REVIEW ARTICLE

Design of nanocarriers for efficient cellular uptake and endosomal release of small molecule and nucleic acid drugs: learning from virus

  • Vaibhav Mundra ,
  • Ram I. Mahato
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  • Department of Pharmaceutical Sciences, University of Nebraska Medical Center (UNMC), Omaha, NE 68198-6025, USA

Received date: 14 Sep 2014

Accepted date: 02 Nov 2014

Published date: 14 Jan 2015

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

Abstract

There are many challenges in developing efficient and target specific delivery systems of small molecule and nucleic acid drugs. Cell membrane presents one of the major barriers for the penetration of hydrophilic macromolecules across the plasma membrane. Nanocarriers have been designed to enhance their cellular uptake via endocytosis but following their cellular uptake, endosomal escape is the rate limiting step which restricts the value associated with the enhanced uptake by nanocarriers. Viruses are an excellent model for efficient cytosolic delivery by nanocarriers. Viruses exploit intracellular cues to release the genome to cytosol. In this review, we first discuss different endocytic uptake pathways and endosomal escape mechanisms. We then summarize the existing tools for studying the intracellular trafficking of nanocarriers. Finally, we highlight the important design elements of recent virus-based nanocarriers for efficient cellular uptake and endosomal escape.

Cite this article

Vaibhav Mundra , Ram I. Mahato . Design of nanocarriers for efficient cellular uptake and endosomal release of small molecule and nucleic acid drugs: learning from virus[J]. Frontiers of Chemical Science and Engineering, 2014 , 8(4) : 387 -404 . DOI: 10.1007/s11705-014-1457-3

Acknowledgements

The National Institutes of Health (1R01EB017853), Fred and Pamela Buffet Cancer Center and Cattlemen’s Ball of Nebraska, Inc. are duly acknowledged for providing financial support for this work. We also acknowledge the Faculty Start-up fund to Ram Mahato from the University of Nebraska Medical Center.
1
Petros R A, DeSimone J M. Strategies in the design of nanoparticles for therapeutic applications. Nature Reviews. Drug Discovery, 2010, 9(8): 615–627

2
Kim S, Kim J H, Jeon O, Kwon I C, Park K. Engineered polymers for advanced drug delivery. European Journal of Pharmaceutics and Biopharmaceutics, 2009, 71(3): 420–430

3
Mahato R I, Rolland A, Tomlinson E. Cationic lipid-based gene delivery systems: Pharmaceutical perspectives. Pharmaceutical Research, 1997, 14(7): 853–859

4
Mahato R I. Water insoluble and soluble lipids for gene delivery. Advanced Drug Delivery Reviews, 2005, 57(5): 699–712

5
Al-Dosari M S, Gao X. Nonviral gene delivery: Principle, limitations, and recent progress. The AAPS Journal, 2009, 11(4): 671–681

6
Mahato R I, Takakura Y, Hashida M. Nonviral vectors for in vivo gene delivery: Physicochemical and pharmacokinetic considerations. Critical Reviews in Therapeutic Drug Carrier Systems, 1997, 14(2): 133–172

7
Mudhakir D, Harashima H. Learning from the viral journey: How to enter cells and how to overcome intracellular barriers to reach the nucleus. The AAPS Journal, 2009, 11(1): 65–77

8
Singer S J, Nicolson G L. The fluid mosaic model of the structure of cell membranes. Science, 1972, 175(4023): 720–731

9
Camenisch G, Alsenz J, van de Waterbeemd H, Folkers G. Estimation of permeability by passive diffusion through caco-2 cell monolayers using the drugs' lipophilicity and molecular weight. European Journal of Pharmaceutical Sciences, 1998, 6(4): 317–324

10
Hsu V W, Bai M, Li J. Getting active: Protein sorting in endocytic recycling. Nature Reviews. Molecular Cell Biology, 2012, 13(5): 323–328

11
Babst M. MVB vesicle formation: ESCRT-dependent, ESCRT-independent and everything in between. Current Opinion in Cell Biology, 2011, 23(4): 452–457

12
Hatakeyama H, Akita H, Harashima H. A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect: A strategy for overcoming the PEG dilemma. Advanced Drug Delivery Reviews, 2011, 63(3): 152–160

