Different Serum, Different Protein Corona! The Impact of the Serum Source on Cellular Targeting of Folic Acid-Modified Chitosan-Based Nanoparticles

The nanoparticle (NP) protein corona represents aninterface between biological components and NPs, dictating theircellular interaction and biological fate. To assess the success ofcellular targeting, NPs modified with targeting ligands areincubated with target cells in serum-free culture medium or inthe presence of fetal bovine serum (FBS). In the former, the role ofthe corona is overlooked, and in the latter, the effects of a coronathat does not represent the one forming in humans nor therespective disease state are considered. Via proteomic analysis, wedemonstrate how the difference in the composition of FBS, serafrom healthy human volunteers, and breast cancer patients (BrCrPt) results in the formation of completely different protein coronasaround the same NP. Successful in vitro targeting of breast cancercells was only observed when NPs were incubated with target cells in the presence of BrCr Pt sera only. In such cases, the success oftargeting was not attributed to the targeting ligand itself, but to the adsorption of specific serum proteins that facilitate NP uptake bycancer cells in the presence of BrCr Pt sera. This work therefore demonstrates how the serum source affects the reliability of in vitroexperiments assessing NP-cell interactions and the consequent success or failure of active targeting and may in fact indicate anadditional reason for the limited clinical success of drug targeting by NPs in cancer