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Dynamic interactions and intracellular fate of label-free, thin graphene oxide sheets within mammalian cells: Role of lateral sheet size

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Chen, Y, Rivers-Auty, J ORCID: 0000-0001-5321-2347, Crica, LE, Barr, K, Rosano, V, Arranz, AE, Loret, T, Spiller, D, Bussy, C, Kostarelos, K and Vranic, S 2021 , 'Dynamic interactions and intracellular fate of label-free, thin graphene oxide sheets within mammalian cells: Role of lateral sheet size' , Nanoscale Advances, vol. 3, no. 14 , pp. 4166-4185 , doi: 10.1039/d1na00133g.

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Abstract

Graphene oxide (GO) holds great potential for biomedical applications, however fundamental understanding of the way it interacts with biological systems is still lacking even though it is essential for successful clinical translation. In this study, we exploit intrinsic fluorescent properties of thin GO sheets to establish the relationship between lateral dimensions of the material, its cellular uptake mechanisms and intracellular fate over time. Label-free GO with distinct lateral dimensions, small (s-GO) and ultra-small (us-GO) were thoroughly characterised both in water and in biologically relevant cell culture medium. Interactions of the material with a range of non-phagocytic mammalian cell lines (BEAS-2B, NIH/3T3, HaCaT, 293T) were studied using a combination of complementary analytical techniques (confocal microscopy, flow cytometry and TEM). The uptake mechanism was initially interrogated using a range of pharmaceutical inhibitors and validated using polystyrene beads of different diameters (0.1 and 1 μm). Subsequently, RNA-Seq was used to follow the changes in the uptake mechanism used to internalize s-GO flakes over time. Regardless of lateral dimensions, both types of GO were found to interact with the plasma membrane and to be internalized by a panel of cell lines studied. However, s-GO was internalized mainly via macropinocytosis while us-GO was mainly internalized via clathrin- and caveolae-mediated endocytosis. Importantly, we report the shift from macropinocytosis to clathrin-dependent endocytosis in the uptake of s-GO at 24 h, mediated by upregulation of mTORC1/2 pathway. Finally, we show that both s-GO and us-GO terminate in lysosomal compartments for up to 48 h. Our results offer an insight into the mechanism of interaction of GO with non-phagocytic cell lines over time that can be exploited for the design of biomedically-applicable 2D transport systems. This journal is

Item Type: Article
Authors/Creators:Chen, Y and Rivers-Auty, J and Crica, LE and Barr, K and Rosano, V and Arranz, AE and Loret, T and Spiller, D and Bussy, C and Kostarelos, K and Vranic, S
Journal or Publication Title: Nanoscale Advances
Publisher: Royal Society of Chemistry
ISSN: 2516-0230
DOI / ID Number: 10.1039/d1na00133g
Copyright Information:

© 2021 The Author(s). Published by the Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported (CC BY-NC 3.0) Licence, (https://creativecommons.org/licenses/by-nc/3.0/)

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