Loss of membrane asymmetry alters the interactions of erythrocytes with engineered silica nanoparticles

Abstract

Disruption of plasma membrane integrity is a primary mechanism of nanoparticle toxicity in cells. Mechanistic studies on nanoparticle-induced membrane damage have been commonly performed using model membranes with a focus on symmetric bilayers, overlooking the fact that the membrane has an asymmetric phospholipid composition. In this study, erythrocytes with normal and scrambled membrane asymmetry were utilized to examine how the loss of membrane asymmetry and the resulting alterations in the outer leaflet lipid composition affect nanoparticle-membrane interactions. Unmodified, amine-modified, and carboxyl-modified silica (30 nm) were used as nanoparticle models. Loss of membrane asymmetry was achieved by induction of eryptosis, using a calcium ionophore. Erythrocyte membrane disruption (hemolysis) by unmodified silica nanoparticles was significantly reduced in eryptotic compared to healthy cells. Amine- and carboxyl-modified particles did not cause hemolysis in either cell. In agreement, a significant reduction in the binding of unmodified silica nanoparticles to the membrane was observed upon loss of membrane asymmetry. Unmodified silica particles also caused significant cell deformation, changing healthy erythrocytes into a spheroid shape. In agreement with findings in the cells, unmodified particles disrupted vesicles mimicking the erythrocyte outer leaflet lipid composition. The degree of disruption and nanoparticle binding to the membrane was reduced in vesicles mimicking the composition of scrambled membranes. Cryo-electron microscopy revealed the presence of lipid layers on particle surfaces, pointing to lipid adsorption as the mechanism for vesicle damage. Together, findings indicate an important role for the lipid composition of the membrane outer leaflet in nanoparticle-induced membrane damage in both vesicles and erythrocytes.

Lipid Composition of the Cell Membrane Outer Leaflet Regulates Endocytosis of Nanomaterials through Alterations in Scavenger Receptor Activity

“…This complements our previous study, showing a difference in nanoparticle-induced membrane disruption depending on membrane lipid chemistry and order. 32,56,57 Electrostatic interactions are also likely to play a role. The significant reduction in ENM uptake after lipid exchange with 36:2 iPC is likely due to the increased phosphate (PO 3 − ) concentration on the membrane and the electrostatic repulsion between the membrane and SiO − on the particle surfaces.…”

Application of non-metal nanoparticles, as a novel approach, for improving the stability of blood products: 2011–2021

“…The level of damage and nanoparticle binding to the membrane was diminished in vesicles mimicking the composition of scrambled membranes. Lipid adsorption was discovered as a mechanism for vesicle damage (Bigdelou et al 2020 ).…”

Hemocompatibility of dextran-graft-polyacrylamide/zinc oxide nanosystems: hemolysis or eryptosis?

“…However, eryptosis, a Ca 2+ -dependent programmed cell death of red blood cells (RBCs), is emerging as an alternative and probably more sensitive marker of hemocompatibility for blood-contacting nanomaterials [38][39][40][41][42][43][44], which can be potentially used as a screening approach for newly synthesized nanomaterials. Moreover, eryptotic erythrocytes are reported to be less sensitive to NPs-induced hemolysis than the healthy ones [45]. To our knowledge, no studies on the ability of ZnO NPs to trigger eryptosis are available at the moment.…”