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WIREs Nanomed Nanobiotechnol
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Nanoescapology: progress toward understanding the endosomal escape of polymeric nanoparticles

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Using nanoparticles to deliver drugs to cells has the potential to revolutionize the treatment of many diseases, including HIV, cancer, and diabetes. One of the major challenges facing this field is controlling where the drug is trafficked once the nanoparticle is taken up into the cell. In particular, if drugs remain localized in an endosomal or lysosomal compartment, the therapeutic can be rendered completely ineffective. To ensure the design of more effective delivery systems we must first develop a better understanding of how nanoparticles and their cargo are trafficked inside cells. This needs to be combined with an understanding of what characteristics are required for nanoparticles to achieve endosomal escape, along with methods to detect endosomal escape effectively. This review is focused into three sections: first, an introduction to the mechanisms governing internalization and trafficking in cells, second, a discussion of methods to detect endosomal escape, and finally, recent advances in controlling endosomal escape from polymer‐ and lipid‐based nanoparticles, with a focus on engineering materials to promote endosomal escape. WIREs Nanomed Nanobiotechnol 2017, 9:e1452. doi: 10.1002/wnan.1452 This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Delivery of GFP into HeLa cells. (a) Confocal image showing GFP delivery into HeLa cells by nanoparticles (NPSCs). (b) Confocal images showing the co‐localization of delivered GFP with expressed mCherry in HeLa cell. (c) Flow cytometry results of HeLa cells treated with GFP‐NPSCs (red) or GFP alone (blue) for 2 h, using untreated HeLa cells as the control (black). Scale bars: 20 µm. (Reprinted with permission from Ref . Copyright 2013 American Chemical Society)
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pH‐responsive nanoparticles induce endosomal escape of calcein in a dendritic cell line. (a–i) Confocal microscopy images. (a–c) Bright‐field images. (d–i) Fluorescence overlays (red, nanoparticles; green, calcein). (a, d, g) Cells were treated with calcein alone. (b, e, h) Cells were co‐incubated with calcein and PDEAEMA‐core/PAEMA‐shell nanoparticles. (c, f, i) Cells were co‐incubated with calcein and PMMA‐core/PAEMA‐shell nanoparticles. Scale bars: (a–f) 20 µm and (g–i) 10 µm. (j) Average percentage of cells observed by confocal microscopy exhibiting endosomal versus cytosolic/nuclear calcein distributions after 1 h from three independent experiments: calcein alone (gray bar), calcein with PDEAEMA core‐shell particles (white bar), or calcein with PMMA core‐shell particles (black bar). (Reprinted with permission from Ref . Copyright 2007 American Chemical Society)
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Cargo enclosed in lysosomes appears as a ring of the labeled lysosome marker around the labeled particle and results in low overlap coefficients. Scale bar = 5 µm. (Reprinted with permission from Ref 44. Copyright 2017 American Chemical Society).
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Fluorescence microscopy image contrasting (a) zero to low levels of endosomal escape with (b) high levels of escape. Fluorescently labeled cargo sequestered in endo/lysosomes appears punctate while a cytosolic localization causes a diffuse appearance. (Reprinted with permission from Ref . Copyright 2014 Nature Publishing Group)
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Mechanisms of endosomal escape. (a) Proton sponge effect—Polymers capable of buffering become protonated as protons are pumped into endosomes as part of the regular trafficking process by ATPases. Chloride ions are also transported to maintain the charge balance within the endosome. The increase in ion concentration causes osmotic swelling and ruptures the membrane. (b) Membrane fusion—Anionic lipids on the cytoplasmic side of the endosomes rearrange to form a neutral ion pair with cationic lipids of the carrier, destabilizing the membrane. The membranes fuse and allow the cargo to move into the cytoplasm. (c) Pore formation—Certain peptides self‐assemble in the lipid membrane to form pores that enable low‐molecular therapeutics to escape. (d) Membrane disruption—Polymers or peptides interact directly with the endosomal membrane causing disruption, allowing cargo to escape.
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Polymer‐enhanced intracellular delivery of FAM‐labeled siRNA. Representative images illustrating (a) punctate staining (green) in the samples treated with Lipofectamine/siRNA complexes alone and (b) dispersed fluorescence within the cytosol following delivery of diblock copolymer/siRNA complexes. Samples were treated for 15 min with 25 nM FAM‐siRNA and prepared for microscopic examination following DAPI nuclear staining (blue). (Reprinted with permission from Ref . Copyright 2010 American Chemical Society)
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Nanoparticles can enter cells through multiple mechanisms. Particles are taken up into vesicles coated with clathrin, caveolin, or by using a clathrin/caveolin‐independent mechanism. EEA1 tethers to RAB5 on internalized vesicles and draws them into RAB5‐positive early endosomes. The pH drops to ~6.3 and cargo is recycled to the surface or trafficked to RAB7‐positive late endosomes (pH ~ 5.5). Contents are trafficked to the lysosome (pH ~ 4.7) where they are degraded by acid hydrolases. Alternative modes of entry include membrane fusion or direct translocation across the membrane, bypassing the trafficking pathway.
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