16889564
  38. Toll-like receptors: critical proteins linking innate and acquired immunity.
    Nat Immunol. 2001 Aug;2(8):675-80 PMID: 11477402
  39. The effect of chemical modification and nanoparticle formulation on stability and biodistribution of siRNA in mice.
    Mol Ther. 2009 Jul;17(7):1225-33 PMID: 19401674
  40. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8.
    Science. 2004 Mar 5;303(5663):1526-9 PMID: 14976262
  41. M-CSF-induced macropinocytosis increases solute endocytosis but not receptor-mediated endocytosis in mouse macrophages.
    J Cell Sci. 1992 Aug;102 ( Pt 4):867-80 PMID: 1429898
  42. In vivo pharmacokinetics, tissue distribution and underlying mechanisms of various PEI(-PEG)/siRNA complexes.
    Toxicol Appl Pharmacol. 2009 Apr 1;236(1):97-108 PMID: 19371615
  43. On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids.
    Gene Ther. 2001 Aug;8(15):1188-96 PMID: 11509950
  44. Lack of interferon response in animals to naked siRNAs.
    Nat Biotechnol. 2004 Dec;22(12):1579-82 PMID: 15558046
  45. Competition for RISC binding predicts in vitro potency of siRNA.
    Nucleic Acids Res. 2006;34(16):4467-76 PMID: 16945958
  46. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs.
    Nature. 2004 Nov 11;432(7014):173-8 PMID: 15538359
  47. Improved specificity of gene silencing by siRNAs containing unlocked nucleobase analogs.
    Nucleic Acids Res. 2011 Mar;39(5):1823-32 PMID: 21047800
  48. A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells.
    Nat Biotechnol. 2006 May;24(5):559-65 PMID: 16648842
  49. CD44 is a phagocytic receptor.
    Blood. 2006 May 15;107(10):4149-58 PMID: 16455948
  50. Tolerated wobble mutations in siRNAs decrease specificity, but can enhance activity in vivo.
    Nucleic Acids Res. 2005 Aug 19;33(15):4704-10 PMID: 16113241
  51. Overexpression of exportin 5 enhances RNA interference mediated by short hairpin RNAs and microRNAs.
    RNA. 2005 Feb;11(2):220-6 PMID: 15613540
  52. Type 1 interferons and the virus-host relationship: a lesson in détente .
    Science. 2006 May 12;312(5775):879-82 PMID: 16690858
  53. Expression profiling reveals off-target gene regulation by RNAi.
    Nat Biotechnol. 2003 Jun;21(6):635-7 PMID: 12754523
  54. Evaluation of locked nucleic acid-modified small interfering RNA in vitro and in vivo.
    Mol Cancer Ther. 2007 Mar;6(3):833-43 PMID: 17363479
  55. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation.
    Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):16369-74 PMID: 21911388
  56. Knocking down barriers: advances in siRNA delivery.
    Nat Rev Drug Discov. 2009 Feb;8(2):129-38 PMID: 19180106
  57. Transfection of small RNAs globally perturbs gene regulation by endogenous microRNAs.
    Nat Biotechnol. 2009 Jun;27(6):549-55 PMID: 19465925
  58. Factors determining the relationship between renal and hepatic excretion of xenobiotics.
    Arzneimittelforschung. 1990 Aug;40(8):942-6 PMID: 2242089
  59. Stability of siRNA polyplexes from poly(ethylenimine) and poly(ethylenimine)-g-poly(ethylene glycol) under in vivo conditions: effects on pharmacokinetics and biodistribution measured by Fluorescence Fluctuation Spectroscopy and Single Photon Emission Computed Tomography (SPECT) imaging.
    J Control Release. 2009 Sep 1;138(2):148-59 PMID: 19463870
  60. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.
    Nature. 2001 May 24;411(6836):494-8 PMID: 11373684
  61. 3' UTR seed matches, but not overall identity, are associated with RNAi off-targets.
    Nat Methods. 2006 Mar;3(3):199-204 PMID: 16489337
  62. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment.
    Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4607-12 PMID: 9539785
  63. Physicochemical characterization and purification of cationic lipoplexes.
    Biophys J. 1999 Jul;77(1):341-53 PMID: 10388762
  64. Phagocytosis by zippers and triggers.
    Trends Cell Biol. 1995 Mar;5(3):89-93 PMID: 14732161
  65. Blood-brain barrier transport of therapeutics via receptor-mediation.
    Pharm Res. 2007 Sep;24(9):1759-71 PMID: 17619996
  66. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs.