13
Rejman J, Oberle V, Zuhorn I S, Hoekstra D. Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. The Biochemical Journal, 2004, 377(Pt 1): 159–169

14
Wang J, Li L, Zhou Y. Creep effect on cellular uptake of viral particles. Chinese Science Bulletin, 2014, 59(19): 2277–2281

15
Mercer J, Schelhaas M, Helenius A. Virus entry by endocytosis. Annual Review of Biochemistry, 2010, 79: 803–833

16
McMahon H T, Boucrot E. Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nature Reviews. Molecular Cell Biology, 2011, 12(8): 517–533

17
Doherty G J, McMahon H T. Mechanisms of endocytosis. Annual Review of Biochemistry, 2009, 78: 857–902

18
Harush-Frenkel O, Debotton N, Benita S, Altschuler Y. Targeting of nanoparticles to the clathrin-mediated endocytic pathway. Biochemical and Biophysical Research Communications, 2007, 353(1): 26–32

19
Rejman J, Bragonzi A, Conese M. Role of clathrin- and caveolae-mediated endocytosis in gene transfer mediated by lipo- and polyplexes. Molecular Therapy, 2005, 12(3): 468–474

20
van der Aa M A, Huth U S, Häfele S Y, Schubert R, Oosting R S, Mastrobattista E, Hennink W E, Peschka-Süss R, Koning G A, Crommelin D J. Cellular uptake of cationic polymer-DNA complexes via caveolae plays a pivotal role in gene transfection in COS-7 cells. Pharmaceutical Research, 2007, 24(8): 1590–1598

21
Le P U, Guay G, Altschuler Y, Nabi I R. Caveolin-1 is a negative regulator of caveolae-mediated endocytosis to the endoplasmic reticulum. The Journal of Biological Chemistry, 2002, 277(5): 3371–3379

22
Sahay G, Alakhova D Y, Kabanov A V. Endocytosis of nanomedicines. Journal of Controlled Release, 2010, 145(3): 182–195

23
Pelkmans L, Helenius A. Endocytosis via caveolae. Traffic, 2002, 3(5): 311–320

24
Parton R G, Howes M T. Revisiting caveolin trafficking: The end of the caveosome. The Journal of Cell Biology, 2010, 191(3): 439–441

25
Raghava S, Giorda K M, Romano F B, Heuck A P, Hebert D N. SV40 late protein VP4 forms toroidal pores to disrupt membranes for viral release. Biochemistry, 2013, 52(22): 3939–3948

26
Damm E M, Pelkmans L, Kartenbeck J, Mezzacasa A, Kurzchalia T, Helenius A. Clathrin- and caveolin-1-independent endocytosis: Entry of simian virus 40 into cells devoid of caveolae. The Journal of Cell Biology, 2005, 168(3): 477–488

27
Kirkham M, Fujita A, Chadda R, Nixon S J, Kurzchalia T V, Sharma D K, Pagano R E, Hancock J F, Mayor S, Parton R G. Ultrastructural identification of uncoated caveolin-independent early endocytic vehicles. The Journal of Cell Biology, 2005, 168(3): 465–476

28
Mercer J, Helenius A. Gulping rather than sipping: Macropinocytosis as a way of virus entry. Current Opinion in Microbiology, 2012, 15(4): 490–499

29
Mercer J, Helenius A. Virus entry by macropinocytosis. Nature Cell Biology, 2009, 11(5): 510–520

30
Hewlett L J, Prescott A R, Watts C. The coated pit and macropinocytic pathways serve distinct endosome populations. The Journal of Cell Biology, 1994, 124(5): 689–703

31
Kerr M C, Lindsay M R, Luetterforst R, Hamilton N, Simpson F, Parton R G, Gleeson P A, Teasdale R D. Visualisation of macropinosome maturation by the recruitment of sorting nexins. Journal of Cell Science, 2006, 119(Pt 19): 3967–3980

32
Meier O, Boucke K, Hammer S V, Keller S, Stidwill R P, Hemmi S, Greber U F. Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake. The Journal of Cell Biology, 2002, 158(6): 1119–1131

33
Muro S, Wiewrodt R, Thomas A, Koniaris L, Albelda S M, Muzykantov V R, Koval M. A novel endocytic pathway induced by clustering endothelial ICAM-1 or PECAM-1. Journal of Cell Science, 2003, 116(Pt 8): 1599–1609

