Core–shell nanoparticles (NPs) with lipid shells and varying water content and rigidity but with the same chemical composition, size, and surface properties are assembled using a microfluidic platform. Rigidity can dramatically alter the cellular uptake efficiency, with more‐rigid NPs able to pass more easily through cell membranes. The mechanism accounting for this rigidity‐dependent cellular uptake is revealed through atomistic‐level simulations.

A fundamental understanding of cell-nanomaterial interaction is of essential importance to nanomedicine and safe applications of nanotechnology. Here we investigate the adhesive wrapping of a soft elastic vesicle by a lipid membrane. We show that there exist a maximum of five distinct wrapping phases based on the stability of full wrapping, partial wrapping, and no wrapping states. The wrapping phases depend on the vesicle size, adhesion energy, surface tension of membrane, and bending rigidity ratio between vesicle and membrane. These results are of immediate interest to the study of vesicular transport and endocytosis or phagocytosis of elastic particles into cells.