Coagulation Matters: ATIII‐Enriched Biomolecular Corona Enhances the Hemocompatibility of PEG Nanoparticles

AbstractNanoparticles in physiological environments acquire a biomolecular corona that defines their biological identity, mediating immune system recognition and accelerating blood clearance of the nanoparticles. Typically, low‐fouling materials are chosen to minimize protein adsorption and thereby immune system responses, contributing to stealth in blood. However, absolute prevention of the biomolecular corona remains tantalizingly out of reach. Herein, it is proposed to leverage the biomolecular corona rather than preventing its formation, in order to overcome immune responses toward nanoparticles. Low‐fouling and stealthy poly(ethylene glycol)(PEG) nanoparticles are used, with a functional biomolecular corona enriched with anticoagulant heparin‐antithrombin III (HEP‐ATIII) complexes that can mitigate undesirable immune responses. Through immune response evaluations and proteomic analyses are used to ascertain the low‐fouling, stealthy character of the nanoparticles, similar to that of PEG nanoparticles. However, PEG nanoparticles alone induce coagulation responses in human blood, which are mitigated by pre‐enrichment of the biomolecular corona with HEP‐ATIII complexes. This shows that coagulation is another factor to be considered in the design of materials for nanomedicine and that the low‐fouling and stealthy properties do not directly translate to hemocompatibility. These findings highlight the potential of biomolecular corona engineering to address key challenges in the field, toward developing safer, efficacious therapeutic nanomaterials.