34
Dausend J, Musyanovych A, Dass M, Walther P, Schrezenmeier H, Landfester K, Mailander V. Uptake mechanism of oppositely charged fluorescent nanoparticles in HeLa cells. Macromolecular Bioscience, 2008, 8(12): 1135–1143

35
Youm I, Bazzil J D, Otto J W, Caruso A N, Murowchick J B, Youan B B. Influence of surface chemistry on cytotoxicity and cellular uptake of nanocapsules in breast cancer and phagocytic cells. The AAPS Journal, 2014, 16(3): 550–567

36
Agarwal R, Singh V, Jurney P, Shi L, Sreenivasan S V, Roy K. Mammalian cells preferentially internalize hydrogel nanodiscs over nanorods and use shape-specific uptake mechanisms. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(43): 17247–17252

37
Fernando L P, Kandel P K, Yu J, McNeill J, Ackroyd P C, Christensen K A. Mechanism of cellular uptake of highly fluorescent conjugated polymer nanoparticles. Biomacromolecules, 2010, 11(10): 2675–2682

38
Meng H, Yang S, Li Z, Xia T, Chen J, Ji Z, Zhang H, Wang X, Lin S, Huang C, Zhou Z H, Zink J I, Nel A E. Aspect ratio determines the quantity of mesoporous silica nanoparticle uptake by a small GTPase-dependent macropinocytosis mechanism. ACS Nano, 2011, 5(6): 4434–4447

39
Sahay G, Querbes W, Alabi C, Eltoukhy A, Sarkar S, Zurenko C, Karaqiannis E, Love K, Chen D, Zoncu R, Buqanin Y, Schroeder A, Langer R, Anderson D G. Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. Nature Biotechnology, 2013, 31(7): 653–658

40
Gilleron J, Querbes W, Zeigerer A, Borodovsky A, Marsico G, Schubert U, Manygoats K, Seifert S, Andree C, Stöter M, Epstein-Barash H, Zhang L, Koteliansky V, Fitzqerald K, Fava E, Bickle M, Kalaidzidis Y, Akinc A, Maier M, Zerial M. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nature Biotechnology, 2013, 31(7): 638–646

41
Kirkham M, Parton R G. Clathrin-independent endocytosis: New insights into caveolae and non-caveolar lipid raft carriers. Biochimica Et Biophysica Acta, 2005, 1745(3): 273–286

42
Grassart A, Dujeancourt A, Lazarow P B, Dautry-Varsat A, Sauvonnet N. Clathrin-independent endocytosis used by the IL-2 receptor is regulated by Rac1, Pak1 and Pak2. EMBO Reports, 2008, 9(4): 356–362

43
Kumari S, Mayor S. ARF1 is directly involved in dynamin-independent endocytosis. Nature Cell Biology, 2008, 10(1): 30–41

44
Sabharanjak S, Mayor S. Folate receptor endocytosis and trafficking. Advanced Drug Delivery Reviews, 2004, 56(8): 1099–1109

45
Wang Y, Huang L. A window onto siRNA delivery. Nature Biotechnology, 2013, 31(7): 611–612

46
Sakai-Kato K, Un K, Nanjo K, Nishiyama N, Kusuhara H, Kataoka K, Kawanishi T, Goda Y, Okuda H. Elucidating the molecular mechanism for the intracellular trafficking and fate of block copolymer micelles and their components. Biomaterials, 2014, 35(5): 1347–1358

47
Ohno S, Takanashi M, Sudo K, Uedo S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T, Ohgi T, Ochiya T, Gotoh N, Kuroda M. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Molecular Therapy, 2013, 21(1): 185–191

48
Meier O, Greber U F. Adenovirus endocytosis. The Journal of Gene Medicine, 2003, 5(6): 451–462

49
Zaitseva E, Yang S T, Melikov K, Pourmal S, Chernomordik L V. Dengue virus ensures its fusion in late endosomes using compartment-specific lipids. PLoS Pathogens, 2010, 6(10): e1001131

50
Schornberg K, Matsuyama S, Kabsch K, Delos S, Bouton A, White J. Role of endosomal cathepsins in entry mediated by the ebola virus glycoprotein. Journal of Virology, 2006, 80(8): 4174–4178

