Intracellular delivery of nanomaterials: how to catch endosomal escape in the act

Summary Successful cytosolic delivery of nanomaterials is becoming more and more important, given the increase in intracellular applications of quantum dots, gold nanoparticles, liposomal drug formulations and polymeric gene delivery vectors. Most nanomaterials are taken up by the cell via endocytosis, yet endosomal escape has long been recognized as a major bottleneck in cytosolic delivery. Although it is essential to detect and reliably quantify endosomal escape, no consensus has been reached so far on the methods to do so. This review will summarize and discuss for the first time the different assays used to investigate this elusive step to date.

[1]  I. Zuhorn,et al.  Mechanism of polyplex- and lipoplex-mediated delivery of nucleic acids: real-time visualization of transient membrane destabilization without endosomal lysis. , 2013, ACS nano.

[2]  Y. Anraku,et al.  Smart multilayered assembly for biocompatible siRNA delivery featuring dissolvable silica, endosome-disrupting polycation, and detachable PEG. , 2012, ACS nano.

[3]  Sangeeta N. Bhatia,et al.  Intracellular Delivery of Quantum Dots for Live Cell Labeling and Organelle Tracking , 2004 .

[4]  Tae Gwan Park,et al.  Temperature-sensitive pluronic/poly(ethylenimine) nanocapsules for thermally triggered disruption of intracellular endosomal compartment. , 2006, Biomacromolecules.

[5]  Warren C W Chan,et al.  Strategies for the intracellular delivery of nanoparticles. , 2011, Chemical Society reviews.

[6]  C. Highley,et al.  Enhanced cellular uptake and long-term retention of chitosan-modified iron-oxide nanoparticles for MRI-based cell tracking , 2012, International journal of nanomedicine.

[7]  Demetri Psaltis,et al.  Precision intracellular delivery based on optofluidic polymersome rupture. , 2012, ACS nano.

[8]  D. Scherman,et al.  A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Can Zhang,et al.  Intracellular delivery and antitumor effects of pH-sensitive liposomes based on zwitterionic oligopeptide lipids. , 2013, Biomaterials.

[10]  D. Inzé,et al.  Biochemical Society Transactions Control of cell division in plants , 2009 .

[11]  N. Demaurex,et al.  Endosome-to-cytosol transport of viral nucleocapsids , 2005, Nature Cell Biology.

[12]  K. Nicolay,et al.  Photochemical activation of endosomal escape of MRI‐Gd‐agents in tumor cells , 2011, Magnetic Resonance in Medicine.

[13]  Wolfgang J. Parak,et al.  Cellular toxicity of inorganic nanoparticles: Common aspects and guidelines for improved nanotoxicity evaluation , 2011 .

[14]  Angelo Bifone,et al.  Cholesterol-dependent macropinocytosis and endosomal escape control the transfection efficiency of lipoplexes in CHO living cells. , 2012, Molecular pharmaceutics.

[15]  I. Pastan,et al.  Role of a low-pH environment in adenovirus enhancement of the toxicity of a Pseudomonas exotoxin-epidermal growth factor conjugate , 1984, Journal of virology.

[16]  K. Bloch モノ不飽和脂肪酸の生合成〔Accounts of Chemical Research 2〔1969〕 p193掲載〕 , 1970 .

[17]  N. M. Zaki,et al.  Nanocarriers for cytoplasmic delivery: cellular uptake and intracellular fate of chitosan and hyaluronic acid-coated chitosan nanoparticles in a phagocytic cell model. , 2011, Macromolecular bioscience.

[18]  N. M. Zaki,et al.  Gateways for the intracellular access of nanocarriers: a review of receptor-mediated endocytosis mechanisms and of strategies in receptor targeting , 2010, Expert opinion on drug delivery.

[19]  Alain Thierry,et al.  Endosome trapping limits the efficiency of splicing correction by PNA-oligolysine conjugates. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[20]  J. Mindell Lysosomal acidification mechanisms. , 2012, Annual review of physiology.

[21]  Samir Mitragotri,et al.  Understanding intracellular transport processes pertinent to synthetic gene delivery via stochastic simulations and sensitivity analyses. , 2007, Biophysical journal.

