Abstract

As nanoscale metal-organic frameworks (MOFs) become increasingly prevalent, elucidating their fundamental interactions with proteins and cells is vital for evaluating their biological effects and biocompatibility. Herein, we investigated the protein corona (PC) formed on three representative MOFs (MIL-88, ZIF-8, UiO-66) and their impacts on macrophage uptake and cytotoxicity. Proteomic analysis revealed that the PC compositions were highly material-dependent, governed by the MOFs' distinct physicochemical properties. MIL-88 and ZIF-8 exhibited significant enrichment of acute-phase proteins and lipoproteins, whereas UiO-66 adsorbed high proportions of complement system proteins and lipoproteins. Apolipoprotein A-I (ApoA-I) was the most abundant protein across all three MOFs, while albumin was predominant on ZIF-8 and complement C3 was highly enriched on MIL-88. Functionally, PC formation reduced macrophage uptake of ZIF-8 and UiO-66 but had a negligible effect on MIL-88. The differences attributed to variations in dysopsonin/opsonin enrichment and surface charge alteration. Notably, the PC formation also significantly mitigated the cytotoxicity of ZIF-8 by reducing its cellular internalization. Together, these findings demonstrated that the PC is a pivotal factor influencing both the cellular interactions and the safety profile of MOFs, providing crucial insights for designing safer nanoparticle-based applications.