51
Kielian M, Rey F A. Virus membrane-fusion proteins: More than one way to make a hairpin. Nature Reviews. Microbiology, 2006, 4(1): 67–76

52
Dimitrov D S. Virus entry: Molecular mechanisms and biomedical applications. Nature Reviews. Microbiology, 2004, 2(2): 109–122

53
Earp L J, Delos S E, Park H E, White J M. The many mechanisms of viral membrane fusion proteins. Current Topics in Microbiology and Immunology, 2005, 285: 25–66

54
Han X, Bushweller J H, Cafiso D S, Tamm L K. Membrane structure and fusion-triggering conformational change of the fusion domain from influenza hemagglutinin. Nature Structural Biology, 2001, 8(8): 715–720

55
Semple S C, Akinc A, Chen J, Sandhu A P, Mui B L, Cho C K, Sah D W, Stebbing D, Crosley E J, Yaworski E, Hafez I M, Dorkin J R, Qin J, Lam K, Rajeev K G, Wong K F, Jeffs L B, Nechev L, Eisenhardt M L, Jayaraman M, Kazem M, Maier M A, Srinivasulu M, Weinstein M J, Chen Q, Alvarez R, Barros S A, De S, Klimuk S K, Borland T, Kosovrasti V, Cantley W L, Tam Y K, Manoharan M, Ciufolini M A, Tracy M A, de Fougerolles A, MacLachlan I, Cullis P R, Madden T D, Hope M J. Rational design of cationic lipids for siRNA delivery. Nature Biotechnology, 2010, 28(2): 172–176

56
Felgner J H, Kumar R, Sridhar C N, Wheeler C J, Tsai Y J, Border R, Ramsey P, Martin M, Felgner P L. Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations. The Journal of Biological Chemistry, 1994, 269(4): 2550–2561

57
Pack D W, Hoffman A S, Pun S, Stayton P S. Design and development of polymers for gene delivery. Nature Reviews. Drug Discovery, 2005, 4(7): 581–593

58
Midoux P, Pichon C, Yaouanc J J, Jaffres P A. Chemical vectors for gene delivery: A current review on polymers, peptides and lipids containing histidine or imidazole as nucleic acids carriers. British Journal of Pharmacology, 2009, 157(2): 166–178

59
Shai Y. Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by alpha-helical antimicrobial and cell non-selective membrane-lytic peptides. Biochimica Et Biophysica Acta, 1999, 1462(1–2): 55–70

60
Mahat R I, Monera O D, Smith L C, Rolland A. Peptide-based gene delivery. Current Opinion in Molecular Therapeutics, 1999, 1(2): 226–243

61
Prchla E, Plank C, Wagner E, Blaas D, Fuchs R. Virus-mediated release of endosomal content in vitro: Different behavior of adenovirus and rhinovirus serotype 2. The Journal of Cell Biology, 1995, 131(1): 111–123

62
Brabec M, Schober D, Wagner E, Bayer N, Murphy R F, Blaas D, Fuchs R. Opening of size-selective pores in endosomes during human rhinovirus serotype 2 in vivo uncoating monitored by single-organelle flow analysis. Journal of Virology, 2005, 79(2): 1008–1016

63
Suikkanen S, Antila M, Jaatinen A, Vihinen-Ranta M, Vuento M. Release of canine parvovirus from endocytic vesicles. Virology, 2003, 316(2): 267–280

64
Farr G A, Zhang L G, Tattersall P. Parvoviral virions deploy a capsid-tethered lipolytic enzyme to breach the endosomal membrane during cell entry. Proceedings of the National Academy of Sciences of the United States of America, 2005, 102(47): 17148–17153

65
Kamper N, Day P M, Nowak T, Selinka H C, Florin L, Bolscher J, Hilbig L, Schiller J T, Sapp M. A membrane-destabilizing peptide in capsid protein L2 is required for egress of papillomavirus genomes from endosomes. Journal of Virology, 2006, 80(2): 759–768

66
Wiethoff C M, Wodrich H, Gerace L, Nemerow G R. Adenovirus protein VI mediates membrane disruption following capsid disassembly. Journal of Virology, 2005, 79(4): 1992–2000

