Tissue-Specific Delivery of Oligonucleotides

  • Xin Xia
  • Nicolette Pollock
  • Jiehua Zhou
  • John RossiEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 2036)


From the initial discovery of short-interfering RNA (siRNA) and antisense oligonucleotides for specific gene knockdown at the posttranscriptional level to the current CRISPR-Cas9 system offering gene editing at the genomic level, oligonucleotides, in addition to their biological functions in storing and conveying genetic information, provide the most prominent solutions to targeted gene therapies. Nonetheless, looking into the future of curing cancer and acute diseases, researchers are only cautiously optimistic as the cellular delivery of these polyanionic biomacromolecules is still the biggest hurdle for their therapeutic realization. To overcome the delivery obstacle, oligonucleotides have been encapsulated within or conjugated with delivery vehicles for enhanced membrane penetration, improved payload, and tissue-specific delivery. Such delivery systems include but not limited to virus-based vehicles, gold-nanoparticle vehicles, formulated liposomes, and synthetic polymers. In this chapter, delivery challenges imposed by biological barriers are briefly discussed; followed by recent advances in tissue-specific oligonucleotide delivery utilizing both viral and nonviral delivery vectors, discussing their advantages, and how judicious design and formulation could improve and expand their potential as delivery vehicles.

Key words

Oligonucleotide therapeutics Tissue-specific Phagocytosis EPR Endosomal escape Ligands Antibodies Aptamers 


  1. 1.
    Montecalvo A, Larregina AT, Shufesky WJ et al (2012) Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119:756–766PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Furusawa M, Nishimura T, Yamaizumi M et al (1974) Injection of foreign substances into single cells by cell fusion. Nature 249:449–450PubMedCrossRefGoogle Scholar
  3. 3.
    McNamara JO, Andrechek ER, Wang Y et al (2006) Cell type–specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol 24:1005–1015PubMedCrossRefGoogle Scholar
  4. 4.
    Dassie JP, Liu X-Y, Thomas GS et al (2009) Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors. Nat Biotechnol 27:839–849PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Rice RR, Muirhead AN, Harrison BT et al (2005) Simple, robust strategies for generating DNA-directed RNA interference constructs, RNA interference. Elsevier, Amsterdam, pp 405–419Google Scholar
  6. 6.
    Jiang H-L, Choi Y-J, Cho M-H et al (2010) Chitosan and chitosan derivatives as DNA and siRNA carriers, Chitin, chitosan, oligosaccharides and their derivatives. CRC Press, London, pp 377–390Google Scholar
  7. 7.
    Aied A, Greiser U, Pandit A et al (2013) Polymer gene delivery: overcoming the obstacles. Drug Discov Today 18:1090–1098PubMedCrossRefGoogle Scholar
  8. 8.
    Mitragotri S, Burke PA, Langer R (2014) Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov 13:655–672PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Naldini L (2015) Gene therapy returns to centre stage. Nature 526:351–360PubMedCrossRefGoogle Scholar
  10. 10.
    Naldini L (2011) Ex vivo gene transfer and correction for cell-based therapies. Nat Rev Genet 12:301–315PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Wittrup A, Lieberman J (2015) Knocking down disease: a progress report on siRNA therapeutics. Nat Rev Genet 16:543–552PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Stewart MP, Sharei A, Ding X et al (2016) In vitro and ex vivo strategies for intracellular delivery. Nature 538:183–192CrossRefGoogle Scholar
  13. 13.
    Yin H, Kanasty RL, Eltoukhy AA et al (2014) Non-viral vectors for gene-based therapy. Nat Rev Genet 15:541–555PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Larocca D, Burg MA, Jensen-Pergakes K et al (2002) Evolving phage vectors for cell targeted gene delivery. Curr Pharm Biotechnol 3:45–57PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Smith GP (1985) Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228:1315–1317PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Poul MA, Marks JD (1999) Targeted gene delivery to mammalian cells by filamentous bacteriophage. J Mol Biol 288:203–211PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Davidson BL, Harper SQ (2005) Viral delivery of recombinant short hairpin RNAs. Methods Enzymol 392:145–173PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Kay MA, Glorioso JC, Naldini L (2001) Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nat Med 7:33–40PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Di Giusto DL, Krishnan A, Li L, et al (2010) RNA-based gene therapy for HIV with lentiviral vector modified CD34 cells in patients undergoing transplantation for AIDS-related lymphoma. Issues Sci Transl Med 2(36): 36ra43Google Scholar
  20. 20.
    Thomas CE, Ehrhardt A, Kay MA (2003) Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet 4:346–358PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Gao G-P, Alvira MR, Wang L et al (2002) Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci U S A 99:11854–11859PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Daya S, Berns KI (2008) Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev 21:583–593PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Pack DW, Hoffman AS, Pun S et al (2005) Design and development of polymers for gene delivery. Nat Rev Drug Discov 4:581–593PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Mintzer MA, Simanek EE (2009) Nonviral vectors for gene delivery. Chem Rev 109:259–302PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Rosenberg SA, Restifo NP (2015) Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348:62–68PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    June CH, Riddell SR, Schumacher TN (2015) Adoptive cellular therapy: a race to the finish line. Sci Transl Med 7:280ps7PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Seow Y, Wood MJ (2009) Biological gene delivery vehicles: beyond viral vectors. Mol Ther 17:767–777PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Li S-D, Huang L (2006) Gene therapy progress and prospects: non-viral gene therapy by systemic delivery. Gene Ther 13:1313–1319PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Zimmermann TS, Lee ACH, Akinc A et al (2006) RNAi-mediated gene silencing in non-human primates. Nature 441:111–114PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Scherer LJ, Rossi JJ (2003) Approaches for the sequence-specific knockdown of mRNA. Nat Biotechnol 21:1457–1465PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Gonzalez H, Hwang SJ, Davis ME (1999) New class of polymers for the delivery of macromolecular therapeutics. Bioconjug Chem 10:1068–1074PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Liu Y, Wenning L, Lynch M (2004) New poly (D-glucaramidoamine) s induce DNA nanoparticle formation and efficient gene delivery into mammalian cells. J Am Chem Soc 126(24):7422–7423PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Park JS, Yi SW, Kim HJ et al (2016) Receptor-mediated gene delivery into human mesenchymal stem cells using hyaluronic acid-shielded polyethylenimine/pDNA nanogels. Carbohydr Polym 136:791–802PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Akinc A, Lynn DM, Anderson DG et al (2003) Parallel synthesis and biophysical characterization of a degradable polymer library for gene delivery. J Am Chem Soc 125:5316–5323PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Green JJ, Langer R, Anderson DG (2008) A combinatorial polymer library approach yields insight into nonviral gene delivery. Acc Chem Res 41:749–759PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Putnam D, Gentry CA, Pack DW et al (2001) Polymer-based gene delivery with low cytotoxicity by a unique balance of side-chain termini. Proc Natl Acad Sci U S A 98:1200–1205PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Oberli MA, Reichmuth AM, Dorkin JR et al (2017) Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy. Nano Lett 17:1326–1335PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Yu AC, Chen H, Chan D et al (2016) Scalable manufacturing of biomimetic moldable hydrogels for industrial applications. Proc Natl Acad Sci U S A 113:14255–14260PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Dahlman JE, Kauffman KJ, Xing Y et al (2017) Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics. Proc Natl Acad Sci U S A 114:2060–2065PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Whitehead KA, Langer R, Anderson DG (2009) Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov 8:129–138PubMedCrossRefGoogle Scholar
  41. 41.
