Pathophysiological Protein Corona Governs the Biological Fate of Nanoparticles

Protein corona fundamentally redefines the biological identity, cellular interactions, and in vivo fate of nanoparticles. Disease-induced alterations in blood composition generate pathological corona profiles; however, the impact of disease-mediated corona remodeling on the biological effects of nanoparticles remains poorly understood. Here, we systematically characterized the protein coronas and biological responses of surface-engineered polystyrene nanoparticles incubated with sera from healthy donors and patients with nonsmall cell lung cancer (NSCLC). Our findings show that disease status and nanoparticle surface chemistry jointly reprogram corona composition, leading to marked alterations in immune recognition and pharmacokinetic profiles. Specifically, NSCLC-derived coronas were enriched in complement proteins, resulting in pronounced complement activation and enhanced macrophage-mediated clearance, while attenuating systemic circulation of nanoparticles. These findings elucidate the critical role of disease-specific protein coronas in modulating nanobio interactions and underscore the necessity of accounting for pathological environments in the rational design and clinical translation of nanomedicines.