67
Zhao H, Yung L Y. Addition of TPGS to folate-conjugated polymer micelles for selective tumor targeting. Journal of Biomedical Materials Research. Part A, 2009, 91(2): 505–518

68
Gao H, Yang Z, Zhang S, Cao S, Shen S, Pang Z, Jiang X. Ligand modified nanoparticles increases cell uptake, alters endocytosis and elevates glioma distribution and internalization. Scientific Reports, 2013, 3: 2534

69
Chen H, Kim S, Li L, Wang S, Park K, Cheng J X. Release of hydrophobic molecules from polymer micelles into cell membranes revealed by forster resonance energy transfer imaging. Proceedings of the National Academy of Sciences of the United States of America, 2008, 105(18): 6596–6601

70
Xu P, Gullotti E, Tong L, Highley C B, Errabelli D R, Hasan T, Cheng J X, Kohane D S, Yeo Y. Intracellular drug delivery by poly(lactic-co-glycolic acid) nanoparticles, revisited. Molecular Pharmaceutics, 2009, 6(1): 190–201

71
Chen H, Kim S, He W, Wang H, Low P S, Park K, Cheng J X. Fast release of lipophilic agents from circulating PEG-PDLLA micelles revealed by in vivo forster resonance energy transfer imaging. Langmuir, 2008, 24(10): 5213–5217

72
Nuutila J, Lilius E M. Flow cytometric quantitative determination of ingestion by phagocytes needs the distinguishing of overlapping populations of binding and ingesting cells. Cytometry. Part A : The Journal of the International Society for Analytical Cytology, 2005, 65(2): 93–102

73
Haas B L, Matson J S, DiRita V J, Biteen J S. Imaging live cells at the nanometer-scale with single-molecule microscopy: Obstacles and achievements in experiment optimization for microbiology. Molecules, 2014, 19(8): 12116–12149

74
Muller B, Heilemann M. Shedding new light on viruses: Super-resolution microscopy for studying human immunodeficiency virus. Trends in Microbiology, 2013, 21(10): 522–533

75
Grove J. Super-resolution microscopy: A virus’ eye view of the cell. Viruses, 2014, 6(3): 1365–1378

76
Perez-Jimenez R, Alonso-Caballero A, Berkovich R, Franco D, Chen M W, Richard P, Badilla C L, Fernandez J M. Probing the effect of force on HIV-1 receptor CD4. ACS Nano, 2014, 8(10): 10313–10320

77
Welsher K, Yang H. Multi-resolution 3D visualization of the early stages of cellular uptake of peptide-coated nanoparticles. Nature Nanotechnology, 2014, 9(3): 198–203

78
Sahay G, Batrakova E V, Kabanov A V. Different internalization pathways of polymeric micelles and unimers and their effects on vesicular transport. Bioconjugate Chemistry, 2008, 19(10): 2023–2029

79
dos Santos T, Varela J, Lynch I, Salvati A, Dawson K A. Effects of transport inhibitors on the cellular uptake of carboxylated polystyrene nanoparticles in different cell lines. PloS ONE, 2011, 6(9): e24438

80
Ivanov A I. Pharmacological inhibition of endocytic pathways: Is it specific enough to be useful? Methods in Molecular Biology, 2008, 440: 15–33

81
Payne C K, Jones S A, Chen C, Zhuang X. Internalization and trafficking of cell surface proteoglycans and proteoglycan-binding ligands. Traffic, 2007, 8(4): 389–401

82
Torgersen M L, Skretting G, van Deurs B, Sandvig K. Internalization of cholera toxin by different endocytic mechanisms. Journal of Cell Science, 2001, 114(Pt 20): 3737–3747

83
Massol R H, Larsen J E, Fujinaga Y, Lencer W I, Kirchhausen T. Cholera toxin toxicity does not require functional Arf6- and dynamin-dependent endocytic pathways. Molecular Biology of the Cell, 2004, 15(8): 3631–3641

84
Rupper A, Lee K, Knecht D, Cardelli J. Sequential activities of phosphoinositide 3-kinase, PKB/aakt, and Rab7 during macropinosome formation in dictyostelium. Molecular Biology of the Cell, 2001, 12(9): 2813–2824

85
Rappoport J Z, Simon S M. A functional GFP fusion for imaging clathrin-mediated endocytosis. Traffic, 2008, 9(8): 1250–1255