    Hamilton AJ, Baulcombe DC (1999) A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 286:950–952PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Zamore PD, Tuschl T, Sharp PA et al (2000) RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101:25–33PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Han M-H, Goud S, Song L et al (2004) The Arabidopsis double-stranded RNA-binding protein HYL1 plays a role in microRNA-mediated gene regulation. Proc Natl Acad Sci U S A 101:1093–1098PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Iorio MV, Ferracin M, Liu C-G et al (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65:7065–7070PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Ling H, Fabbri M, Calin GA (2013) MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 12:847–865PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Roberts TC, Wood MJA (2013) Therapeutic targeting of non-coding RNAs. Essays Biochem 54:127–145PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Hobert O (2008) Gene regulation by transcription factors and microRNAs. Science 319:1785–1786PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Xia H, Mao Q, Paulson HL et al (2002) siRNA-mediated gene silencing in vitro and in vivo. Nat Biotechnol 20:1006–1010PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Morris KV, Chan SW-L, Jacobsen SE et al (2004) Small interfering RNA-induced transcriptional gene silencing in human cells. Science 305:1289–1292PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Meister G, Tuschl T (2004) Mechanisms of gene silencing by double-stranded RNA. Nature 431:343–349PubMedCrossRefGoogle Scholar
  51. 51.
    Chendrimada TP, Gregory RI, Kumaraswamy E et al (2005) TRBP recruits the dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436:740–744PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    McManus MT, Sharp PA (2002) Gene silencing in mammals by small interfering RNAs. Nat Rev Genet 3:737–747PubMedCrossRefGoogle Scholar
  53. 53.
    Liang X-H, Sun H, Nichols JG et al (2017) RNase H1-dependent antisense oligonucleotides are robustly active in directing RNA cleavage in both the cytoplasm and the nucleus. Mol Ther 25:2075–2092PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Nowotny M, Gaidamakov SA, Crouch RJ et al (2005) Crystal structures of RNase H bound to an RNA/DNA hybrid: substrate specificity and metal-dependent catalysis. Cell 121:1005–1016PubMedCrossRefGoogle Scholar
  55. 55.
    Inoue H, Hayase Y, Iwai S et al (1987) Sequence-dependent hydrolysis of RNA using modified oligonucleotide splints and RNase H. FEBS Lett 215:327–330PubMedCrossRefGoogle Scholar
  56. 56.
    Walder RY, Walder JA (1988) Role of RNase H in hybrid-arrested translation by antisense oligonucleotides. Proc Natl Acad Sci U S A 85:5011–5015PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Vickers TA, Koo S, Bennett CF et al (2003) Efficient reduction of target RNAs by small interfering RNA and RNase H-dependent antisense agents. A comparative analysis. J Biol Chem 278:7108–7118PubMedCrossRefGoogle Scholar
  58. 58.
    Bonham MA, Brown S, Boyd AL et al (1995) An assessment of the antisense properties of RNase H-competent and steric-blocking oligomers. Nucleic Acids Res 23:1197–1203PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Kole R, Krainer AR, Altman S (2012) RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat Rev Drug Discov 11:125–140PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Morcos PA (2007) Achieving targeted and quantifiable alteration of mRNA splicing with Morpholino oligos. Biochem Biophys Res Commun 358:521–527PubMedCrossRefGoogle Scholar
  61. 61.
    Woolf TM (1995) To Cleave or Not To Cleave: Ribozymes and Antisense. Antisense Res Dev 5:227–232PubMedCrossRefGoogle Scholar
  62. 62.
    Dias N, Dheur S, Nielsen PE et al (1999) Antisense PNA tridecamers targeted to the coding region of ha-ras mRNA arrest polypeptide chain elongation1. J Mol Biol 294:403–416PubMedCrossRefGoogle Scholar
  63. 63.
    Lennox KA, Behlke MA (2016) Cellular localization of long non-coding RNAs affects silencing by RNAi more than by antisense oligonucleotides. Nucleic Acids Res 44:863–877CrossRefGoogle Scholar
  64. 64.
    Lee JT (2012) Epigenetic regulation by long noncoding RNAs. Science 338:1435–1439PubMedCrossRefGoogle Scholar
  65. 65.
    Mercer TR, Mattick JS (2013) Structure and function of long noncoding RNAs in epigenetic regulation. Nat Struct Mol Biol 20:300–307PubMedCrossRefGoogle Scholar
  66. 66.
    Huarte M (2015) The emerging role of lncRNAs in cancer. Nat Med 21:1253–1261CrossRefGoogle Scholar
  67. 67.
    Kher G, Trehan S, Misra A (2011) 7- Antisense Oligonucleotides and RNA Interference. In: Misra A (ed) Challenges in delivery of therapeutic genomics and proteomics. Elsevier, London, pp 325–386CrossRefGoogle Scholar
  68. 68.
    Karikó K, Bhuyan P, Capodici J et al (2004) Exogenous siRNA mediates sequence-independent gene suppression by signaling through toll-like receptor 3. Cells Tissues Organs 177:132–138PubMedCrossRefGoogle Scholar
  69. 69.
    Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376PubMedCrossRefGoogle Scholar
  70. 70.
    Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384PubMedCrossRefGoogle Scholar
  71. 71.
    Nair JK, Attarwala H, Sehgal A et al (2017) Impact of enhanced metabolic stability on pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates. Nucleic Acids Res 45:10969–10977PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Sashital DG, Doudna JA (2010) Structural insights into RNA interference. Curr Opin Struct Biol 20:90–97PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Murante RS, Henricksen LA, Bambara RA (1998) Junction ribonuclease: an activity in Okazaki fragment processing. Proc Natl Acad Sci U S A 95:2244–2249PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Liu B, Hu J, Wang J et al (2017) Direct visualization of RNA-DNA primer removal from Okazaki fragments provides support for flap cleavage and exonucleolytic pathways in eukaryotic cells. J Biol Chem 292(12):4777–4788PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Qiu J, Qian Y, Frank P et al (1999) Saccharomyces cerevisiae RNase H(35) functions in RNA primer removal during lagging-strand DNA synthesis, most efficiently in cooperation with Rad27 nuclease. Mol Cell Biol 19:8361–8371PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Cerritelli SM, Crouch RJ (2009) Ribonuclease H: the enzymes in eukaryotes. FEBS J 276:1494–1505PubMedCrossRefGoogle Scholar
  77. 77.