    Nat Biotechnol. 2005 Aug;23(8):1002-7 PMID: 16041363
  67. Lysosomal enzyme trafficking between phagosomes, endosomes, and lysosomes in J774 macrophages. Enrichment of cathepsin H in early endosomes.
    J Biol Chem. 1998 Apr 17;273(16):9842-51 PMID: 9545324
  68. Chemical modification of siRNA.
    Curr Protoc Nucleic Acid Chem. 2009 Dec;Chapter 16:Unit 16.3 PMID: 20013783
  69. Ribonuclease A.
    Chem Rev. 1998 May 7;98(3):1045-1066 PMID: 11848924
  70. Differences between fluid-phase endocytosis (pinocytosis) and receptor-mediated endocytosis in isolated rat hepatocytes.
    Eur J Cell Biol. 1997 May;73(1):28-39 PMID: 9174669
  71. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.
    Science. 2005 Jan 7;307(5706):58-62 PMID: 15637262
  72. Toxicity pathway focused gene expression profiling of PEI-based polymers for pulmonary applications.
    Mol Pharm. 2010 Jun 7;7(3):727-37 PMID: 20429563
  73. Visualization of in vitro protein-rejecting properties of PEGylated stealth polycyanoacrylate nanoparticles.
    Biomaterials. 1999 Jul;20(14):1269-75 PMID: 10403044
  74. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.
    Nat Immunol. 2010 May;11(5):373-84 PMID: 20404851
  75. Micro RNAs are complementary to 3' UTR sequence motifs that mediate negative post-transcriptional regulation.
    Nat Genet. 2002 Apr;30(4):363-4 PMID: 11896390
  76. Expression of shRNA from a tissue-specific pol II promoter is an effective and safe RNAi therapeutic.
    Mol Ther. 2008 Sep;16(9):1630-6 PMID: 18665161
  77. Parameters influencing the stealthiness of colloidal drug delivery systems.
    Biomaterials. 2006 Aug;27(24):4356-73 PMID: 16650890
  78. Specificity of microRNA target selection in translational repression.
    Genes Dev. 2004 Mar 1;18(5):504-11 PMID: 15014042
  79. "Alternative" endocytic mechanisms exploited by pathogens: new avenues for therapeutic delivery?
    Adv Drug Deliv Rev. 2007 Aug 10;59(8):798-809 PMID: 17707545
  80. Inhibition of protein kinase C by cationic amphiphiles.
    Biochemistry. 1992 Sep 22;31(37):9025-30 PMID: 1390689
  81. Targeted delivery systems for oligonucleotide therapeutics.
    AAPS J. 2009 Mar;11(1):195-203 PMID: 19296227
  82. Lipid-based nanotherapeutics for siRNA delivery.
    J Intern Med. 2010 Jan;267(1):9-21 PMID: 20059641
  83. Interactions of mammalian cells with lipid dispersions containing novel metabolizable cationic amphiphiles.
    Biochim Biophys Acta. 1990 Mar 30;1023(1):124-32 PMID: 2317491
  84. Molecular basis for target RNA recognition and cleavage by human RISC.
    Cell. 2007 Jul 13;130(1):101-12 PMID: 17632058
  85. Exploring polyethylenimine-mediated DNA transfection and the proton sponge hypothesis.
    J Gene Med. 2005 May;7(5):657-63 PMID: 15543529
  86. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles.
    Int J Pharm. 2006 Jan 3;307(1):93-102 PMID: 16303268
  87. Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity.
    J Clin Invest. 2009 Aug;119(8):2231-44 PMID: 19620771
  88. Methods to evaluate biliary excretion of drugs in humans: an updated review.
    Mol Pharm. 2006 May-Jun;3(3):198-211 PMID: 16749853
  89. Sequence-specific inhibition of small RNA function.
    PLoS Biol. 2004 Apr;2(4):E98 PMID: 15024405
  90. Specificity of short interfering RNA determined through gene expression signatures.
    Proc Natl Acad Sci U S A. 2003 May 27;100(11):6347-52 PMID: 12746500
  91. RNAi-mediated gene silencing in non-human primates.
    Nature. 2006 May 4;441(7089):111-4 PMID: 16565705
  92. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine.
    Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7297-301 PMID: 7638184
  93. Strand-specific 5'-O-methylation of siRNA duplexes controls guide strand selection and targeting specificity.
    RNA. 2008 Feb;14(2):263-74 PMID: 18094121
  94. Virus entry: open sesame.
    Cell. 2006 Feb 24;124(4):729-40 PMID: 16497584
  95. Off-target effects by siRNA can induce toxic phenotype.
    RNA. 2006 Jul;12(7):1188-96 PMID: 16682561
  96. Prediction of human pharmacokinetics-biliary and intestinal clearance and enterohepatic circulation.
    J Pharm Pharmacol. 2008 May;60(5):535-42 PMID: 18416932
  97. Design of a genome-wide siRNA library using an artificial neural network.
    Nat Biotechnol. 2005 Aug;23(8):995-1001 PMID: 16025102
  98. ATP requirements and small interfering RNA structure in the RNA interference pathway.
    Cell. 2001 Nov 2;107(3):309-21 PMID: 11701122
  99. Breaking down the barriers: siRNA delivery and endosome escape.
    J Cell Sci. 2010 Apr 15;123(Pt 8):1183-9 PMID: 20356929
  100. A novel mechanism is involved in cationic lipid-mediated functional siRNA delivery.
    Mol Pharm. 2009 May-Jun;6(3):763-71 PMID: 19292453
  101. A screen of chemical modifications identifies position-specific modification by UNA to most potently reduce siRNA off-target effects.
    Nucleic Acids Res. 2010 Sep;38(17):5761-73 PMID: 20453030
  102. Lipid-like materials for low-dose, in vivo gene silencing.
    Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1864-9 PMID: 20080679
  103. Rational design of cationic lipids for siRNA delivery.
    Nat Biotechnol. 2010 Feb;28(2):172-6 PMID: 20081866
  104. Toxicogenomics of non-viral vectors for gene therapy: a microarray study of lipofectin- and oligofectamine-induced gene expression changes in human epithelial cells.
    J Drug Target. 2003 Jul;11(6):311-23 PMID: 14668052
  105. Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography.
    J Clin Invest. 2004 Nov;114(10):1475-83 PMID: 15545998
  106. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates.
    Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11915-20 PMID: 18695239
  107. Dynamin 2 is required for phagocytosis in macrophages.
    J Exp Med. 1999 Dec 20;190(12):1849-56 PMID: 10601359
  108. Argonaute proteins are key determinants of RNAi efficacy, toxicity, and persistence in the adult mouse liver.
    J Clin Invest. 2010 Sep;120(9):3106-19 PMID: 20697157
  109. Stealth Me.PEG-PLA nanoparticles avoid uptake by the mononuclear phagocytes system.
    J Pharm Sci. 1995 Apr;84(4):493-8 PMID: 7629743
  110. The impact of target site accessibility on the design of effective siRNAs.
    Nat Biotechnol. 2008 May;26(5):578-83 PMID: 18438400
  111. Porous substructure of the glomerular slit diaphragm in the rat and mouse.
    J Cell Biol. 1974 Feb;60(2):423-33 PMID: 4204974
  112. Toxicogenomics of non-viral drug delivery systems for RNAi: potential impact on siRNA-mediated gene silencing activity and specificity.
    Adv Drug Deliv Rev. 2007 Mar 30;59(2-3):164-82 PMID: 17481774
  113. Oxygen radical-mediated pulmonary toxicity induced by some cationic liposomes.
    Pharm Res. 2000 May;17(5):521-5 PMID: 10888302
  114. Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases.
    Science. 1998 Nov 27;282(5394):1717-21 PMID: 9831565
  115. Pathogen recognition and innate immunity.
    Cell. 2006 Feb 24;124(4):783-801 PMID: 16497588
  116. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon.
    Cell. 1990 Jul 27;62(2):379-90 PMID: 1695551
  117. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates.
    Science. 2006 Nov 10;314(5801):997-1001 PMID: 17038589
  118. Endocytic mechanisms for targeted drug delivery.
    Adv Drug Deliv Rev. 2007 Aug 10;59(8):748-58 PMID: 17659804
  119. Drug delivery-mediated control of RNA immunostimulation.
    Mol Ther. 2009 Sep;17(9):1555-62 PMID: 19584813
  120. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs.