86
Greber U F, Willetts M, Webster P, Helenius A. Stepwise dismantling of adenovirus 2 during entry into cells. Cell, 1993, 75(3): 477–486

87
Colin M, Maurice M, Trugnan G, Kornprobst M, Harbottle R P, Knight A, Cooper R G, Miller A D, Capeau J, Coutelle C, Brahimi-Horn M C. Cell delivery, intracellular trafficking and expression of an integrin-mediated gene transfer vector in tracheal epithelial cells. Gene Therapy, 2000, 7(2): 139–152

88
Drose S, Altendorf K. Bafilomycins and concanamycins as inhibitors of V-ATPases and P-ATPases. The Journal of Experimental Biology, 1997, 200(Pt 1): 1–8

89
van Rossenberg S M, Sliedregt-Bol K M, Meeuwenoord N J, van Berkel T J, van Boom J H, van der Marel G A, Biessen E A. Targeted lysosome disruptive elements for improvement of parenchymal liver cell-specific gene delivery. The Journal of Biological Chemistry, 2002, 277(48): 45803–45810

90
Mastrobattista E, Koning G A, van Bloois L, Filipe A C, Jiskoot W, Storm G. Functional characterization of an endosome-disruptive peptide and its application in cytosolic delivery of immunoliposome-entrapped proteins. The Journal of Biological Chemistry, 2002, 277(30): 27135–27143

91
Boeneman K, Delehanty J B, Blanco-Canosa J B, Susumu K, Stewart M H, Oh E, Huston A L, Dawson G, Ingale S, Walters R, Domowicz M, Deschamps J R, Algar W R, Dimaggio S, Manono J, Spillmann C M, Thompson D, Jennings T L, Dawson P E, Medintz I L. Selecting improved peptidyl motifs for cytosolic delivery of disparate protein and nanoparticle materials. ACS Nano, 2013, 7(5): 3778–3796

92
El-Sayed A, Khalil I A, Kogure K, Futaki S, Harashima H. Octaarginine- and octalysine-modified nanoparticles have different modes of endosomal escape. The Journal of Biological Chemistry, 2008, 283(34): 23450–23461

93
Alabi C A, Sahay G, Langer R, Anderson D G. Development of siRNA-probes for studying intracellular trafficking of siRNA nanoparticles. Integrative Biology: Quantitative Biosciences from Nano to Macro, 2013, 5(1): 224–230

94
Hama S, Akita H, Ito R, Mizuguchi H, Hayakawa T, Harashima H. Quantitative comparison of intracellular trafficking and nuclear transcription between adenoviral and lipoplex systems. Molecular Therapy, 2006, 13(4): 786–794

95
Mishra S, Webster P, Davis M E. PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. European Journal of Cell Biology, 2004, 83(3): 97–111

96
Ma Y, Nolte R J, Cornelissen J J. Virus-based nanocarriers for drug delivery. Advanced Drug Delivery Reviews, 2012, 64(9): 811–825

97
Galdiero S, Vitiello M, Falanga A, Cantisani M, Incoronato N, Galdiero M. Intracellular delivery: Exploiting viral membranotropic peptides. Current Drug Metabolism, 2012, 13(1): 93–104

98
Berry C C. Intracellular delivery of nanoparticles via the HIV-1 tat peptide. Nanomedicine, 2008, 3(3): 357–365

99
Chugh A, Eudes F, Shim Y S. Cell-penetrating peptides: Nanocarrier for macromolecule delivery in living cells. IUBMB Life, 2010, 62(3): 183–193

100
Schwarze S R, Ho A, Vocero-Akbani A, Dowdy S F. In vivo protein transduction: Delivery of a biologically active protein into the mouse. Science, 1999, 285(5433): 1569–1572

101
Torchilin V P, Levchenko T S, Rammohan R, Volodina N, Papahadjopoulos-Sternberg B, D’Souza G G. Cell transfection in vitro and in vivo with nontoxic TAT peptide-liposome-DNA complexes. Proceedings of the National Academy of Sciences of the United States of America, 2003, 100(4): 1972–1977

102
Mitchell D J, Kim D T, Steinman L, Fathman C G, Rothbard J B. Polyarginine enters cells more efficiently than other polycationic homopolymers. The Journal of Peptide Research, 2000, 56(5): 318–325