    Kielpinski LJ, Hagedorn PH, Lindow M et al (2017) RNase H sequence preferences influence antisense oligonucleotide efficiency. Nucleic Acids Res 45:12932–12944PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Resina S, Kole R, Travo A et al (2007) Switching on transgene expression by correcting aberrant splicing using multi-targeting steric-blocking oligonucleotides. J Gene Med 9:498–510PubMedCrossRefGoogle Scholar
  79. 79.
    Owens DE 3rd, Peppas NA (2006) Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 307:93–102PubMedCrossRefGoogle Scholar
  80. 80.
    Liu Y, Li J, Shao K et al (2010) A leptin derived 30-amino-acid peptide modified pegylated poly-L-lysine dendrigraft for brain targeted gene delivery. Biomaterials 31:5246–5257PubMedCrossRefGoogle Scholar
  81. 81.
    Rosales C, Uribe-Querol E (2017) Phagocytosis: a fundamental process in immunity. Biomed Res Int 2017:9042851PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Sansonetti PJ (2000) Phagocytosis, a cell biology view. J Cell Sci 113:3355–3356Google Scholar
  83. 83.
    Aderem A (2003) Phagocytosis and the Inflammatory Response. J Infect Dis 187:S340–S345PubMedCrossRefGoogle Scholar
  84. 84.
    Czuprynski CJ (2016) Opsonization and Phagocytosis. In: Vohr H-W (ed) Encyclopedia of immunotoxicology. Springer, Berlin, Heidelberg, pp 674–676CrossRefGoogle Scholar
  85. 85.
    Choi HS, Liu W, Misra P et al (2007) Renal clearance of quantum dots. Nat Biotechnol 25:1165–1170PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Harris JM, Chess RB (2003) Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2:214–221PubMedCrossRefGoogle Scholar
  87. 87.
    Hatakeyama H, Akita H, Harashima H (2011) A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect: a strategy for overcoming the PEG dilemma. Adv Drug Deliv Rev 63:152–160PubMedCrossRefGoogle Scholar
  88. 88.
    Mishra S, Webster P, Davis ME (2004) PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. Eur J Cell Biol 83:97–111PubMedCrossRefGoogle Scholar
  89. 89.
    Suk JS, Xu Q, Kim N et al (2016) PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev 99:28–51PubMedCrossRefGoogle Scholar
  90. 90.
    Webber MJ, Appel EA, Vinciguerra B et al (2016) Supramolecular PEGylation of biopharmaceuticals. Proc Natl Acad Sci U S A 113:14189–14194PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Salvati A, Pitek AS, Monopoli MP et al (2013) Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat Nanotechnol 8:137–143PubMedCrossRefGoogle Scholar
  92. 92.
    Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46:6387–6392PubMedGoogle Scholar
  93. 93.
    Maeda H, Wu J, Sawa T et al (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65:271–284PubMedCrossRefGoogle Scholar
  94. 94.
    Fang J, Nakamura H, Maeda H (2011) The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 63:136–151PubMedCrossRefGoogle Scholar
  95. 95.
    Prabhakar U, Maeda H, Jain RK et al (2013) Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res 73:2412–2417PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Nakamura Y, Mochida A, Choyke PL et al (2016) Nanodrug delivery: is the enhanced permeability and retention effect sufficient for curing cancer? Bioconjug Chem 27:2225–2238PubMedCrossRefGoogle Scholar
  97. 97.
    Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987–989PubMedCrossRefGoogle Scholar
  98. 98.
    Ferretti S, Allegrini PR, Becquet MM et al (2009) Tumor interstitial fluid pressure as an early-response marker for anticancer therapeutics. Neoplasia 11:874–881PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Northey JJ, Przybyla L, Weaver VM (2017) tissue force programs cell fate and tumor aggression. Cancer Discov 7:1224–1237PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Greish K (2010) Enhanced permeability and retention (EPR) effect for anticancer nanomedicine drug targeting. Methods Mol Biol 624:25–37PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Doherty GJ, McMahon HT (2009) Mechanisms of endocytosis. Annu Rev Biochem 78:857–902PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Mishra S, Heidel JD, Webster P et al (2006) Imidazole groups on a linear, cyclodextrin-containing polycation produce enhanced gene delivery via multiple processes. J Control Release 116:179–191PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Varkouhi AK, Scholte M, Storm G et al (2011) Endosomal escape pathways for delivery of biologicals. J Control Release 151:220–228PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Stewart MP, Lorenz A, Dahlman J et al (2016) Challenges in carrier-mediated intracellular delivery: moving beyond endosomal barriers. Wiley Interdiscip Rev Nanomed Nanobiotechnol 8:465–478PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Akinc A, Thomas M, Klibanov AM et al (2005) Exploring polyethylenimine-mediated DNA transfection and the proton sponge hypothesis. J Gene Med 7:657–663PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Obermeier B, Daneman R, Ransohoff RM (2013) Development, maintenance and disruption of the blood-brain barrier. Nat Med 19:1584–1596PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Pardridge WM (2007) shRNA and siRNA delivery to the brain. Adv Drug Deliv Rev 59:141–152PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Pardridge WM (2002) Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov 1:131–139PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Georgieva JV, Hoekstra D, Zuhorn IS (2014) Smuggling drugs into the brain: an overview of ligands targeting transcytosis for drug delivery across the blood-brain barrier. Pharmaceutics 6:557–583PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Bertrand N, Wu J, Xu X et al (2014) Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev 66:2–25PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Karimi M, Ghasemi A, Sahandi Zangabad P et al (2016) Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems. Chem Soc Rev 45:1457–1501PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Blanco E, Shen H, Ferrari M (2015) Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol 33:941–951PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Schiffelers RM, Ansari A, Xu J et al (2004) Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res 32:e149PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Veiman K-L, Künnapuu K, Lehto T et al (2015) PEG shielded MMP sensitive CPPs for efficient and tumor specific gene delivery in vivo. J Control Release 209:238–247PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Kaul G, Amiji M (2005) Tumor-targeted gene delivery using poly(ethylene glycol)-modified gelatin nanoparticles: in vitro and in vivo studies. Pharm Res 22:951–961PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Hu Y, Haynes MT, Wang Y et al (2013) A Highly efficient synthetic vector: nonhydrodynamic delivery of DNA to hepatocyte nuclei in vivo. ACS Nano 7:5376–5384PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Rodriguez PL, Harada T, Christian DA et al (2013) Minimal “Self” peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles. Science 339:971–975PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Usman WM, Pham TC, Kwok YY et al (2018) Efficient RNA drug delivery using red blood cell extracellular vesicles. Nat Commun 9:2359PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Villa CH, Anselmo AC, Mitragotri S et al (2016) Red blood cells: supercarriers for drugs, biologicals, and nanoparticles and inspiration for advanced delivery systems. Adv Drug Deliv Rev 106:88–103PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Muzykantov VR (2010) Drug delivery by red blood cells: vascular carriers designed by mother nature. Expert Opin Drug Deliv 7:403–427PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Parodi A, Quattrocchi N, van de Ven AL et al (2013) Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nat Nanotechnol 8:61–68PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Hu Q, Sun W, Qian C et al (2015) Anticancer platelet-mimicking nanovehicles. Adv Mater 27:7043–7050PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Anselmo AC, Modery-Pawlowski CL, Menegatti S et al (2014) Platelet-like nanoparticles: mimicking shape, flexibility, and surface biology of platelets to target vascular injuries. ACS Nano 8:11243–11253PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Kraus M, Wolf B (1996) Implications of acidic tumor microenvironment for neoplastic growth and cancer treatment: a computer analysis. Tumour Biol 17:133–154PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Estrella V, Chen T, Lloyd M et al (2013) Acidity generated by the tumor microenvironment drives local invasion. Cancer Res 73:1524–1535PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Danhier F, Feron O, Préat V (2010) To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release 148:135–146PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Xia J, Tian H, Chen J et al (2016) pH-triggered sheddable shielding system for polycationic gene carriers. Polymers 8:141PubMedCentralCrossRefGoogle Scholar
  128. 128.
