The Combination of Morphology and Surface Chemistry Defines the Immunological Identity of Nanocarriers in Human Blood

Upon exposure to blood, a corona of proteins adsorbs to nanocarrier surfaces to confer a biological identity that interfaces with the immune system. While the nanocarrier surface chemistry has long been the focus of protein corona formation, the influence of nanostructure has remained unclear despite established influences on biodistribution, clearance, and inflammation. Here, combinations of nanocarrier morphology and surface chemistry are engineered to i) achieve compositionally distinct protein coatings in human blood and ii) control protein-mediated interactions with the immune system. A library of nine PEGylated nanocarriers differing in their combination of morphology (spheres, vesicles, and cylinders) and surface chemistry (methoxy, hydroxyl, and phosphate) are synthesized to represent properties of therapeutic and biomimetic delivery vehicles. Analysis by quantitative label-free proteomic techniques reveal that specific surface chemistry and morphology combinations adsorb unique protein signatures from human blood, resulting in differential complement activation and elicitation of distinct proinflammatory cytokine responses. Furthermore, nanocarrier morphology is shown to primarily influence uptake and clearance by human monocytes, macrophages, and dendritic cells. This comprehensive analysis provides mechanistic insights into rational design choices that impact the immunological identity of nanocarriers in human blood, which can be leveraged to engineer drug delivery vehicles for precision medicine and immunotherapy.