Silica nanoparticles permeabilize lipid bilayers

Potential toxic effects of synthetic nanoparticles are of great public concern. Presently, the impact of nanoparticles at a cellular level is assessed by adding nanoparticles to cell cultures and subsequent evaluation of particle uptake by confocal fluorescence microscopy and of cell viability by conventional (fluorescence) assays. Cytotoxic effects of nanoparticles have been reported but a correlation between nanoparticle properties (e.g. size, shape, surface chemistry) and cell viability remains elusive. However, cellular uptake of nanoparticles is almost universally observed. Membrane translocation of nanoparticles is generally considered to be an active process, requiring the presence of receptors that mediate encapsulation of the nanoparticles into an intracellular vesicle, from which the particles may or may not escape into the cytosol. Using electrophysiological methods we have demonstrated that spherical silica nanoparticles, under development for intracellular drug delivery, are able to permeabilize protein-free lipid bilayers as a function of size and surface charge. Single channel-like conductances, similar to those induced by membrane-disrupting ?-amyloid peptides, are observed for rigid sterol-containing bilayers. For more fluid bilayers of DOPC the conductance gradually increases until the bilayer disintegrates, which has also been observed for cytotoxic amyloid oligomers. The most disruptive nanospheres were shown by confocal fluorescence microscopy to accumulate at the bilayer surface, and we demonstrated that a fraction of these particles translocate across the lipid bilayer, suggesting that passive uptake of nanoparticles may contribute to cellular uptake. Our combined electrophysiology and fluorescence microscopy approach is experimentally straightforward and enables rapid systematic investigation of the interactions between nanoparticles and the lipid components of the cell membrane. These model studies will aid in the rational design of safe nanoparticles -for drug delivery and subcellular labeling- that traverse the plasma membrane without adverse effects on membrane integrity