    Dimde M, Neumann F, Reisbeck F et al (2017) Defined pH-sensitive nanogels as gene delivery platform for siRNA mediated in vitro gene silencing. Biomater Sci 5:2328–2336PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Sethuraman VA, Na K, Bae YH (2006) pH-responsive sulfonamide/PEI system for tumor specific gene delivery: an in vitro study. Biomacromolecules 7:64–70PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Li H-J, Du J-Z, Liu J et al (2016) Smart superstructures with ultrahigh pH-sensitivity for targeting acidic tumor microenvironment: instantaneous size switching and improved tumor penetration. ACS Nano 10:6753–6761PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Teotia AK, Sami H, Kumar A (2015) 1- Thermo-responsive polymers: structure and design of smart materials. In: zhang z (ed) switchable and responsive surfaces and materials for biomedical applications. Woodhead Publishing, Oxford, pp 3–43CrossRefGoogle Scholar
  132. 132.
    Hoogenboom R (2014) Temperature-responsive polymers: properties, synthesis and applications. In: Aguilar MR, San Román J (eds) Smart polymers and their applications. Woodhead Publishing, Oxford, pp 15–44CrossRefGoogle Scholar
  133. 133.
    Schmaljohann D (2006) Thermo- and pH-responsive polymers in drug delivery. Adv Drug Deliv Rev 58:1655–1670PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Twaites BR, de las HAC, Cunliffe D et al (2004) Thermo and pH responsive polymers as gene delivery vectors: effect of polymer architecture on DNA complexation in vitro. J Control Release 97:551–566PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Mykhaylyk O, Zelphati O, Rosenecker J et al (2008) siRNA delivery by magnetofection. Curr Opin Mol Ther 10:493–505PubMedPubMedCentralGoogle Scholar
  136. 136.
    Scherer F, Anton M, Schillinger U et al (2002) Magnetofection: enhancing and targeting gene delivery by magnetic force in vitro and in vivo. Gene Ther 9:102–109PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Bae KH, Lee K, Lee J et al (2011) Surface functionalized hollow manganese oxide nanoparticles for cancer targeted siRNA delivery and magnetic resonance imaging. J Control Release 152(Suppl 1):e133–e134PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Lee JH, Lee K, Moon SH et al (2009) All-in-one target-cell-specific magnetic nanoparticles for simultaneous molecular imaging and siRNA delivery. Angew Chem Int Ed Engl 48(23):4174–4179PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Medarova Z, Pham W, Farrar C et al (2007) In vivo imaging of siRNA delivery and silencing in tumors. Nat Med 13:372–377PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Torchilin VP (2014) Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat Rev Drug Discov 13:813–827PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Kelley EG, Albert JNL, Sullivan MO et al (2013) Stimuli-responsive copolymer solution and surface assemblies for biomedical applications. Chem Soc Rev 42:7057–7071PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Shen Y, Fu X, Fu W et al (2015) Biodegradable stimuli-responsive polypeptide materials prepared by ring opening polymerization. Chem Soc Rev 44:612–622PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Becker AL, Orlotti NI, Folini M et al (2011) Redox-active polymer microcapsules for the delivery of a survivin-specific siRNA in prostate cancer cells. ACS Nano 5:1335–1344PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Han L, Tang C, Yin C (2015) Dual-targeting and pH/redox-responsive multi-layered nanocomplexes for smart co-delivery of doxorubicin and siRNA. Biomaterials 60:42–52PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Zhuang Y, Deng H, Su Y et al (2016) Aptamer-functionalized and backbone redox-responsive hyperbranched polymer for targeted drug delivery in cancer therapy. Biomacromolecules 17:2050–2062PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Srinivasarao M, Low PS (2017) Ligand-targeted drug delivery. Chem Rev 117:12133–12164PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Yang T, Li B, Qi S et al (2014) Co-delivery of doxorubicin and Bmi1 siRNA by folate receptor targeted liposomes exhibits enhanced anti-tumor effects in vitro and in vivo. Theranostics 4:1096–1111PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Yang C, Gao S, Kjems J (2014) Folic acid conjugated chitosan for targeted delivery of siRNA to activated macrophages in vitro and in vivo. J Mater Chem B Mater Biol Med 2:8608–8615CrossRefGoogle Scholar
  149. 149.
    Lee H, Lytton-Jean AKR, Chen Y et al (2012) Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery. Nat Nanotechnol 7:389–393PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Venturelli L, Nappini S, Bulfoni M et al (2016) Glucose is a key driver for GLUT1-mediated nanoparticles internalization in breast cancer cells. Sci Rep 6:21629PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Murata J-I, Ohya Y, Ouchi T (1997) Design of quaternary chitosan conjugate having antennary galactose residues as a gene delivery tool. Carbohydr Polym 32:105–109CrossRefGoogle Scholar
  152. 152.
    Kim TH, Kim SI, Akaike T et al (2005) Synergistic effect of poly(ethylenimine) on the transfection efficiency of galactosylated chitosan/DNA complexes. J Control Release 105:354–366PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Thapa B, Kumar P, Zeng H et al (2015) Asialoglycoprotein receptor-mediated gene delivery to hepatocytes using galactosylated polymers. Biomacromolecules 16:3008–3020PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Zacco E, Hütter J, Heier JL et al (2015) Tailored presentation of carbohydrates on a coiled coil-based scaffold for asialoglycoprotein receptor targeting. ACS Chem Biol 10:2065–2072PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Matsuda S, Keiser K, Nair JK et al (2015) siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes. ACS Chem Biol 10:1181–1187PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    Nair JK, Willoughby JLS, Chan A et al (2014) Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc 136:16958–16961PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Rajeev KG, Nair JK, Jayaraman M et al (2015) Hepatocyte-specific delivery of siRNAs conjugated to novel non-nucleosidic trivalent N-acetylgalactosamine elicits robust gene silencing in vivo. Chembiochem 16:903–908PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Zhao L, Liu M, Wang J et al (2015) Chondroitin sulfate-based nanocarriers for drug/gene delivery. Carbohydr Polym 133:391–399PubMedCrossRefPubMedCentralGoogle Scholar
  159. 159.
