Mechanisms of Uptake and Membrane Curvature Generation for the Internalization of Silica Nanoparticles by Cells

[Image: see text] Nanosized drug carriers enter cells via active mechanisms of endocytosis but the pathways involved are often not clarified. Cells possess several mechanisms to generate membrane curvature during uptake. However, the mechanisms of membrane curvature generation for nanoparticle uptake have not been explored so far. Here, we combined different methods to characterize how silica nanoparticles with a human serum corona enter cells. In these conditions, silica nanoparticles are internalized via the LDL receptor (LDLR). We demonstrate that despite the interaction with LDLR, uptake is not clathrin-mediated, as usually observed for this receptor. Additionally, silencing the expression of different proteins involved in clathrin-independent mechanisms and several BAR-domain proteins known to generate membrane curvature strongly reduces nanoparticle uptake. Thus, nanosized objects targeted to specific receptors, such as here LDLR, can enter cells via different mechanisms than their endogenous ligands. Additionally, nanoparticles may trigger alternative mechanisms of membrane curvature generation for their internalization.