Programming of Extra- and Intracellular Protein Coronation through Thiol-Independent Ligand Engineering

Area of Science:

• Nanotechnology
• Biomaterials Science
• Cell Biology

Background:

• The distal end of ligands influences biological functions, but the proximal end's role remains less understood.
• Poly(ethylene glycol) (PEG) ligands offer versatile binding capabilities beyond traditional gold-thiol chemistry.

Purpose of the Study:

• To investigate the impact of the proximal end of ligand (PEL) on nanomaterial behavior and biological effects.
• To develop novel PEG ligands for gold nanomaterials with enhanced functionalities.
• To elucidate the mechanisms underlying PEL-mediated cellular interactions and therapeutic outcomes.

Main Methods:

• Synthesis of biotin-PEG-modified gold nanomaterials.
• Protein corona analysis and characterization.
• All-atom molecular dynamics simulations.
• Super-resolution imaging.
• Photoproximity labeling and chemoetching.

Main Results:

• Biotin-PEG nanomaterials exhibited unique protein corona-assisted uptake, influenced by TMSB4x orientation.
• TMSB4x was shown to facilitate receptor-ligand binding by expanding the binding pocket.
• PEL-dependent intracellular effects were confirmed via photoproximity labeling.
• Lipoic acid as PEL enabled gold nanomaterials to inhibit microfilament assembly and destabilize organelle contact sites.

Conclusions:

• The proximal end of the ligand plays a crucial role in nanomaterial-cell interactions and biological outcomes.
• Novel PEG ligands can impart unique properties to gold nanomaterials, including targeted uptake and therapeutic effects.
• Lipoic acid-functionalized gold nanomaterials exhibit promising anticancer activity through disruption of cellular infrastructure, offering a chemotherapy-free approach.