Multi-resolution 3D visualization of the early stages of cellular uptake of peptide-coated nanoparticles

Abstract

A detailed understanding of the cellular uptake process is essential to the development of cellular delivery strategies1 and to the study of viral trafficking2. However, visualization of the entire process, encompassing the fast dynamics (local to the freely diffusing nanoparticle) as well the state of the larger-scale cellular environment, remains challenging3. Here, we introduce a three-dimensional multi-resolution method to capture, in real time, the transient events leading to cellular binding and uptake of peptide (HIV1-Tat)-modified nanoparticles. Applying this new method to observe the landing of nanoparticles on the cellular contour in three dimensions revealed long-range deceleration of the delivery particle, possibly due to interactions with cellular receptors. Furthermore, by using the nanoparticle as a nanoscale ‘dynamics pen’, we discovered an unexpected correlation between small membrane terrain structures and local nanoparticle dynamics. This approach could help to reveal the hidden mechanistic steps in a variety of multiscale processes.

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Figure 1: Three-dimensional multi-resolution microscopy of the early stages of cellular uptake.
Figure 2: Transient interactions of Tat-coated nanoparticles with the cell surface.
Figure 3: Cell surface terrain features display ‘hot’ dynamics.
Figure 4: Anisotropic diffusion along filopodia.

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Acknowledgements

The authors thank S. McManus for assistance with TEM measurements. This work was supported by the US Department of Energy (DE-SC0006838) and by Princeton University.

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Contributions

K.W. and H.Y. conceived and designed the experiments. K.W. performed the experiments. K.W. and H.Y. analysed the data. K.W. and H.Y. wrote the paper.

Corresponding author

Correspondence to Haw Yang.

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The authors declare no competing financial interests.

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Welsher, K., Yang, H. Multi-resolution 3D visualization of the early stages of cellular uptake of peptide-coated nanoparticles. Nature Nanotech 9, 198–203 (2014). https://doi.org/10.1038/nnano.2014.12

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