    Xia W, Low PS (2010) Folate-targeted therapies for cancer. J Med Chem 53:6811–6824PubMedCrossRefPubMedCentralGoogle Scholar
  160. 160.
    Guo S, Huang F, Guo P (2006) Construction of folate-conjugated pRNA of bacteriophage phi29 DNA packaging motor for delivery of chimeric siRNA to nasopharyngeal carcinoma cells. Gene Ther 13:814–820PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Thomas M, Kularatne SA, Qi L et al (2009) Ligand-targeted delivery of small interfering RNAs to malignant cells and tissues. Ann N Y Acad Sci 1175:32–39PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Shim MS, Kwon YJ (2010) Efficient and targeted delivery of siRNA in vivo: In vivo siRNA delivery. FEBS J 277:4814–4827PubMedCrossRefGoogle Scholar
  163. 163.
    York AW, Zhang Y, Holley AC et al (2009) Facile synthesis of multivalent folate-block copolymer conjugates via aqueous RAFT polymerization: targeted delivery of siRNA and subsequent gene suppression. Biomacromolecules 10:936–943PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Arima H, Yoshimatsu A, Ikeda H et al (2012) Folate-PEG-appended dendrimer conjugate with α-cyclodextrin as a novel cancer cell-selective siRNA delivery carrier. Mol Pharm 9:2591–2604PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Fernandes JC, Qiu X, Winnik FM et al (2012) Low molecular weight chitosan conjugated with folate for siRNA delivery in vitro: optimization studies. Int J Nanomedicine 7:5833–5845PubMedPubMedCentralGoogle Scholar
  166. 166.
    York AW, Huang F, McCormick CL (2010) Rational design of targeted cancer therapeutics through the multiconjugation of folate and cleavable siRNA to RAFT-synthesized (HPMA-s-APMA) copolymers. Biomacromolecules 11:505–514PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Roggenbuck D, Mytilinaiou MG, Lapin SV et al (2012) Asialoglycoprotein receptor (ASGPR): a peculiar target of liver-specific autoimmunity. Auto Immun Highlights 3:119–125PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Nishikawa M, Takemura S, Takakura Y et al (1998) Targeted delivery of plasmid DNA to hepatocytes in vivo: optimization of the pharmacokinetics of plasmid DNA/galactosylated poly(L-lysine) complexes by controlling their physicochemical properties. J Pharmacol Exp Ther 287:408–415PubMedGoogle Scholar
  169. 169.
    Lepenies B, Lee J, Sonkaria S (2013) Targeting C-type lectin receptors with multivalent carbohydrate ligands. Adv Drug Deliv Rev 65:1271–1281PubMedCrossRefPubMedCentralGoogle Scholar
  170. 170.
    Medina SH, Tekumalla V, Chevliakov MV et al (2011) N-acetylgalactosamine-functionalized dendrimers as hepatic cancer cell-targeted carriers. Biomaterials 32:4118–4129PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Rouet R, Thuma BA, Roy MD et al (2018) Receptor-mediated delivery of CRISPR-Cas9 endonuclease for cell-type-specific gene editing. J Am Chem Soc 140:6596–6603PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Nakagawa O, Ming X, Huang L et al (2010) Targeted intracellular delivery of antisense oligonucleotides via conjugation with small-molecule ligands. J Am Chem Soc 132:8848–8849PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Tai W, Li J, Corey E et al (2018) A ribonucleoprotein octamer for targeted siRNA delivery. Nat Biomed Eng 2:326–337PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Lee JB, Zhang K, Tam YYC et al (2016) A Glu-urea-Lys ligand-conjugated lipid nanoparticle/siRNA system inhibits androgen receptor expression in vivo. Mol Ther Nucleic Acids 5:e348PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Langut Y, Talhami A, Mamidi S et al (2017) PSMA-targeted polyinosine/polycytosine vector induces prostate tumor regression and invokes an antitumor immune response in mice. Proc Natl Acad Sci U S A 114:13655–13660PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Li Y, Xu X-L, Zhao D et al (2015) TLR3 ligand poly IC attenuates reactive astrogliosis and improves recovery of rats after focal cerebral ischemia. CNS Neurosci Ther 21:905–913PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Chen J, Gamou S, Takayanagi A et al (1994) A novel gene delivery system using EGF receptor-mediated endocytosis. FEBS Lett 338:167–169PubMedCrossRefGoogle Scholar
  178. 178.
    Yu H, Nie Y, Dohmen C et al (2011) Epidermal growth factor–PEG functionalized PAMAM-Pentaethylenehexamine dendron for targeted gene delivery produced by click chemistry. Biomacromolecules 12:2039–2047PubMedCrossRefGoogle Scholar
  179. 179.
    Shir A, Ogris M, Wagner E et al (2006) EGF receptor-targeted synthetic double-stranded RNA eliminates glioblastoma, breast cancer, and adenocarcinoma tumors in mice. PLoS Med 3:e6PubMedCrossRefGoogle Scholar
  180. 180.
    Schaffert D, Kiss M, Rödl W et al (2011) Poly(I:C)-mediated tumor growth suppression in EGF-receptor overexpressing tumors using EGF-polyethylene glycol-linear polyethylenimine as carrier. Pharm Res 28:731–741PubMedCrossRefGoogle Scholar
  181. 181.
    Jandl JH, Inman JK, Simmons RL et al (1959) Transfer of iron from serum iron-binding protein to human reticulocytes. J Clin Invest 38:161–185PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Ponka P (2004) Iron and cell proliferation: another piece of the puzzle. Blood 104:2620–2621CrossRefGoogle Scholar
  183. 183.
    Le NTV, Richardson DR (2002) The role of iron in cell cycle progression and the proliferation of neoplastic cells. Biochim Biophys Acta 1603:31–46PubMedGoogle Scholar
  184. 184.
    Koppu S, Oh YJ, Edrada-Ebel R et al (2010) Tumor regression after systemic administration of a novel tumor-targeted gene delivery system carrying a therapeutic plasmid DNA. J Control Release 143:215–221PubMedCrossRefGoogle Scholar
  185. 185.
    Li H, Qian ZM (2002) Transferrin/transferrin receptor-mediated drug delivery. Med Res Rev 22:225–250PubMedCrossRefGoogle Scholar
  186. 186.
    Pun SH, Tack F, Bellocq NC et al (2004) Targeted delivery of RNA-cleaving DNA enzyme (DNAzyme) to tumor tissue by transferrin-modified, cyclodextrin-based particles. Cancer Biol Ther 3:641–650PubMedCrossRefGoogle Scholar
  187. 187.
