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 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. Using a three-dimensional multi-resolution method the early events leading to the cellular uptake of peptide-modified nanoparticles are visualized in real time.