Cellular Trafficking and Subcellular Interactions of Cationic Gene Delivery Nanomaterials


Cellular trafficking
gene delivery systems
cationic gene therapy

How to Cite

Barar, J., & Omidi, Y. (2022). Cellular Trafficking and Subcellular Interactions of Cationic Gene Delivery Nanomaterials. Journal of Pharmacy and Nutrition Sciences, 1(1), 68–81. https://doi.org/10.6000/1927-5951.2011.01.01.12


Various cationic nanobiomaterials have been widely used as gene delivery nanosystems (GDNSs) in vitro and in vivo. Various cellular machineries are involved in trafficking of GDNSs, whose surface functional moieties and architectural properties confer great potential to interact with cell membranes and subcellular biomolecules. It appears such intrinsic inadvertent biological functionalities may impact the outcome of the biomedical applications of these nanobiomaterials. Various advanced materials used as GDNSs may display selective phenotypic effects in target cells/tissues as a result of initiation of various signaling pathways perhaps due to its cellular interactions with plasma cell membranes and/or intracellular compartments including genetic materials. Thus, better understanding about cellular/molecular impacts of GDNSs may maximize their clinical outcomes and accordingly minimize their inevitable undesired consequences. The main focus of this review is based on the cellular trafficking and interactions of cationic gene delivery nanobiomaterials with target cells or subcellular compartments.



Hughes, M.D., Hussain, M., Nawaz, Q., Sayyed, P. and Akhtar, S. 2001. The Cellular Delivery of Antisense Oligonucleotides and Ribozymes. Drug Discov Today 6: 303-315.

Akhtar, S. 1998. Antisense Technology: Selection and Delivery of Optimally Acting Antisense Oligonucleotides. J. Drug Target 5: 225-234.

Sohail, M. and Southern, E.M. 2000a. Antisense Arrays. Mol. Cell Biol. Res. Commun. 3: 67-72.

Sohail, M. and Southern, E.M. 2000b. Selecting Optimal Antisense Reagents. Adv. Drug Deliv. Rev. 44: 23-34.

Shi, F., Visser, W.H., de Jong, N.M., Liem, R.S., Ronken, E. and Hoekstra, D. 2003. Antisense Oligonucleotides Reach MRNA Targets Via the RNA Matrix: Downregulation of the 5- HT1A Receptor. Exp. Cell Res. 291: 313-325.

Dias, N. and Stein, C.A. 2002. Antisense Oligonucleotides: Basic Concepts and Mechanisms. Mol. Cancer Ther. 1: 347-355.

Boiziau, C., Larrouy, B., Moreau, S., Cazenave, C., Shire, D. and Toulme, J.J. 1992. Ribonuclease H-Mediated Inhibition of Translation and Reverse Transcription by Antisense Oligodeoxynucleotides. Biochem. Soc. Trans. 20: 764-767.

Larrouy, B., Blonski, C., Boiziau, C., Stuer, M., Moreau, S., Shire, D. et al. 1992. RNase H-Mediated Inhibition of Translation by Antisense Oligodeoxyribonucleotides: Use of Backbone Modification to Improve Specificity. Gene 121: 189-194.

Monia, B.P., Lesnik, E.A., Gonzalez, C., Lima, W.F., McGee, D., Guinosso, C.J. et al. 1993. Evaluation of 2'-Modified Oligonucleotides Containing 2'-Deoxy Gaps As Antisense Inhibitors of Gene Expression. J. Biol. Chem. 268: 14514- 14522.

Sazani, P., Graziewicz, M.A. and Kole, R. 2008. Splice Switching Oligonucleotides As Potential Therapeutics, In: Antisense Drug Technology: Principles, Strategies, and Applications, Crooke ST, Ed. CRC Press, London, pp 89- 114.

Crooke, S.T., Vickers, T., Lima, W. and Wu, H. 2008. Mechanisms of Antisense Drug Action, an Introduction, In: Antisense Drug Technology: Principles, Strategies, and Applications, Crooke ST, Ed. CRC Press, London, pp 3- 46.