    Cardoso ALC, Simões S, de Almeida LP et al (2007) siRNA delivery by a transferrin-associated lipid-based vector: a non-viral strategy to mediate gene silencing. J Gene Med 9:170–183PubMedCrossRefGoogle Scholar
  188. 188.
    Tietze N, Pelisek J, Philipp A et al (2008) Induction of apoptosis in murine neuroblastoma by systemic delivery of transferrin-shielded siRNA polyplexes for downregulation of Ran. Oligonucleotides 18:161–174PubMedCrossRefGoogle Scholar
  189. 189.
    Yang X, Koh CG, Liu S et al (2009) Transferrin receptor-targeted lipid nanoparticles for delivery of an antisense oligodeoxyribonucleotide against Bcl-2. Mol Pharm 6:221–230PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Wiley DT, Webster P, Gale A et al (2013) Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor. Proc Natl Acad Sci U S A 110:8662–8667PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Huang R-Q, Qu Y-H, Ke W-L et al (2007) Efficient gene delivery targeted to the brain using a transferrin-conjugated polyethyleneglycol-modified polyamidoamine dendrimer. FASEB J 21:1117–1125PubMedCrossRefGoogle Scholar
  192. 192.
    Wei L, Guo X-Y, Yang T et al (2016) Brain tumor-targeted therapy by systemic delivery of siRNA with Transferrin receptor-mediated core-shell nanoparticles. Int J Pharm 510:394–405PubMedCrossRefGoogle Scholar
  193. 193.
    Firer MA, Gellerman G (2012) Targeted drug delivery for cancer therapy: the other side of antibodies. J Hematol Oncol 5:70PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Ngamcherdtrakul W, Morry J, Gu S et al (2015) Cationic polymer modified mesoporous silica nanoparticles for targeted SiRNA delivery to HER2+ breast cancer. Adv Funct Mater 25:2646–2659PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Wang CY, Huang L (1987) pH-sensitive immunoliposomes mediate target-cell-specific delivery and controlled expression of a foreign gene in mouse. Proc Natl Acad Sci U S A 84:7851–7855PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Guo J, Russell EG, Darcy R et al (2017) Antibody-targeted cyclodextrin-based nanoparticles for siRNA delivery in the treatment of acute myeloid leukemia: physicochemical characteristics, in vitro mechanistic studies, and ex vivo patient derived therapeutic efficacy. Mol Pharm 14:940–952PubMedCrossRefGoogle Scholar
  197. 197.
    Lee J, Yun K-S, Choi CS et al (2012) T cell-specific siRNA delivery using antibody-conjugated chitosan nanoparticles. Bioconjug Chem 23:1174–1180PubMedCrossRefGoogle Scholar
  198. 198.
    Chen Y, Zhu X, Zhang X et al (2010) Nanoparticles modified with tumor-targeting scFv deliver siRNA and miRNA for cancer therapy. Mol Ther 18:1650–1656PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Bäumer S, Bäumer N, Appel N et al (2015) Antibody-mediated delivery of anti-KRAS-siRNA in vivo overcomes therapy resistance in colon cancer. Clin Cancer Res 21:1383–1394PubMedCrossRefGoogle Scholar
  200. 200.
    Di Paolo D, Brignole C, Pastorino F et al (2011) Neuroblastoma-targeted nanoparticles entrapping siRNA specifically knockdown ALK. Mol Ther 19:1131–1140PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Song E, Zhu P, Lee S-K et al (2005) Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol 23:709–717PubMedCrossRefPubMedCentralGoogle Scholar
  202. 202.
    Sugo T, Terada M, Oikawa T et al (2016) Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles. J Control Release 237:1–13PubMedCrossRefPubMedCentralGoogle Scholar
  203. 203.
    Laroui H, Viennois E, Xiao B et al (2014) Fab’-bearing siRNA TNFα-loaded nanoparticles targeted to colonic macrophages offer an effective therapy for experimental colitis. J Control Release 186:41–53PubMedCrossRefPubMedCentralGoogle Scholar
  204. 204.
    Gao J, Liu W, Xia Y et al (2011) The promotion of siRNA delivery to breast cancer overexpressing epidermal growth factor receptor through anti-EGFR antibody conjugation by immunoliposomes. Biomaterials 32:3459–3470PubMedCrossRefPubMedCentralGoogle Scholar
  205. 205.
    Lu H, Wang D, Kazane S et al (2013) Site-specific antibody-polymer conjugates for siRNA delivery. J Am Chem Soc 135:13885–13891PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Kumar P, Ban H-S, Kim S-S et al (2008) T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell 134:577–586PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Derfus AM, Chen AA, Min D-H et al (2007) Targeted quantum dot conjugates for siRNA delivery. Bioconjug Chem 18:1391–1396PubMedCrossRefGoogle Scholar
  208. 208.
    Liu Y, Huang R, Han L et al (2009) Brain-targeting gene delivery and cellular internalization mechanisms for modified rabies virus glycoprotein RVG29 nanoparticles. Biomaterials 30:4195–4202PubMedCrossRefGoogle Scholar
  209. 209.
    Ren J, Shen S, Wang D et al (2012) The targeted delivery of anticancer drugs to brain glioma by PEGylated oxidized multi-walled carbon nanotubes modified with angiopep-2. Biomaterials 33:3324–3333PubMedCrossRefGoogle Scholar
  210. 210.
    Shao K, Huang R, Li J et al (2010) Angiopep-2 modified PE-PEG based polymeric micelles for amphotericin B delivery targeted to the brain. J Control Release 147:118–126PubMedCrossRefPubMedCentralGoogle Scholar
  211. 211.
    Gao H, Zhang S, Cao S et al (2014) Angiopep-2 and activatable cell-penetrating peptide dual-functionalized nanoparticles for systemic glioma-targeting delivery. Mol Pharm 11:2755–2763PubMedCrossRefPubMedCentralGoogle Scholar
  212. 212.
    Huile G, Shuaiqi P, Zhi Y et al (2011) A cascade targeting strategy for brain neuroglial cells employing nanoparticles modified with angiopep-2 peptide and EGFP-EGF1 protein. Biomaterials 32:8669–8675PubMedCrossRefPubMedCentralGoogle Scholar
  213. 213.
    Deshane J, Garner CC, Sontheimer H (2003) Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J Biol Chem 278:4135–4144PubMedCrossRefPubMedCentralGoogle Scholar
  214. 214.
    Veiseh O, Kievit FM, Fang C et al (2010) Chlorotoxin bound magnetic nanovector tailored for cancer cell targeting, imaging, and siRNA delivery. Biomaterials 31:8032–8042PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Costa PM, Cardoso AL, Mendonça LS et al (2013) Tumor-targeted Chlorotoxin-coupled nanoparticles for nucleic acid delivery to glioblastoma cells: a promising system for glioblastoma treatment. Mol Ther Nucleic Acids 2:e100PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Kievit FM, Veiseh O, Fang C et al (2010) Chlorotoxin labeled magnetic nanovectors for targeted gene delivery to glioma. ACS Nano 4:4587–4594PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Huang R, Ke W, Han L et al (2011) Targeted delivery of chlorotoxin-modified DNA-loaded nanoparticles to glioma via intravenous administration. Biomaterials 32:2399–2406PubMedCrossRefPubMedCentralGoogle Scholar
  218. 218.
