Comparison of Protein Coronas and Internalized Cell Surface Proteins of Positive and Negative Liposomes

Positive nanoparticles have often a higher uptake than neutral and negative nanoparticles. This is usually attributed to electrostatic interactions with negatively charged proteoglycans on the cell membrane. However, upon contact with serum, nanoparticles adsorb a biomolecule corona and tend toward neutrality, suggesting that electrostatic interactions alone cannot explain the different uptake. Here, we used oppositely charged liposomes as an example to explore at a fundamental level why positive nanoparticles usually show a higher uptake than the negative ones. Two proteomic-based approaches were combined to compare their protein coronas and the cell surface proteins involved in their internalization. The results showed that the higher uptake of the positive liposomes used for this study could not be simply explained by the involvement of specific corona proteins and dominating cell surface proteins. Instead, small differences in the abundances of a large number of corona proteins and cell surface proteins were observed, including multiple low-abundance proteins. Importantly, the positive liposomes had higher uptake than the negative liposomes only when added to cells in the presence of serum, suggesting that the higher uptake likely resulted from the observed subtle differences in their corona and the collective contribution and interactions with multiple cell surface proteins.