Lima, W., Wu, H. and Crooke, S.T. 2008. The RNase H Mechanism, In: Antisense Drug Technology: Principles, Strategies, and Applications, Crooke ST, Ed. CRC Press, London, pp 47-74.

Ferber, D. 2001. Gene Therapy. Safer and Virus-Free? Science 294: 1638-42.

Reeves, L. and Cornetta, K. 2000. Clinical Retroviral Vector Production: Step Filtration Using Clinically Approved Filters Improves Titers. Gene Ther. 7: 1993-1998.

Medina-Kauwe, L.K., Xie, J. and Hamm-Alvarez, S. 2005. Intracellular Trafficking of Nonviral Vectors. Gene Ther. 12: 1734-1751.

Omidi, Y., Barar, J. and Akhtar, S. 2005a. Toxicogenomics of Cationic Lipid-Based Vectors for Gene Therapy: Impact of Microarray Technology. Curr. Drug Deliv. 2: 429-441.

Omidi, Y., Barar, J., heidari, H.R., Ahmadian, S., Ahmadpour Yazdi, H. and Akhtar, S. 2008. Microarray Analysis of the Toxicogenomics and the Genotoxic Potential of a Cationic Lipid-Based Gene Delivery Nanosystem in Human Alveolar Epithelial A549 Cells. Toxicology Mechanisms and Methods 18: 369-378.

Anwer, K., Rhee, B.G. and Mendiratta, S.K. 2003. Recent Progress in Polymeric Gene Delivery Systems. Crit Rev. Ther. Drug Carrier Syst. 20: 249-293.

Ilies, M.A., Seitz, W.A. and Balaban, A.T. 2002. Cationic Lipids in Gene Delivery: Principles, Vector Design and Therapeutical Applications. Curr. Pharm. Des 8: 2441-2473.

Vasir, J.K. and Labhasetwar, V. 2006. Polymeric Nanoparticles for Gene Delivery. Expert. Opin. Drug Deliv. 3: 325-344.

Omidi, Y. and Gumbleton, M. 2005. Biological Membranes and Barriers, In: Biomaterials for Delivery and Targeting of Proteins Nucleic Acids, Mahato RI, Ed. CRC Press, New York, pp 232-274.

Elouahabi, A. and Ruysschaert, J.M. 2005. Formation and Intracellular Trafficking of Lipoplexes and Polyplexes. Molecular Therapy 11: 336-347.

Willoughby, C.E., Ponzin, D., Ferrari, S., Lobo, A., Landau, K. and Omidi, Y. 2010. Anatomy and Physiology of the Human Eye: Effects of Mucopolysaccharidoses Disease on Structure and Function - a Review. Clinical and Experimental Ophthalmology 38: 2-11.

da Cruz, M.T., Simoes, S., Pires, P.P., Nir, S. and de Lima, M.C. 2001. Kinetic Analysis of the Initial Steps Involved in Lipoplex--Cell Interactions: Effect of Various Factors That Influence Transfection Activity. Biochim. Biophys. Acta 1510: 136-151.

Omidi, Y. and Barar, J. 2009. Induction of Human Alveolar Epithelial Cell Growth Factor Receptors by Dendrimeric Nanostructures. Int. J. Toxicol. 28: 113-122.

Guo, W. and Lee, R.L. 1999. Receptor-Targeted Gene Delivery Via Folate-Conjugated Polyethylenimine. AAPS PharmSci 1: E19.

Hattori, Y. and Maitani, Y. 2005. Folate-Linked Lipid-Based Nanoparticle for Targeted Gene Delivery. Curr. Drug Deliv. 2: 243-252.

Hofland, H.E., Masson, C., Iginla, S., Osetinsky, I., Reddy, J.A., Leamon, C.P. et al. 2002. Folate-Targeted Gene Transfer in Vivo. Mol Ther 5: 739-44.

Johnston, J.B., Navaratnam, S., Pitz, M.W., Maniate, J.M., Wiechec, E., Baust, H. et al. 2006. Targeting the EGFR Pathway for Cancer Therapy. Curr. Med. Chem. 13: 3483- 3492.