    Wei X, Zhan C, Chen X et al (2014) Retro-inverso isomer of Angiopep-2: a stable d-peptide ligand inspires brain-targeted drug delivery. Mol Pharm 11:3261–3268PubMedCrossRefPubMedCentralGoogle Scholar
  219. 219.
    Wei X, Zhan C, Shen Q et al (2015) A D-peptide ligand of nicotine acetylcholine receptors for brain-targeted drug delivery. Angew Chem Int Ed Engl 127:3066–3070CrossRefGoogle Scholar
  220. 220.
    Li Z, Zhao R, Wu X et al (2005) Identification and characterization of a novel peptide ligand of epidermal growth factor receptor for targeted delivery of therapeutics. FASEB J 19:1978–1985PubMedCrossRefPubMedCentralGoogle Scholar
  221. 221.
    Lo A, Lin C-T, Wu H-C (2008) Hepatocellular carcinoma cell-specific peptide ligand for targeted drug delivery. Mol Cancer Ther 7:579–589PubMedCrossRefPubMedCentralGoogle Scholar
  222. 222.
    Kortylewski M, Swiderski P, Herrmann A et al (2009) In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat Biotechnol 27:925–932PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Zhang Q, Hossain DMS, Nechaev S et al (2013) TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo. Blood 121:1304–1315PubMedPubMedCentralCrossRefGoogle Scholar
  224. 224.
    Ni X, Castanares M, Mukherjee A et al (2011) Nucleic acid aptamers: clinical applications and promising new horizons. Curr Med Chem 18:4206–4214PubMedPubMedCentralCrossRefGoogle Scholar
  225. 225.
    Keefe AD, Pai S, Ellington A (2010) Aptamers as therapeutics. Nat Rev Drug Discov 9:537–550PubMedCrossRefPubMedCentralGoogle Scholar
  226. 226.
    Röthlisberger P, Hollenstein M (2018) Aptamer chemistry. Adv Drug Deliv Rev 134:3–21PubMedCrossRefPubMedCentralGoogle Scholar
  227. 227.
    Liao J, Liu B, Liu J et al (2015) Cell-specific aptamers and their conjugation with nanomaterials for targeted drug delivery. Expert Opin Drug Deliv 12:493–506PubMedCrossRefPubMedCentralGoogle Scholar
  228. 228.
    Zhu G, Niu G, Chen X (2015) Aptamer-drug conjugates. Bioconjug Chem 26:2186–2197PubMedPubMedCentralCrossRefGoogle Scholar
  229. 229.
    Blind M, Blank M (2015) Aptamer selection technology and recent advances. Mol Ther Nucleic Acids 4:e223PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    Velez TE, Singh J, Xiao Y et al (2012) Systematic evaluation of the dependence of deoxyribozyme catalysis on random region length. ACS Comb Sci 14:680–687PubMedPubMedCentralCrossRefGoogle Scholar
  231. 231.
    Kwon YS, Ahmad Raston NH, Gu MB (2014) An ultra-sensitive colorimetric detection of tetracyclines using the shortest aptamer with highly enhanced affinity. Chem Commun 50:40–42CrossRefGoogle Scholar
  232. 232.
    Li Y, Geyer CR, Sen D (1996) Recognition of anionic porphyrins by DNA aptamers. Biochemistry 35:6911–6922PubMedCrossRefPubMedCentralGoogle Scholar
  233. 233.
    Jiang F, Liu B, Lu J et al (2015) Progress and challenges in developing aptamer-functionalized targeted drug delivery systems. Int J Mol Sci 16:23784–23822PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Hirao I, Kimoto M, Lee KH (2018) DNA aptamer generation by ExSELEX using genetic alphabet expansion with a mini-hairpin DNA stabilization method. Biochimie 145:15–21PubMedCrossRefPubMedCentralGoogle Scholar
  235. 235.
    Esposito CL, Cerchia L, Catuogno S et al (2014) Multifunctional aptamer-miRNA conjugates for targeted cancer therapy. Mol Ther 22:1151–1163PubMedPubMedCentralCrossRefGoogle Scholar
  236. 236.
    Kim JK, Choi K-J, Lee M et al (2012) Molecular imaging of a cancer-targeting theragnostics probe using a nucleolin aptamer- and microRNA-221 molecular beacon-conjugated nanoparticle. Biomaterials 33:207–217PubMedCrossRefPubMedCentralGoogle Scholar
  237. 237.
    Zhou J, Li H, Li S et al (2008) Novel dual inhibitory function aptamer–siRNA delivery system for HIV-1 therapy. Mol Ther 16:1481–1489PubMedPubMedCentralCrossRefGoogle Scholar
  238. 238.
    Chu TC, Twu KY, Ellington AD et al (2006) Aptamer mediated siRNA delivery. Nucleic Acids Res 34:e73PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    Yoon S, Huang K-W, Reebye V et al (2016) Targeted delivery of C/EBPα -saRNA by pancreatic ductal adenocarcinoma (PDAC)-specific RNA aptamers Inhibits tumor growth in vivo. Mol Ther 24(6):1106–1116PubMedPubMedCentralCrossRefGoogle Scholar
  240. 240.
    Yoon S, Huang K-W, Reebye V et al (2017) Aptamer-drug conjugates of active metabolites of nucleoside analogs and cytotoxic agents inhibit pancreatic tumor cell growth. Mol Ther Nucleic Acids 6:80–88PubMedCrossRefPubMedCentralGoogle Scholar
  241. 241.
    Zhou J, Preston Neff C, Swiderski P et al (2013) Functional in vivo delivery of multiplexed anti-HIV-1 siRNAs via a chemically synthesized aptamer with a sticky bridge. Mol Ther 21:192–200PubMedCrossRefPubMedCentralGoogle Scholar
  242. 242.
    Zhou J, Li H, Zhang J et al (2011) Development of cell-type specific anti-HIV gp120 aptamers for siRNA delivery. In: J Vis ExpGoogle Scholar
  243. 243.
    Zhou J, Lazar D, Li H et al (2018) Receptor-targeted aptamer-siRNA conjugate-directed transcriptional regulation of HIV-1. Theranostics 8:1575–1590PubMedPubMedCentralCrossRefGoogle Scholar
  244. 244.
    Shangguan D, Li Y, Tang Z et al (2006) Aptamers evolved from live cells as effective molecular probes for cancer study. Proc Natl Acad Sci U S A 103:11838–11843PubMedPubMedCentralCrossRefGoogle Scholar
  245. 245.
    Wu Y, Zhang L, Cui C et al (2018) Enhanced targeted gene transduction: AAV2 vectors conjugated to multiple aptamers via reducible disulfide linkages. J Am Chem Soc 140:2–5PubMedCrossRefPubMedCentralGoogle Scholar
  246. 246.