103
Ludtke J J, Zhang G, Sebestyen M G, Wolff J A. A nuclear localization signal can enhance both the nuclear transport and expression of 1 kb DNA. Journal of Cell Science, 1999, 112(Pt 12): 2033–2041

104
Chen F, Gerion D. Fluorescent CdSe/ZnS Nanocrystal peptide conjugates for long-term, nontoxic imaging and nuclear targeting in living cells. Nano Letters, 2004, 4(10): 1827–1832

105
Kang M J, Park S H, Kang M H, Park M J, Choi Y W. Folic acid-tethered pep-1 peptide-conjugated liposomal nanocarrier for enhanced intracellular drug delivery to cancer cells: Conformational characterization and in vitro cellular uptake evaluation. International Journal of Nanomedicine, 2013, 8: 1155–1165

106
Hatakeyama H, Ito E, Akita H, Oishi M, Nagasaki Y, Futaki S, Harashima H. A pH-sensitive fusogenic peptide facilitates endosomal escape and greatly enhances the gene silencing of siRNA-containing nanoparticles in vitro and in vivo. Journal of Controlled Release, 2009, 139(2): 127–132

107
Milletti F. Cell-penetrating peptides: Classes, origin, and current landscape. Drug Discovery Today, 2012, 17(15–16): 850–860

108
Bartz R, Fan H, Zhang J, Innocent N, Cherrin C, Beck S C, Pei Y, Momose A, Jadhav V, Tellers D M, Meng F, Crocker L S, Sepp-Lorenzino L, Barnett S F. Effective siRNA delivery and target mRNA degradation using an amphipathic peptide to facilitate pH-dependent endosomal escape. The Biochemical Journal, 2011, 435(2): 475–487

109
Li W, Nicol F, Szoka F C, Jr. GALA: A designed synthetic pH-responsive amphipathic peptide with applications in drug and gene delivery. Advanced Drug Delivery Reviews, 2004, 56(7): 967–985

110
Wadia J S, Stan R V, Dowdy S F. Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis. Nature Medicine, 2004, 10(3): 310–315

111
Funhoff A M, van Nostrum C F, Lok M C, Fretz M M, Crommelin D J, Hennink W E. Poly(3-guanidinopropyl methacrylate): A novel cationic polymer for gene delivery. Bioconjugate Chemistry, 2004, 15(6): 1212–1220

112
Oliveira S, van Rooy I, Kranenburg O, Storm G, Schiffelers R M. Fusogenic peptides enhance endosomal escape improving siRNA-induced silencing of oncogenes. International Journal of Pharmaceutics, 2007, 331(2): 211–214

113
Kwon E J, Bergen J M, Pun S H. Application of an HIV gp41-derived peptide for enhanced intracellular trafficking of synthetic gene and siRNA delivery vehicles. Bioconjugate Chemistry, 2008, 19(4): 920–927

114
Aoyama Y, Kanamori T, Nakai T, Sasaki T, Horiuchi S, Sando S, Niidome T. Artificial viruses and their application to gene delivery. Size-controlled gene coating with glycocluster nanoparticles. Journal of the American Chemical Society, 2003, 125(12): 3455–3457

115
Schatz C, Louguet S, le Meins J F, Lecommandoux S. Polysaccharide-block-polypeptide copolymer vesicles: Towards synthetic viral capsids. Angewandte Chemie (International ed. in English), 2009, 48(14): 2572–2575

116
Bui L, Abbou S, Ibarboure E, Guidolin N, Staedel C, Toulme J J, Lecommandoux S, Schatz C. Encapsidation of RNA-polyelectrolyte complexes with amphiphilic block copolymers: Toward a new self-assembly route. Journal of the American Chemical Society, 2012, 134(49): 20189–20196

117
Muller K, Nahde T, Fahr A, Muller R, Brusselbach S. Highly efficient transduction of endothelial cells by targeted artificial virus-like particles. Cancer Gene Therapy, 2001, 8(2): 107–117

118
Wu D T, Roth M J. MLV based viral-like-particles for delivery of toxic proteins and nuclear transcription factors. Biomaterials, 2014, 35(29): 8416–8426

