Albumin Precoating of Nanoparticles: A Reliable Stealth Strategy?

Albumin precoating has emerged as a strategy to impart nanoparticles (NPs) with stealth-like properties and as an alternative to NP surface PEGylation. Yet how such coatings influence protein corona formation and hemocompatibility in human blood remains poorly understood. To address this, we precoated model hydrophilic and hydrophobic polystyrene NPs with either fatted or defatted human serum albumin (HSA) and exposed them to human plasma and blood-based models. Proteomic analysis of the adsorbed protein corona revealed formulation-dependent differences in composition, but an overall favorable profile characterized by enrichment of dysopsonins (HSA and apolipoproteins) and depletion of major opsonins (complement proteins and immunoglobulins). Consistent with these findings, NP uptake by phagocytic blood cells was low across all formulations. However, evaluation in physiologically relevant human-derived models uncovered formulation-dependent biological responses. Specifically, three of the four HSA-precoated NPs exhibited complement activation or prothrombotic tendencies, whereas fatted HSA on hydrophobic NPs showed consistent blood compatibility across multiple assays. Taken together, these findings demonstrate that the hemocompatibility of albumin-coated NPs is determined by the interplay between NP core surface chemistry and albumin formulation, rather than by albumin precoating alone, providing important design criteria for albumin-based NP coatings.