Diebold, S.S., Plank, C., Cotten, M., Wagner, E. and Zenke, M. 2002. Mannose Receptor-Mediated Gene Delivery into Antigen Presenting Dendritic Cells. Somat Cell Mol Genet 27: 65-74.

Shi, F. and Hoekstra, D. 2004. Effective Intracellular Delivery of Oligonucleotides in Order to Make Sense of Antisense. J. Control Release 97: 189-209.

Lee, R., Kim, P.H., Choi, J.W., Oh-Joon, K., Kim, K., Kim, D. et al. 2010. Capacitance-Based Real Time Monitoring of Receptor-Mediated Endocytosis. Biosensors and Bioelectronics 25: 1325-1332.

Lundmark, R.; Carlsson, S. R. Driving membrane curvature in clathrin-dependent and clathrin-independent endocytosis. Seminars in Cell and Developmental Biology. Ref Type: In Press.

Lakhan, S.E., Sabharanjak, S. and De, A. 2009. Endocytosis of Glycosylphosphatidylinositol-Anchored Proteins. Journal of Biomedical Science 16.

Schnitzer, J.E., Liu, J. and Oh, P. 1995. Endothelial Caveolae Have the Molecular Transport Machinery for Vesicle Budding, Docking, and Fusion Including VAMP, NSF, SNAP, Annexins, and GTPases. Journal of Biological Chemistry 270: 14399-14404.

Wu, F. and Yao, P.J. 2009. Clathrin-Mediated Endocytosis and Alzheimer's Disease: An Update. Ageing Research Reviews 8: 147-149.

Thiel, S., Dahmen, H., Martens, A., M__ller-Newen, G., Schaper, F., Heinrich, P.C. et al. 1998. Constitutive Internalization and Association With Adaptor Protein-2 of the Interleukin-6 Signal Transducer Gp130. FEBS Letters 441: 231-234.

McClure, S.J. and Robinson, P.J. 1996. Dynamin, Endocytosis and Intracellular Signalling (Review). Molecular Membrane Biology 13: 189-215.

Vega, V.L., Charles, W. and De, M.A. 2010. A New Feature of the Stress Response: Increase in Endocytosis Mediated by Hsp70. Cell Stress. Chaperones. 15: 517-527.

Overmeyer, J.H., Wilson, A.L. and Maltese, W.A. 2001. Membrane Targeting of a Rab GTPase That Fails to Associate With Rab Escort Protein (REP) or Guanine Nucleotide Dissociation Inhibitor (GDI). Journal of Biological Chemistry 276: 20379-20386.

Conner, S.D. and Schmid, S.L. 2003. Regulated Portals of Entry into the Cell. Nature 422: 37-44.

Spang, A. 2008. The Life Cycle of a Transport Vesicle. Cell Mol. Life Sci. 65: 2781-2789.

Gumbleton, M., Hollins, A.J., Omidi, Y., Campbell, L. and Taylor, G. 2003. Targeting Caveolae for Vesicular Drug Transport. J Control Release 87: 139-51.

Anderson, R.G. 1998. The Caveolae Membrane System. Annu. Rev. Biochem. 67: 199-225.

Meder, D. and Simons, K. 2006. Lipid Rafts, Caveolae, and Membrane Traffic, In: Lipid Rafts and Caveolae: From Membrane Biophysics to Cell Biology, WILEY-VCH Verlag GmbH & Co., Weinheim, pp 1-17.

Keller, S., Sanderson, M.P., Stoeck, A. and Altevogt, P. 2006. Exosomes: From Biogenesis and Secretion to Biological Function. Immunol. Lett. 107: 102-108.

Lakkaraju, A. and Rodriguez-Boulan, E. 2008. Itinerant Exosomes: Emerging Roles in Cell and Tissue Polarity. Trends Cell Biol. 18: 199-209.

Chaput, N., Taieb, J., Andre, F. and Zitvogel, L. 2005. The Potential of Exosomes in Immunotherapy. Expert. Opin. Biol. Ther. 5: 737-747.

Tan, A., De La Pena, H. and Seifalian, A.M. 2010. The Application of Exosomes As a Nanoscale Cancer Vaccine. Int. J. Nanomedicine. 5: 889-900.

