Investigation of the protein corona of nanoscale metal–organic frameworks (NMOFs) is crucial for their safety assessment; however, it remains inadequately addressed. This study specifically focused on the impact of the bridging linker on the protein corona formation of NMOFs by utilizing nanoscale UiO66/UiO66-NH2 and human serum albumin (HSA) as models. Both UiO66 and UiO66-NH2 effectively quenched the endogenous fluorescence of HSA through a static quenching mechanism. Notably, UiO66 with higher hydrophobicity exhibited a stronger binding affinity (5.62 × 104 L·mol–1) with HSA than the UiO66-NH2–HSA system (2.51 × 104 L·mol–1) at 310 K. UiO66 also adsorbed a greater amount of HSA, induced conformational rearrangement in HSA to a greater extent, and finally led to a significant reduction in the protein surface hydrophobicity. Computer docking and molecular dynamics (MD) simulations further confirmed that HSA demonstrated a higher binding energy, lower total energy, and smaller solvent-accessible surface area when interacting with the bridging linker of UiO66. Moreover, although UiO66 displayed lower cytotoxicity toward 293T cells, UiO66-NH2 exhibited better blood compatibility as evidenced by the elevated values of activated partial thromboplastin time (APTT, 28–57 s) and prothrombin time (PT, 11.7–13.1 s).

Experimental and Computational Investigations of the Effects of Bridging Linkers on the Protein Corona of Nanoscale Metal–Organic Frameworks