[22]  U. Greber,et al.  Genetic reconstitution of the human Adenovirus type 2 temperature-sensitive 1 mutant defective in endosomal escape , 2009, Virology Journal.

[23]  Sarah Seifert,et al.  Image-based analysis of lipid nanoparticle–mediated siRNA delivery, intracellular trafficking and endosomal escape , 2013, Nature Biotechnology.

[24]  S. Futaki,et al.  Octaarginine- and Octalysine-modified Nanoparticles Have Different Modes of Endosomal Escape* , 2008, Journal of Biological Chemistry.

[25]  C. Wiethoff,et al.  An N-terminal domain of adenovirus protein VI fragments membranes by inducing positive membrane curvature. , 2010, Virology.

[26]  Mauro Ferrari,et al.  Logic-embedded vectors for intracellular partitioning, endosomal escape, and exocytosis of nanoparticles. , 2010, Small.

[27]  E. Wagner,et al.  Sequence defined disulfide-linked shuttle for strongly enhanced intracellular protein delivery. , 2012, Molecular pharmaceutics.

[28]  K. Altendorf,et al.  Bafilomycins and concanamycins as inhibitors of V-ATPases and P-ATPases. , 1997, The Journal of experimental biology.

[29]  N. Ingle,et al.  Polymeric nucleic acid vehicles exploit active interorganelle trafficking mechanisms. , 2013, ACS nano.

[30]  Michael J Rust,et al.  Visualizing infection of individual influenza viruses , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[31]  L G Griffith,et al.  Quantitative comparison of polyethylenimine formulations and adenoviral vectors in terms of intracellular gene delivery processes , 2005, Gene Therapy.

[32]  K. L. Douglas Toward Development of Artificial Viruses for Gene Therapy: A Comparative Evaluation of Viral and Non‐viral Transfection , 2008, Biotechnology progress.

[33]  O. Urakawa,et al.  Small - , 2007 .

[34]  Tana,et al.  pH-Sensitive fusogenic polymer-modified liposomes as a carrier of antigenic proteins for activation of cellular immunity. , 2010, Biomaterials.

[35]  L. Chernomordik,et al.  Cell-penetrating peptide induces leaky fusion of liposomes containing late endosome-specific anionic lipid. , 2010, Biophysical journal.

[36]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[37]  O. Danos,et al.  Polyethylenimine‐mediated gene delivery: a mechanistic study , 2001, The journal of gene medicine.

[38]  Daniel K. Bonner,et al.  Intracellular trafficking of polyamidoamine-poly(ethylene glycol) block copolymers in DNA delivery. , 2011, Bioconjugate chemistry.

[39]  A. V. van Oijen,et al.  University of Groningen Visualization of Membrane Fusion , One Particle at a Time Otterstrom , 2018 .

[40]  Young Jik Kwon,et al.  Stimuli-responsive polymers and nanomaterials for gene delivery and imaging applications. , 2012, Advanced drug delivery reviews.

[41]  Jayanth Panyam,et al.  Rapid endo‐lysosomal escape of poly(DL‐lactide‐coglycolide) nanoparticles: implications for drug and gene delivery , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[42]  Kristiaan Neyts,et al.  Correlation of Dual Colour Single Particle Trajectories for Improved Detection and Analysis of Interactions in Living Cells , 2013, International journal of molecular sciences.

[43]  R. Langer,et al.  Exploring polyethylenimine‐mediated DNA transfection and the proton sponge hypothesis , 2005, The journal of gene medicine.

[44]  D. Dimitrov,et al.  Virus entry: molecular mechanisms and biomedical applications , 2004, Nature Reviews Microbiology.

[45]  F. Young Biochemistry , 1955, The Indian Medical Gazette.

[46]  A. Miller,et al.  Cell delivery, intracellular trafficking and expression of an integrin-mediated gene transfer vector in tracheal epithelial cells , 2000, Gene Therapy.

[47]  Kinam Park,et al.  Polycation gene delivery systems: escape from endosomes to cytosol , 2003, The Journal of pharmacy and pharmacology.

