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

Area of Science:

• Materials Science
• Nanotechnology
• Biomedical Engineering

Background:

• Metal-organic frameworks' (MOFs) biomedical applications depend on their surface ligands and the protein corona formed in vivo.
• Understanding how ligands influence protein corona formation and subsequent biological interactions is crucial but poorly understood.

Purpose of the Study:

• To investigate how ligand functionalization of MIL-101(Fe) affects protein corona composition and subsequent cellular responses.
• To elucidate the mechanisms by which different protein coronas modulate MOF biocompatibility and cytotoxicity.

Main Methods:

• Synthesis of three functionalized MIL-101(Fe) derivatives (H-, NH2-, NO2-MIL-101(Fe)) using electron-donating and withdrawing groups.
• Assessment of MOF binding affinities and interaction mechanisms with serum proteins (HSA, transferrin) using surface ligand electronic effects.
• In vitro cellular studies using normal hepatocytes and 4T1 cancer cells to evaluate biocompatibility and cytotoxicity.

Main Results:

• Ligand electronic properties critically modulated protein binding affinities (H >= NH2 > NO2) and interaction mechanisms (hydrogen bonding vs. electrostatic).
• HSA coronas enhanced MOF biocompatibility in normal hepatocytes.
• Transferrin (TRF) coronas promoted MOF uptake, reactive oxygen species generation, and mitochondrial damage in cancer cells, increasing cytotoxicity.

Conclusions:

• Ligand functionalization is a key strategy to orchestrate protein corona structure and subsequent biological cascades.
• This study provides a mechanistic understanding for designing MOFs with tailored biomedical performance.
• The findings offer a design strategy for precise control over MOF interactions in biomedical applications.