Research on nanoparticle (NP)-cell interactions has been extensively carried out in dilute cell cultures, where NPs are heavily internalized by cells. However, it is not known whether the findings from cell culture studies are still true in tissues where cells are tightly packed. Here, we show experimentally and theoretically that when cells are tightly packed, cellular uptake is strongly hindered. When simultaneously encountering two adjacent cells as is often the case in tissues, adhesion, bending and protrusion of at least two membranes from these cells generate complicated energy contributions that cause trapping of NPs at cell junctions with impeded uptake.