    Nat Biotechnol. 2007 Oct;25(10):1149-57 PMID: 17873866
  121. Functional siRNAs and miRNAs exhibit strand bias.
    Cell. 2003 Oct 17;115(2):209-16 PMID: 14567918
  122. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds.
    Circ Res. 2007 Feb 2;100(2):174-90 PMID: 17272819
  123. 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-formulated, immune-stimulatory vascular endothelial growth factor a small interfering RNA (siRNA) increases antitumoral efficacy in murine orthotopic hepatocellular carcinoma with liver fibrosis.
    Mol Med. 2008 Jul-Aug;14(7-8):365-73 PMID: 18392108
  124. Interferon induction by siRNAs and ssRNAs synthesized by phage polymerase.
    Nat Biotechnol. 2004 Mar;22(3):321-5 PMID: 14990954
  125. New insights into the role of podocytes in proteinuria.
    Nat Rev Nephrol. 2009 Aug;5(8):463-8 PMID: 19581907
  126. Prediction of mammalian microRNA targets.
    Cell. 2003 Dec 26;115(7):787-98 PMID: 14697198
  127. Cellular siRNA delivery using cell-penetrating peptides modified for endosomal escape.
    Adv Drug Deliv Rev. 2009 Jul 25;61(9):704-9 PMID: 19383521
  128. Design of siRNAs producing unstructured guide-RNAs results in improved RNA interference efficiency.
    Nat Biotechnol. 2005 Nov;23(11):1440-4 PMID: 16258545
  129. Tumor-selective delivery of macromolecular drugs via the EPR effect: background and future prospects.
    Bioconjug Chem. 2010 May 19;21(5):797-802 PMID: 20397686
  130. Biodistribution of phosphodiester and phosphorothioate siRNA.
    Bioorg Med Chem Lett. 2004 Mar 8;14(5):1139-43 PMID: 14980652
  131. Macropinocytosis.
    Trends Cell Biol. 1995 Nov;5(11):424-8 PMID: 14732047
  132. The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation.
    Biomaterials. 2010 Sep;31(26):6867-75 PMID: 20541799
  133. Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality.
    Nucleic Acids Res. 2005 Jan 14;33(1):439-47 PMID: 15653644
  134. Mechanism of pH-triggered collapse of phosphatidylethanolamine liposomes stabilized by an ortho ester polyethyleneglycol lipid.
    Biophys J. 2003 Mar;84(3):1784-95 PMID: 12609880
  135. Delivering nanomedicine to solid tumors.
    Nat Rev Clin Oncol. 2010 Nov;7(11):653-64 PMID: 20838415
  136. Position-specific chemical modification of siRNAs reduces "off-target" transcript silencing.
    RNA. 2006 Jul;12(7):1197-205 PMID: 16682562
  137. Biodistribution of small interfering RNA at the organ and cellular levels after lipid nanoparticle-mediated delivery.
