Correlating Corona Composition and Cell Uptake to Identify Proteins Affecting Nanoparticle Entry into Endothelial Cells

Abstract

The formation of the biomolecule corona on the surface of nanoparticles upon exposure to biological fluids critically influences nanocarrier performance in drug delivery. It has been shown that in some cases corona proteins can mediate specific nanoparticle interactions with cell receptors. Within this context, in order to identify corona proteins affecting nanoparticle uptake, in this work, correlation analysis is performed between the corona composition of a panel of silica nanoparticles of different sizes and surface functionalities and their uptake in four endothelial cell types derived from different organs. In this way, proteins that correlate with increased or decreased uptake were identified, and their effects were validated by studying the uptake of nanoparticles coated with a single protein corona and competition studies in brain and liver endothelium. The results showed that precoating nanoparticles with histidine-rich glycoprotein (HRG) alone strongly decreased uptake in both liver and brain endothelium. Furthermore, our results suggested the involvement of the transferrin receptor in nanoparticle uptake in liver endothelium and redirection of the nanoparticles to other receptors with higher uptake efficiency when the transferrin receptor was blocked by free transferrin. These data suggested that changes in the cell microenvironment can also affect nanoparticle uptake and may lead to a different interaction site with nanoparticles, affecting their uptake efficiency. Overall, correlating the composition of the protein corona and nanoparticle uptake by cells allows for the identification of corona molecules that can be used to increase as well as to reduce nanoparticle uptake by cells.

Effect of Titanium Dioxide Nanoparticles on Mammalian Cell Cycle In Vitro: A Systematic Review and Meta-Analysis

“…It is worth mentioning that both agglomeration size (Supporting Information, Excel S1) and protein corona (data are not displayed) of nano-TiO 2 are affected by the composition of medium (especially the type and concentration of proteins) and, consequently, influence the uptake of nanoparticles by cells. − Moreover, the dispersion process of the nano-TiO 2 used also affects its cytotoxicity . Although these factors cannot be further analyzed in this study because they have not been reported in all the included studies, their roles in the effects of nano-TiO 2 on cell cycle cannot be ignored.…”

Drug Targeting and Nanomedicine: Lessons Learned from Liver Targeting and Opportunities for Drug Innovation

“…Based on similar observations, more studies are focusing on the screening of the corona forming on panel of nanoparticles as a novel tool to identify molecules that can promote or reduce uptake by cells [155][156][157][158]. We performed similar studies using silica nanoparticles of different size and surface functionalization, as well as liposomes of different charge which showed very different uptake levels by cells [153,159]. Similarly, we have used a panel of different nanoparticles thus different corona to identify receptors involved in nanoparticle uptake into endothelial cells from different organs (Aliyandi et al unpublished) [160].…”

“…Interestingly, the authors identified this protein as a major component in the corona forming on PEGylated nanoparticles and suggested that it is this specific protein in the corona to confer the socalled PEG "stealth-effect", as opposed to the overall reduced protein binding. Recently reduced uptake has been observed also for nanoparticles with a corona rich in histidine rich glycoprotein [153,154]. Interestingly, reduced uptake could be achieved also when pre-coating nanoparticles with an artificial corona of histidine rich glycoprotein [153].…”

“…Recently reduced uptake has been observed also for nanoparticles with a corona rich in histidine rich glycoprotein [153,154]. Interestingly, reduced uptake could be achieved also when pre-coating nanoparticles with an artificial corona of histidine rich glycoprotein [153]. Thus, the corona may be engineered prior to administration to promote the desired interactions.…”

“…Corona formation Can mask targeting ligands in vitro [139] Opsonin proteins in the corona Activation of immune cells, nanoparticle removal from circulation [135][136][137] PEGylation Reduced protein adsorption and/or binding of dysopsonin proteins in the corona such as clusterin [135,141,152] Dysopsonin proteins in the corona Prolonged circulation time [150] Albumin in the corona Prolonged circulation time [151] Clusterin (apolipoprotein J) in the corona Prolonged circulation time [152] Histidine rich glycoprotein in the corona Prolonged circulation time [153,154] Table 2. Cont.…”