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Due to the amphiphilic nature of phospholipids in the cell membrane, the amphipathicity of the nanomedicine plays a crucial role in the endocytosis. However, limited biological characterization methods restrict the study of the state of nanoparticles with different amphiphilicities on cell membranes. The understanding of interaction of amphiphilic particle with cell membrane is still lacking. Herein, by combining the dissipative particle dynamics (DPD) with the framework construction of mesoporous silica nanoparticles (MSNs), we demonstrate the enhanced endocytosis induced by the hydrophobicity. DPD results confirm that the presence of hydrophobic groups on the surface of nanoparticles can disturb the integrity of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane and induce activation of phospholipids to a higher energy level, thereby facilitating the wrapping of nanoparticles. To validate the simulation findings, uniform MSNs with hydrophilic pure silica framework and two types of amphiphilic MSNs with varying hydrophilic organic groups in the framework are rationally synthesized by using different silane precursors. The obtained three kinds of MSNs show similar diameter (~ 100 nm) and mesopores (~ 2 nm), but distinct hydrophobicity/hydrophilicity ratio. The phenyl-bridged MSN with a carbon content of 27.1% exhibits enhanced cellular uptake, consistent with the theoretical simulation results. This work sheds light on how the surface amphipathicity influences endocytosis through the interaction with cell membrane.
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