Simons, M. and Raposo, G. 2009. Exosomes--Vesicular Carriers for Intercellular Communication. Curr. Opin. Cell Biol. 21: 575-581.

Record, M., Subra, C., Silvente-Poirot, S. and Poirot, M. 2011. Exosomes As Intercellular Signalosomes and Pharmacological Effectors. Biochem. Pharmacol. 81: 1171- 1182.

Tuma, P.L. and Hubbard, A.L. 2003. Transcytosis: Crossing Cellular Barriers. Physiological Reviews 83: 871-932.

Boussif, O., Lezoualc'h, F., Zanta, M.A., Mergny, M.D., Scherman, D., Demeneix, B. et al. 1995. A Versatile Vector for Gene and Oligonucleotide Transfer into Cells in Culture and in Vivo: Polyethylenimine. Proc Natl Acad Sci U S A 92: 7297-301.

Rejman, J., Bragonzi, A. and Conese, M. 2005. Role of Clathrin- and Caveolae-Mediated Endocytosis in Gene Transfer Mediated by Lipo- and Polyplexes. Mol. Ther. 12: 468-474.

Young, A. 2007. Structural Insights into the Clathrin Coat. Semin. Cell Dev. Biol. 18: 448-458.

Ke, W., Shao, K., Huang, R., Han, L., Liu, Y., Li, J. et al. 2009. Gene Delivery Targeted to the Brain Using an Angiopep-Conjugated Polyethyleneglycol-Modified Polyamidoamine Dendrimer. Biomaterials 30: 6976-6985.

Mounkes, L.C., Zhong, W., Cipres-Palacin, G., Heath, T.D. and Debs, R.J. 1998. Proteoglycans Mediate Cationic Liposome-DNA Complex-Based Gene Delivery in Vitro and in Vivo. J Biol Chem 273: 26164-70.

Mislick, K.A. and Baldeschwieler, J.D. 1996. Evidence for the Role of Proteoglycans in Cation-Mediated Gene Transfer. Proc. Natl. Acad. Sci. U. S. A 93: 12349-12354.

Hess, G.T., Humphries, W.H., Fay, N.C. and Payne, C.K. 2007. Cellular Binding, Motion, and Internalization of Synthetic Gene Delivery Polymers. Biochim. Biophys. Acta 1773: 1583-1588.

Farhood, H., Serbina, N. and Huang, L. 1995. The Role of Dioleoyl Phosphatidylethanolamine in Cationic Liposome Mediated Gene Transfer. Biochim. Biophys. Acta 1235: 289- 295.

Rawat, A., Vaidya, B., Khatri, K., Goyal, A.K., Gupta, P.N., Mahor, S. et al. 2007. Targeted Intracellular Delivery of Therapeutics: an Overview. Pharmazie 62: 643-658.

Kabanov, V.A. 2006. Polymer Genomics: An Insight into Pharmacology and Toxicology of Nanomedicines. Adv Drug Deliv Rev 58: 1597-1621.

Jevprasesphant, R., Penny, J., Jalal, R., Attwood, D., McKeown, N.B. and D'Emanuele, A. 2003. The Influence of Surface Modification on the Cytotoxicity of PAMAM Dendrimers. Int J Pharm 252: 263-6.

Omidi, Y., Hollins, A.J., Drayton, R.M. and Akhtar, S. 2005b. Polypropylenimine Dendrimer-Induced Gene Expression Changes: the Effect of Complexation With DNA, Dendrimer Generation and Cell Type. J. Drug Target 13: 431-443.

Yaroslavov, A.A., Kul'kov, V.E., Polinsky, A.S., Baibakov, B.A. and Kabanov, V.A. 1994. A Polycation Causes Migration of Negatively Charged Phospholipids From the Inner to Outer Leaflet of the Liposomal Membrane. FEBS Lett. 340: 121-123.

Yaroslavov, A.A., Melik-Nubarov, N.S. and Menger, F.M. 2006. Polymer-Induced Flip-Flop in Biomembranes. Acc. Chem. Res. 39: 702-710.