119
Keswani R K, Pozdol I M, Pack D W. Design of hybrid lipid/retroviral-like particle gene delivery vectors. Molecular Pharmaceutics, 2013, 10(5): 1725–1735

120
de la Escosura A, Janssen P G, Schenning A P, Nolte R J, Cornelissen J J. Encapsulation of DNA-templated chromophore assemblies within virus protein nanotubes. Angewandte Chemie (International ed. in English), 2010, 49(31): 5335–5338

121
Ruff Y, Moyer T, Newcomb C J, Demeler B, Stupp S I. Precision templating with DNA of a virus-like particle with peptide nanostructures. Journal of the American Chemical Society, 2013, 135(16): 6211–6219

122
Li F, Chen Y, Chen H, He W, Zhang Z P, Zhang X E, Wang Q. Monofunctionalization of protein nanocages. Journal of the American Chemical Society, 2011, 133(50): 20040–20043

123
Murthy N, Robichaud J R, Tirrell D A, Stayton P S, Hoffman A S. The design and synthesis of polymers for eukaryotic membrane disruption. Journal of Controlled Release, 1999, 61(1–2): 137–143

124
Shima F, Akagi T, Akashi M. Synthesis and preparation of nanoparticles composed of amphiphilic poly(I^3<?Pub Caret?><?A3B2 h=-0.3h?>-glutamic acid) with different hydrophobic side chains and their potential of membrane disruptive activity. Colloid and Polymer Science, 2014, 292(10): 2663–2671

125
Lin Y L, Jiang G, Birrell L K, El-Sayed M E. Degradable, pH-sensitive, membrane-destabilizing, comb-like polymers for intracellular delivery of nucleic acids. Biomaterials, 2010, 31(27): 7150–7166

126
Liu Q, Chen J, Du J. Asymmetrical polymer vesicles with a “stealthy” outer corona and an endosomal-escape-accelerating inner corona for efficient intracellular anticancer drug delivery. Biomacromolecules, 2014, 15(8): 3072–3082

127
Buerkli C, Lee S H, Moroz E, Stuparu M C, Leroux J C, Khan A. Amphipathic homopolymers for siRNA delivery: Probing impact of bifunctional polymer composition on transfection. Biomacromolecules, 2014, 15(5): 1707–1715

128
Shima F, Akagi T, Uto T, Akashi M. Manipulating the antigen-specific immune response by the hydrophobicity of amphiphilic poly(gamma-glutamic acid) nanoparticles. Biomaterials, 2013, 34(37): 9709–9716

129
Henry S M, El-Sayed M E, Pirie C M, Hoffman A S, Stayton P S. pH-responsive poly(styrene-alt-maleic anhydride) alkylamide copolymers for intracellular drug delivery. Biomacromolecules, 2006, 7(8): 2407–2414

130
Convertine A J, Diab C, Prieve M, Paschal A, Hoffman A S, Johnson P H, Stayton P S. pH-responsive polymeric micelle carriers for siRNA drugs. Biomacromolecules, 2010, 11(11): 2904–2911

131
Gu W, Jia Z, Truong N P, Prasadam I, Xiao Y, Monteiro M J. Polymer nanocarrier system for endosome escape and timed release of siRNA with complete gene silencing and cell death in cancer cells. Biomacromolecules, 2013, 14(10): 3386–3389

132
Petersen J, Dandri M, Mier W, Lütgehetmann M, Volz T, von Weizsäcker F, Haberkorn U, Fischer L, Pollok J M, Erbes B, Seitz S, Urban S. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nature Biotechnology, 2008, 26(3): 335–341

133
Zhang X, Zhang Q, Peng Q, Zhou J, Liao L, Sun X, Zhang L, Gong T. Hepatitis B virus preS1-derived lipopeptide functionalized liposomes for targeting of hepatic cells. Biomaterials, 2014, 35(23): 6130–6141

134
Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood M J. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotechnology, 2011, 29(4): 341–345

135
Hwang do W, Son S, Jang J, Youn H, Lee S, Lee D, Lee Y S, Jeong J M, Kim W J, Lee D S. A brain-targeted rabies virus glycoprotein-disulfide linked PEI nanocarrier for delivery of neurogenic microRNA. Biomaterials, 2011, 32(21): 4968–4975

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