Significance Nanoparticles are widely investigated for intracellular drug delivery and molecular imaging and should be designed to maximize cell uptake. Here the effects of particle geometry to maximize nanoparticle uptake by mammalian cells are evaluated. The findings show that uptake is governed by a combination of cell–particle adhesion, strain energy for membrane wrapping around the particle, and local particle concentration at the cell membrane, all of which are particle-shape–dependent. Under typical culture conditions, disc-shaped hydrophilic nanoparticles were internalized more efficiently than nanorods. Interestingly, larger nanodiscs and rods had higher uptake compared with the smallest particles tested. Mechanisms of uptake were also shape- and cell type-specific. These results provide important insights for rational design of nanocarriers to maximize intracellular delivery efficacy.

Mammalian cells preferentially internalize hydrogel nanodiscs over nanorods and use shape-specific uptake mechanisms