[48]  Vadim Zinchuk,et al.  Quantitative Colocalization Analysis of Multicolor Confocal Immunofluorescence Microscopy Images: Pushing Pixels to Explore Biological Phenomena , 2007, Acta histochemica et cytochemica.

[49]  F. Cordelières,et al.  A guided tour into subcellular colocalization analysis in light microscopy , 2006, Journal of microscopy.

[50]  Juliane Nguyen,et al.  Nucleic acid delivery: the missing pieces of the puzzle? , 2012, Accounts of chemical research.

[51]  M. Tirrell,et al.  Structural effects and lipid membrane interactions of the pH-responsive GALA peptide with fatty acid acylation. , 2012, Biochemistry.

[52]  Kevin Braeckmans,et al.  Assessing nanoparticle toxicity in cell-based assays: influence of cell culture parameters and optimized models for bridging the in vitro-in vivo gap. , 2013, Chemical Society reviews.

[53]  K. Braeckmans,et al.  Effect of covalent fluorescence labeling of plasmid DNA on its intracellular processing and transfection with lipid-based carriers. , 2014, Molecular pharmaceutics.

[54]  V. Georgiev Virology , 1955, Nature.

[55]  Kristian Berg,et al.  Cellular uptake of DNA-chitosan nanoparticles: the role of clathrin- and caveolae-mediated pathways. , 2012, International journal of biological macromolecules.

[56]  H Akita,et al.  Quantitative three-dimensional analysis of the intracellular trafficking of plasmid DNA transfected by a nonviral gene delivery system using confocal laser scanning microscopy. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[57]  K. Braeckmans,et al.  Nucleic acid delivery: Where material sciences and bio-sciences meet , 2007 .

[58]  宁北芳,et al.  疟原虫var基因转换速率变化导致抗原变异[英]/Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A , 2005 .

[59]  Yuichi Yamasaki,et al.  In situ single cell observation by fluorescence resonance energy transfer reveals fast intra‐cytoplasmic delivery and easy release of plasmid DNA complexed with linear polyethylenimine , 2004, The journal of gene medicine.

[60]  Angelo Bifone,et al.  Transfection efficiency boost of cholesterol-containing lipoplexes. , 2012, Biochimica et biophysica acta.

[61]  C. Wiethoff,et al.  Spatiotemporal Dynamics of Adenovirus Membrane Rupture and Endosomal Escape , 2012, Journal of Virology.

[62]  J. Engbersen,et al.  Dynamic colocalization microscopy to characterize intracellular trafficking of nanomedicines. , 2011, ACS nano.

[63]  L. Rajendran,et al.  Subcellular targeting strategies for drug design and delivery , 2010, Nature Reviews Drug Discovery.

[64]  A. Jones,et al.  Establishment of subcellular fractionation techniques to monitor the intracellular fate of polymer therapeutics II. Identification of endosomal and lysosomal compartments in HepG2 cells combining single-step subcellular fractionation with fluorescent imaging , 2007, Journal of drug targeting.

[65]  Igor L. Medintz,et al.  Delivering quantum dot-peptide bioconjugates to the cellular cytosol: escaping from the endolysosomal system. , 2010, Integrative biology : quantitative biosciences from nano to macro.

[66]  Tim Leshuk,et al.  Emerging nanomaterials for targeting subcellular organelles , 2011 .

[67]  Won Jong Kim,et al.  Photothermally controlled gene delivery by reduced graphene oxide-polyethylenimine nanocomposite. , 2014, Small.

[68]  K. Berg,et al.  Photochemical internalization provides time- and space-controlled endolysosomal escape of therapeutic molecules. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[69]  S Moein Moghimi,et al.  The possible "proton sponge " effect of polyethylenimine (PEI) does not include change in lysosomal pH. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[70]  Gert Storm,et al.  Endosomal escape pathways for delivery of biologicals. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[71]  T. Park,et al.  Thermally sensitive cationic polymer nanocapsules for specific cytosolic delivery and efficient gene silencing of siRNA: swelling induced physical disruption of endosome by cold shock. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[72]  G. Nemerow,et al.  Adenovirus Protein VI Mediates Membrane Disruption following Capsid Disassembly , 2005, Journal of Virology.

