Engineered protein corona sustains stealth functionality of nanocarriers in plasma.

Pre-adsorption of selective proteins is instrumental in forming functionally important protein coronas that allow for achieving long circulation in blood stream. This is an important prerequisite for subsequent specific uptake into target cells. Despite a wide range of studies aimed at identifying these effective pre-adsorbed proteins, the separate experiments and varying conditions carried out in human and murine systems, respectively, have left a gap in our comprehensive understanding of how these proteins help to maintain the stability of dysopsonin character at both the intra- and inter-species level. To address this, we systematically experimented with human- and murine-derived stealth proteins, clusterin and apolipoprotein A1, to engineer protein coronas of nanoparticles. We then exposed the pre-coated nanoparticles to human and murine blood plasma and evaluated the stability of the stealth protein corona and the stealth properties against macrophages. Our proteomics data elucidate that the further recruitment in the amount of the two stealth proteins before and after pre-adsorption accounts for the stable targeting property of nanoparticles by enabling them to evade macrophage phagocytosis (stealth effects). However, significant discrepancies were observed between these interspecies experiments, which is largely attributed to diverse protein corona compositions. These observations shed lights on the guidance to overcome conversion barriers from murine experiments to human clinical trials.