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WIREs Nanomed Nanobiotechnol
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Challenges in carrier‐mediated intracellular delivery: moving beyond endosomal barriers

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The deployment of molecular to microscale carriers for intracellular delivery has tremendous potential for biology and medicine, especially for in vivo therapies. The field remains limited, however, by a poor understanding of how carriers gain access to the cell interior. In this review, we provide an overview of the different types of carriers, their speculated modes of entry, putative pathways of vesicular transport, and sites of endosomal escape. We compare this alongside pertinent examples from the cell biology of how viruses, bacteria, and their effectors enter cells and escape endosomal confinement. We anticipate insights into the mechanisms of cellular entry and endosomal escape will benefit future research efforts on effective carrier‐mediated intracellular delivery. WIREs Nanomed Nanobiotechnol 2016, 8:465–478. doi: 10.1002/wnan.1377 This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Example of the wide range of carrier architectures employed for intracellular delivery and their approximate size ranges. Carriers with fusogenic potential are shown with red text. The others (black text) generally enter cells via endocytosis. Example cargoes are shown as miscellaneous (green spheres) or nucleic acids (wavey, black lines).
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Autophagy‐based capture of transiently disrupted endosomes. Activation of autophagy leads to the formation of a, phagophore, that recruits microtubule‐associated protein 1A/1B‐light chain 3 (LC3), onto its surface, leading to sequestration of cytosolic components or organelles within the cell into a double membrane‐auto‐phagosome, which fuses, with the endo/lysosomal system for degradation of its constituents. Few nanoparticles can penetrate endosomal membranes and cause transient vesicular disruption, initiating autophagy. These vesicular compartments containing large amounts of drug‐carriers are quarantined in autophagosomes and directed to lysosomal degradation.
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Intracellular transport of macromolecules in the endo/lysosomal system. Nanoparticles can utilize multiple pathways to enter cells, once inside the cargo faces a changing environment of the maturing endosome, i.e., decrease in pH and shape change, the unilamellar EE, becomes multivesicular, followed by a multilamellar lysosome. Several effector proteins bind to the cytosolic end of the endosomal lumen and transport the vesicles to different subcellular organelles. Genetic manipulation of these components has been used to unravel endosomal transport of different bacteria and viruses. Investigation of nanocarriers–endosome interactions using these methods can reveal new methods to enhance endosomal escape.
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Pathways for carrier‐mediated endosomal escape and cytosolic delivery of drugs/nucleic acids. Fusion can occur between a membrane‐bound carrier and the plasma membrane, or inside endosomal compartments. Alternatively, back‐fusion of a smaller vesicle (ILV) inside a limiting multivesicular body may inadvertently release the cargo. Other purported mechanisms of endosomal escape may involve active transport via membrane proteins (red), passage through transient disruptions or pores, or complete lysis of the containing endosomal compartment.
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Cell surface interactions direct the pathway of uptake. Carriers interact with the cell surface by specifically or nonspecifically binding exposed carbohydrate moieties from lipids or proteins, extracellular proteins domains/receptors, or different phases of the plasma membrane, such as cholesterol‐rich lipid rafts. Alternatively they remain unbound and are taken up by fluid phase endocytosis. Illustrated are generic carriers (purple), ligands (red squares), cholesterol (red/brown wedges), lipid heads (light blue, dark blue circles), bilayer (light brown strip), carbohydrate residues (black hexagons), and membrane proteins (orange).
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Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Nanotechnology Approaches to Biology > Cells at the Nanoscale

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