Understanding and controlling the interaction of graphene-based materials with cell membranes is key to the development of graphene-enabled biomedical technologies and to the management of graphene health and safety issues. Very little is known about the fundamental behavior of cell membranes exposed to ultrathin 2D synthetic materials. Here we investigate the interactions of graphene and few-layer graphene (FLG) microsheets with three cell types and with model lipid bilayers by combining coarse-grained molecular dynamics (MD), all-atom MD, analytical modeling, confocal fluorescence imaging, and electron microscopic imaging. The imaging experiments show edge-first uptake and complete internalization for a range of FLG samples of 0.5-to 10-μm lateral dimension. In contrast, the simulations show large energy barriers relative to k B T for membrane penetration by model graphene or FLG microsheets of similar size. More detailed simulations resolve this paradox by showing that entry is initiated at corners or asperities that are abundant along the irregular edges of fabricated graphene materials. Local piercing by these sharp protrusions initiates membrane propagation along the extended graphene edge and thus avoids the high energy barrier calculated in simple idealized MD simulations. We propose that this mechanism allows cellular uptake of even large multilayer sheets of micrometer-scale lateral dimension, which is consistent with our multimodal bioimaging results for primary human keratinocytes, human lung epithelial cells, and murine macrophages. molecular dynamics simulation | graphene-cell interaction | lipid membrane | edge cutting | corner penetration

The cell uptake rate of nanoparticles (NPs) coated with mixed hydrophilic/hydrophobic ligands is known to be strongly influenced by the ligand pattern on the nanoparticle surface. To help reveal the physical mechanism behind this intriguing phenomenon, here we perform dissipative particle dynamics simulations to analyze the evolution of free energy as the ligand-coated NPs pierce through a lipid bilayer. Four characteristic ligand patterns are considered: striated NPs with alternating hydrophilic and hydrophobic groups compared to NPs with randomly mixed ligands at the same hydrophilic to hydrophobic ratio, as well as NPs coated with homogeneous hydrophilic or hydrophobic ligands. The free energy analysis indicates that among the four ligand patterns under study, the striated NP encounters the lowest energy barrier during translocation across the membrane. Further analysis reveals that the translocation of the striated NP is facilitated by the constraint of its rotational degree of freedom by the anisotropic ligand pattern, which prevented the free energy of the system from sinking to a deeper valley as the NP passes through the hydrophobic core of the bilayer. Finally, the critical forces required for almost instant penetration of these patterned NPs across the bilayer are calculated and shown to be consistent with the free energy analysis. These findings provide useful guidelines for the molecular design of patterned NPs for controllable cell penetrability.