Hong, S., Leroueil, P.R., Janus, E.K., Peters, J.L., Kober, M.M., Islam, M.T. et al. 2006. Interaction of Polycationic Polymers With Supported Lipid Bilayers and Cells: Nanoscale Hole Formation and Enhanced Membrane Permeability. Bioconjug. Chem. 17: 728-734.

Kafil, V. and Omidi, Y. 2011. Cytotoxic Impacts of Linear and Branched Polyethylenimine Nanostructures in A431 Cells. BioImpacts 1: 23-30.

Leroueil, P.R., Hong, S., Mecke, A., Baker, J.R., Jr., Orr, B.G. and Banaszak Holl, M.M. 2007. Nanoparticle Interaction With Biological Membranes: Does Nanotechnology Present a Janus Face? Acc. Chem. Res. 40: 335-342.

Suh, J., Wirtz, D. and Hanes, J. 2003. Efficient Active Transport of Gene Nanocarriers to the Cell Nucleus. Proc. Natl. Acad. Sci. U. S. A 100: 3878-3882.

Erickson, B., Dimaggio, S.C., Mullen, D.G., Kelly, C.V., Leroueil, P.R., Berry, S.A. et al. 2008. Interactions of Poly(Amidoamine) Dendrimers With Survanta Lung Surfactant: The Importance of Lipid Domains. Langmuir.

Hollins, A.J., Benboubetra, M., Omidi, Y., Zinselmeyer, B.H., Schatzlein, A.G., Uchegbu, I.F. et al. 2004. Evaluation of Generation 2 and 3 Poly(Propylenimine) Dendrimers for the Potential Cellular Delivery of Antisense Oligonucleotides Targeting the Epidermal Growth Factor Receptor. Pharm Res 21: 458-466.

Hollins, A.J., Omidi, Y., Benter, I.F. and Akhtar, S. 2007. Toxicogenomics of Drug Delivery Systems: Exploiting Delivery System-Induced Changes in Target Gene Expression to Enhance SiRNA Activity. J. Drug Target 15: 83-88.

Omidi, Y., Hollins, A.J., Benboubetra, M., Drayton, R., Benter, I.F. and Akhtar, S. 2003. 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 11: 311-23.

Lechardeur, D. and Lukacs, G.L. 2002. Intracellular Barriers to Non-Viral Gene Transfer. Curr Gene Ther 2: 183-94.

Lukacs, G.L., Haggie, P., Seksek, O., Lechardeur, D., Freedman, N. and Verkman, A.S. 2000. Size-Dependent DNA Mobility in Cytoplasm and Nucleus. J. Biol. Chem. 275: 1625-1629.

Lechardeur, D., Sohn, K.J., Haardt, M., Joshi, P.B., Monck, M., Graham, R.W. et al. 1999. Metabolic Instability of Plasmid DNA in the Cytosol: a Potential Barrier to Gene Transfer. Gene Ther. 6: 482-497.

Godbey, W.T., Wu, K.K. and Mikos, A.G. 1999. Tracking the Intracellular Path of Poly(Ethylenimine)/DNA Complexes for Gene Delivery. Proc Natl Acad Sci U S A 96: 5177-81.

Marcusson, E.G., Bhat, B., Manoharan, M., Bennett, C.F. and Dean, N.M. 1998. Phosphorothioate Oligodeoxyribonucleotides Dissociate From Cationic Lipids Before Entering the Nucleus. Nucleic Acids Res. 26: 2016-2023.

Pollard, H., Remy, J.S., Loussouarn, G., Demolombe, S., Behr, J.P. and Escande, D. 1998. Polyethylenimine but Not Cationic Lipids Promotes Transgene Delivery to the Nucleus in Mammalian Cells. J. Biol. Chem. 273: 7507-7511.

Oidi, Y., Hollins, A.J., Drayton, R.M. and Akhtar, S. 2005c. Polypropylenimine Dendrimer-Induced Gene Expression Changes: the Effect of Complexation With DNA, Dendrimer Generation and Cell Type. J. Drug Target 13: 431-443.

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