    J Histochem Cytochem. 2011 Aug;59(8):727-40 PMID: 21804077
  138. The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer.
    Gene Ther. 2008 Sep;15(17):1193-9 PMID: 18401434
  139. Utilization of unlocked nucleic acid (UNA) to enhance siRNA performance in vitro and in vivo.
    Mol Biosyst. 2010 May;6(5):862-70 PMID: 20567772
  140. Novel pyridinium surfactants for efficient, nontoxic in vitro gene delivery.
    Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1160-5 PMID: 9037023
  141. The TNF and TNF receptor superfamilies: integrating mammalian biology.
    Cell. 2001 Feb 23;104(4):487-501 PMID: 11239407
  142. On the art of identifying effective and specific siRNAs.
    Nat Methods. 2006 Sep;3(9):670-6 PMID: 16929310
  143. Endocytosis.
    Physiol Rev. 1997 Jul;77(3):759-803 PMID: 9234965
  144. Elucidating the encapsulation of short interfering RNA in PEGylated cationic liposomes.
    Langmuir. 2009 May 5;25(9):4886-91 PMID: 19341292
  145. Neovasculature induced by vascular endothelial growth factor is fenestrated.
    Cancer Res. 1997 Feb 15;57(4):765-72 PMID: 9044858
  146. Asymmetry in the assembly of the RNAi enzyme complex.
    Cell. 2003 Oct 17;115(2):199-208 PMID: 14567917
  147. MicroRNAs direct rapid deadenylation of mRNA.
    Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4034-9 PMID: 16495412
  148. Regulated portals of entry into the cell.
    Nature. 2003 Mar 6;422(6927):37-44 PMID: 12621426
  149. Therapeutic siRNA silencing in inflammatory monocytes in mice.
    Nat Biotechnol. 2011 Oct 09;29(11):1005-10 PMID: 21983520
  150. Glomerular basement membrane composition and the filtration barrier.
    Pediatr Nephrol. 2011 Sep;26(9):1413-7 PMID: 21327778
  151. Addressing the problem of cationic lipid-mediated toxicity: the magnetoliposome model.
    Biomaterials. 2009 Aug;30(22):3691-701 PMID: 19371948
  152. The glomerulus--a view from the inside--the endothelial cell.
    Int J Biochem Cell Biol. 2010 Sep;42(9):1388-97 PMID: 20541032
  153. Increased siRNA duplex stability correlates with reduced off-target and elevated on-target effects.
    RNA. 2011 Apr;17(4):737-49 PMID: 21367974
  154. A two-stage poly(ethylenimine)-mediated cytotoxicity: implications for gene transfer/therapy.
    Mol Ther. 2005 Jun;11(6):990-5 PMID: 15922971
  155. Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals.
    Nature. 2005 Mar 17;434(7031):338-45 PMID: 15735639
  156. Combinatorial delivery of small interfering RNAs reduces RNAi efficacy by selective incorporation into RISC.
    Nucleic Acids Res. 2007;35(15):5154-64 PMID: 17660190
  157. Selecting effective siRNAs based on guide RNA structure.
    Nat Protoc. 2006;1(4):1832-9 PMID: 17487166
  158. Design and gene delivery activity of modified polyethylenimines.
    Adv Drug Deliv Rev. 2001 Dec 31;53(3):341-58 PMID: 11744176
  159. 5'-Triphosphate RNA is the ligand for RIG-I.
    Science. 2006 Nov 10;314(5801):994-7 PMID: 17038590
  160. siRNA function in RNAi: a chemical modification analysis.
    RNA. 2003 Sep;9(9):1034-48 PMID: 12923253
  161. Gene delivery by cationic lipid vectors: overcoming cellular barriers.
    Eur Biophys J. 2007 Apr;36(4-5):349-62 PMID: 17019592
  162. Reduced levels of Ago2 expression result in increased siRNA competition in mammalian cells.
    Nucleic Acids Res. 2007;35(19):6598-610 PMID: 17905815
  163. Silencing or stimulation? siRNA delivery and the immune system.
    Annu Rev Chem Biomol Eng. 2011;2:77-96 PMID: 22432611
  164. The widespread impact of mammalian MicroRNAs on mRNA repression and evolution.
    Science. 2005 Dec 16;310(5755):1817-21 PMID: 16308420
  165. siDirect 2.0: updated software for designing functional siRNA with reduced seed-dependent off-target effect.
    BMC Bioinformatics. 2009 Nov 30;10:392 PMID: 19948054
  166. Update on the glomerular filtration barrier.
    Curr Opin Nephrol Hypertens. 2009 May;18(3):226-32 PMID: 19374010
  167. The human RNA kinase hClp1 is active on 3' transfer RNA exons and short interfering RNAs.
    Nature. 2007 May 10;447(7141):222-6 PMID: 17495927
  168. Atomic structure and chemistry of human serum albumin.
    Nature. 1992 Jul 16;358(6383):209-15 PMID: 1630489
  169. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways.
    Nature. 2006 May 25;441(7092):537-41 PMID: 16724069
  170. Toxicity of cationic lipids and cationic polymers in gene delivery.
    J Control Release. 2006 Aug 10;114(1):100-9 PMID: 16831482
Article Info
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
Abbr.
Mol Ther
ISSN
1525-0024
DOI
10.1038/mt.2011.294
Published
2012-03-00
Epub
2012-00-17
Pages
513-24
Language
English
Region
United States
NLM ID
100890581
PMCID
PMC3293611
Subset
IM
External Links
PubMed source DOI: 10.1038/mt.2011.294 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2