    Lakhin AV, Kazakov AA, Makarova AV et al (2012) Isolation and characterization of high affinity aptamers against DNA polymerase iota. Nucleic Acid Ther 22:49–57PubMedCrossRefPubMedCentralGoogle Scholar
  247. 247.
    Lakhin AV, Tarantul VZ, Gening LV (2013) Aptamers: problems, solutions and prospects. Acta Naturae 5:34–43PubMedPubMedCentralCrossRefGoogle Scholar
  248. 248.
    Catuogno S, Esposito CL (2017) Aptamer cell-based selection: overview and advances. Biomedicines 5(3). pii: E49Google Scholar
  249. 249.
    Pranatharthiharan S, Patel MD, Malshe VC et al (2017) Asialoglycoprotein receptor targeted delivery of doxorubicin nanoparticles for hepatocellular carcinoma. Drug Deliv 24:20–29PubMedCrossRefPubMedCentralGoogle Scholar
  250. 250.
    Van Der Heijden JW, Oerlemans R, Dijkmans BAC et al (2009) Folate receptor β as a potential delivery route for novel folate antagonists to macrophages in the synovial tissue of rheumatoid arthritis patients. Arthritis Rheum 60:12–21PubMedCrossRefPubMedCentralGoogle Scholar
  251. 251.
    Tsuneyoshi Y, Tanaka M, Nagai T et al (2012) Functional folate receptor beta-expressing macrophages in osteoarthritis synovium and their M1/M2 expression profiles. Scand J Rheumatol 41:132–140PubMedCrossRefPubMedCentralGoogle Scholar
  252. 252.
    Nakashima-Matsushita N, Homma T, Yu S et al (1999) Selective expression of folate receptor β and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis. Arthritis Rheum 42:1609–1616PubMedCrossRefPubMedCentralGoogle Scholar
  253. 253.
    Parker N, Turk MJ, Westrick E et al (2005) Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal Biochem 338:284–293PubMedCrossRefPubMedCentralGoogle Scholar
  254. 254.
    Rifai N, Gillette MA, Carr SA (2006) Protein biomarker discovery and validation: the long and uncertain path to clinical utility. Nat Biotechnol 24:971–983PubMedCrossRefPubMedCentralGoogle Scholar
  255. 255.
    Srinivasarao M, Galliford CV, Low PS (2015) Principles in the design of ligand-targeted cancer therapeutics and imaging agents. Nat Rev Drug Discov 14:203–219PubMedCrossRefPubMedCentralGoogle Scholar
  256. 256.
    Maxfield FR, McGraw TE (2004) Endocytic recycling. Nat Rev Mol Cell Biol 5:121–132PubMedCrossRefPubMedCentralGoogle Scholar
  257. 257.
    Bareford LM, Swaan PW (2007) Endocytic mechanisms for targeted drug delivery. Adv Drug Deliv Rev 59:748–758PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Pierschbacher MD, Ruoslahti E (1984) Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature 309:30–33PubMedCrossRefPubMedCentralGoogle Scholar
  259. 259.
    Alam MR, Ming X, Fisher M et al (2011) Multivalent cyclic RGD conjugates for targeted delivery of small interfering RNA. Bioconjug Chem 22:1673–1681PubMedPubMedCentralCrossRefGoogle Scholar
  260. 260.
    Kong L, Alves CS, Hou W et al (2015) RGD peptide-modified dendrimer-entrapped gold nanoparticles enable highly efficient and specific gene delivery to stem cells. ACS Appl Mater Interfaces 7:4833–4843PubMedCrossRefPubMedCentralGoogle Scholar
  261. 261.
    Pritchard LK, Spencer DIR, Royle L et al (2015) Glycan clustering stabilizes the mannose patch of HIV-1 and preserves vulnerability to broadly neutralizing antibodies. Nat Commun 6:7479PubMedPubMedCentralCrossRefGoogle Scholar
  262. 262.
    Sanders RW, Venturi M, Schiffner L et al (2002) The mannose-dependent epitope for neutralizing antibody 2G12 on human immunodeficiency virus type 1 glycoprotein gp120. J Virol 76:7293–7305PubMedPubMedCentralCrossRefGoogle Scholar
  263. 263.
    Raska M, Takahashi K, Czernekova L et al (2010) Glycosylation patterns of HIV-1 gp120 depend on the type of expressing cells and affect antibody recognition. J Biol Chem 285:20860–20869PubMedPubMedCentralCrossRefGoogle Scholar
  264. 264.
    Donkor DA, Bhakta V, Eltringham-Smith LJ et al (2017) Selection and characterization of a DNA aptamer inhibiting coagulation factor XIa. Sci Rep 7:2102PubMedPubMedCentralCrossRefGoogle Scholar
  265. 265.
    Seiwert SD, Stines Nahreini T, Aigner S et al (2000) RNA aptamers as pathway-specific MAP kinase inhibitors. Chem Biol 7:833–843PubMedCrossRefPubMedCentralGoogle Scholar
  266. 266.
    Zhou J, Rossi JJ, Shum KT (2015) Methods for assembling B-cell lymphoma specific and internalizing aptamer-siRNA nanoparticles via the sticky bridge. Methods Mol Biol 1297:169–185PubMedCrossRefPubMedCentralGoogle Scholar
  267. 267.
    Chan DPY, Deleavey GF, Owen SC et al (2013) Click conjugated polymeric immuno-nanoparticles for targeted siRNA and antisense oligonucleotide delivery. Biomaterials 34:8408–8415PubMedCrossRefPubMedCentralGoogle Scholar
  268. 268.
    Taratula O, Garbuzenko OB, Kirkpatrick P et al (2009) Surface-engineered targeted PPI dendrimer for efficient intracellular and intratumoral siRNA delivery. J Control Release 140:284–293PubMedPubMedCentralCrossRefGoogle Scholar
  269. 269.
    Kim E, Jung Y, Choi H et al (2010) Prostate cancer cell death produced by the co-delivery of Bcl-xL shRNA and doxorubicin using an aptamer-conjugated polyplex. Biomaterials 31:4592–4599PubMedCrossRefPubMedCentralGoogle Scholar
  270. 270.
    Kim HA, Nam K, Kim SW (2014) Tumor targeting RGD conjugated bio-reducible polymer for VEGF siRNA expressing plasmid delivery. Biomaterials 35:7543–7552PubMedPubMedCentralCrossRefGoogle Scholar
  271. 271.
    Wu X, Ding B, Gao J et al (2011) Second-generation aptamer-conjugated PSMA-targeted delivery system for prostate cancer therapy. Int J Nanomed 6:1747–1756Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Xin Xia
    • 1
  • Nicolette Pollock
    • 1
  • Jiehua Zhou
    • 1
  • John Rossi
    • 1
    Email author
  1. 1.Department of Molecular and Cellular BiologyBeckman Research InstituteCity of Hope, DuarteUSA

Personalised recommendations