[73]  C. Bräuchle,et al.  Dynamics of photoinduced endosomal release of polyplexes. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[74]  J. Pellois,et al.  Real-time fluorescence detection of protein transduction into live cells. , 2008, Journal of the American Chemical Society.

[75]  Jindrich Kopecek,et al.  Intracellular Processing of Poly(Ethylene Imine)/Ribozyme Complexes Can Be Observed in Living Cells by Using Confocal Laser Scanning Microscopy and Inhibitor Experiments , 2002, Pharmaceutical Research.

[76]  A. J. Clifford,et al.  BIOCHIMICA ET BIOPHYSICA ACTA , 2022 .

[77]  O. A. Trowell Annual Review of Physiology , 1948, Nature.

[78]  Boris Klebanov,et al.  Influence of Cationic Lipid Composition on Gene Silencing Properties of Lipid Nanoparticle Formulations of siRNA in Antigen-Presenting Cells , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[79]  R. Misra,et al.  Biomaterials , 2008 .

[80]  O. Lambert,et al.  Asymmetrical membranes and surface tension. , 2002, Biophysical journal.

[81]  M. Kortylewski,et al.  Intracellular processing of immunostimulatory CpG-siRNA: Toll-like receptor 9 facilitates siRNA dicing and endosomal escape. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[82]  Igor L. Medintz,et al.  Selecting improved peptidyl motifs for cytosolic delivery of disparate protein and nanoparticle materials. , 2013, ACS nano.

[83]  Boris E. Burakov,et al.  Advanced Materials , 2019, Springer Proceedings in Physics.

[84]  F. Beltram,et al.  A novel chimeric cell-penetrating peptide with membrane-disruptive properties for efficient endosomal escape. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[85]  T. Tanabe,et al.  The conjugation of diphtheria toxin T domain to poly(ethylenimine) based vectors for enhanced endosomal escape during gene transfection. , 2009, Biomaterials.

[86]  G. Melikyan,et al.  HIV Enters Cells via Endocytosis and Dynamin-Dependent Fusion with Endosomes , 2009, Cell.

[87]  P. Schwille,et al.  New effects in polynucleotide release from cationic lipid carriers revealed by confocal imaging, fluorescence cross-correlation spectroscopy and single particle tracking. , 2005, Biochimica et biophysica acta.

[88]  Igor L. Medintz,et al.  Delivering quantum dots into cells: strategies, progress and remaining issues , 2009, Analytical and bioanalytical chemistry.

[89]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[90]  R. Duncan,et al.  Intracellular fate of bioresponsive poly(amidoamine)s in vitro and in vivo. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[91]  G. A. van der Marel,et al.  Targeted Lysosome Disruptive Elements for Improvement of Parenchymal Liver Cell-specific Gene Delivery* , 2002, The Journal of Biological Chemistry.

[92]  G. Nemerow,et al.  Functional Genetic and Biophysical Analyses of Membrane Disruption by Human Adenovirus , 2011, Journal of Virology.

[93]  K. Rock,et al.  Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization , 2008, Nature Immunology.

[94]  K. Scheffzek,et al.  Enhancing Endosomal Escape of Transduced Proteins by Photochemical Internalisation , 2012, PloS one.

[95]  Kevin Braeckmans,et al.  On the cellular processing of non-viral nanomedicines for nucleic acid delivery: mechanisms and methods. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[96]  Zhenpeng Qin,et al.  Thermophysical and biological responses of gold nanoparticle laser heating. , 2012, Chemical Society reviews.

[97]  S. Futaki,et al.  Modeling the endosomal escape of cell-penetrating peptides using a transmembrane pH gradient. , 2013, Biochimica et biophysica acta.

[98]  W. Jiskoot,et al.  Functional Characterization of an Endosome-disruptive Peptide and Its Application in Cytosolic Delivery of Immunoliposome-entrapped Proteins* , 2002, The Journal of Biological Chemistry.

