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

A detailed understanding of the cellular uptake process is essential to the development of cellular delivery strategies 1 and to the study of viral trafficking 2 . 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 challenging 3 . 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. Using a three-dimensional multi-resolution method the early events leading to the cellular uptake of peptide-modified nanoparticles are visualized in real time.