Ligand-Mediated Protein Corona on MIL-101(Fe) Governs Cytotoxicity via a Structure-Protein-Cell Cascade

Metal-organic frameworks' (MOFs) biomedical performance is largely determined by surface ligands and the "protein corona" that forms in biological environments. Corona composition critically influences MOF behavior, yet how ligands direct corona formation and subsequent structure-protein-cell cascades remains poorly understood. Here, using MIL-101(Fe) as a model, three functionalized derivatives (H-, NH₂-, NO₂-MIL-101(Fe)) were constructed via electron-donating and electron-withdrawing groups. Ligand electronic effects critically modulate binding to serum proteins (HSA and transferrin), yielding distinct affinities (H ≥ NH₂ > NO₂) and interaction mechanisms (hydrogen bonding vs electrostatic). Cellular studies revealed that HSA coronas enhance the biocompatibility of MOFs in normal hepatocytes, while TRF coronas promote uptake, reactive oxygen species generation, and mitochondrial damage in 4T1 cancer cells, thereby amplifying cytotoxicity. This work systematically elucidates how ligand functionalization orchestrates protein corona structure and the subsequent protein-cell cascade, providing a mechanistic basis and design strategy for precise biomedical applications of MOFs.