Protein Corona Formed from Different Blood Plasma Proteins Affects the Colloidal Stability of Nanoparticles Differently.

Significant progress in the characterization of protein corona has been made. However, insights on how the corona affects the aggregation of nanoparticles (NPs) and consequent biological identity are still lacking. Here, we examined how the corona formed from four major serum proteins, immunoglobulin G (IgG), fibrinogen (FBG), apolipoprotein A1 (ApoA1), and human serum albumin (HSA), over a range of concentrations affects the aggregation of gold NPs (AuNPs). We found that at physiological pH of 7.4, all four proteins aggregated the AuNPs at low concentrations but conferred colloidal stability at high concentrations due to the complete "corona coat" around individual AuNPs. Due to their immune-related functions, IgG and FBG aggregated the AuNPs to a greater extent compared to HSA and ApoA1 which were mostly involved in transport of small molecules. We then introduced the AuNP-corona formed from each protein into an acidic solution at pH 6.2 with high ionic concentration for up to 24 h as a model of the tumor microenvironment to examine for changes in their aggregation. We observed that protein corona formation sterically stabilized the AuNP-corona for all four proteins, resulting in a smaller increase in aggregation and size compared to citrate-capped AuNPs. This was especially true for corona formed at high protein:AuNP ratios. Our study therefore showed that the formation of a complete "corona coat" around NPs at sufficiently high protein:NP ratio was required for colloidal stability of designed NP systems in both physiological and cancer microenvironment to maintain efficiency and efficacy in cancer drug delivery.