[99]  F. Szoka,et al.  GALA: a designed synthetic pH-responsive amphipathic peptide with applications in drug and gene delivery. , 2004, Advanced drug delivery reviews.

[100]  Evgeny Polushkin,et al.  Nonbilayer phase of lipoplex-membrane mixture determines endosomal escape of genetic cargo and transfection efficiency. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[101]  Raul Vicente,et al.  Polymeric micelles based on poly(methacrylic acid) block-containing copolymers with different membrane destabilizing properties for cellular drug delivery. , 2013, International journal of pharmaceutics.

[102]  C. Pichon,et al.  Chemical vectors for gene delivery: uptake and intracellular trafficking. , 2010, Current opinion in biotechnology.

[103]  E. Wagner,et al.  Virus-mediated release of endosomal content in vitro: different behavior of adenovirus and rhinovirus serotype 2 , 1995, The Journal of cell biology.

[104]  B. Cohen,et al.  Rapid cytosolic delivery of luminescent nanocrystals in live cells with endosome-disrupting polymer colloids. , 2010, Nano letters.

[105]  Ari Helenius,et al.  Stepwise dismantling of adenovirus 2 during entry into cells , 1993, Cell.

[106]  W. J. Meek,et al.  THE FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY. , 1938, Science.

[107]  R. Fischer,et al.  A Stepwise Dissection of the Intracellular Fate of Cationic Cell-penetrating Peptides* , 2004, Journal of Biological Chemistry.

[108]  Joseph A. Mindell,et al.  The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes , 2008, Nature.

[109]  L. Wang,et al.  Virology Journal , 1966, Nature.

[110]  I. Zuhorn,et al.  Gene delivery by cationic lipids: in and out of an endosome. , 2007, Biochemical Society transactions.

[111]  Yu-qiang Ma,et al.  Insights into the endosomal escape mechanism via investigation of dendrimer–membrane interactions , 2012 .

[112]  Kirsten Sandvig,et al.  Endocytosis and intracellular transport of nanoparticles: Present knowledge and need for future studies , 2011 .

[113]  Takao Hayakawa,et al.  Quantitative comparison of intracellular trafficking and nuclear transcription between adenoviral and lipoplex systems. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[114]  Mark E. Davis,et al.  PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. , 2004, European journal of cell biology.

[115]  V. Sée,et al.  Inflicting controlled nonthermal damage to subcellular structures by laser-activated gold nanoparticles. , 2010, Nano letters.

[116]  Taeghwan Hyeon,et al.  Inorganic Nanoparticles for MRI Contrast Agents , 2009 .

[117]  S. Smedt,et al.  Efficient delivery of intact phosphodiester oligonucleotides by poly-beta-amino esters. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[118]  D. Hoekstra,et al.  Cationic lipids, lipoplexes and intracellular delivery of genes. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[119]  T. Bieber,et al.  Intracellular route and transcriptional competence of polyethylenimine-DNA complexes. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[120]  K. Na,et al.  Endolysosomal environment-responsive photodynamic nanocarrier to enhance cytosolic drug delivery via photosensitizer-mediated membrane disruption. , 2013, Biomaterials.

[121]  N. M. Moore,et al.  The effect of endosomal escape peptides on in vitro gene delivery of polyethylene glycol‐based vehicles , 2008, The journal of gene medicine.

[122]  J. Zia,et al.  Poly(2-alkylacrylic acid) polymers deliver molecules to the cytosol by pH-sensitive disruption of endosomal vesicles. , 2003, The Biochemical journal.

[123]  P. Cosson,et al.  Separation and Characterization of Late Endosomal Membrane Domains* , 2002, The Journal of Biological Chemistry.

[124]  K. Braeckmans,et al.  Elucidating the pre- and post-nuclear intracellular processing of 1,4-dihydropyridine based gene delivery carriers. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[125]  J. Feijen,et al.  Novel bioreducible poly(amido amine)s for highly efficient gene delivery. , 2007, Bioconjugate chemistry.

[126]  S. Futaki,et al.  Endosomal escape and the knockdown efficiency of liposomal-siRNA by the fusogenic peptide shGALA. , 2011, Biomaterials.