Ligand Separation on Nanoconstructs Affects Targeting Selectivity to Protein Dimers on Cell Membranes

This work demonstrates that targeting ligand density on nanoparticles can affect interactions between the nanoconstructs and cell membrane receptors. We discovered that when the separation between covalently grafted DNA aptamers on gold nanostars was comparable to the distance between binding sites on a receptor dimer (matched density; MD), nanoconstructs exhibited a higher selectivity for binding to the dimeric form of the protein. Single-particle dynamics of MD nanoconstructs showed slower rotational rates and larger translational footprints on cancer cells expressing more dimeric forms of receptors (dimer+) compared with cells having more monomeric forms (dimer-). In contrast, nanoconstructs with either increased (nonmatched density; ND_low) or decreased ligand spacing (ND_high) had minimal changes in dynamics on either dimer+ or dimer- cells. Real-time, single-particle analyses can reveal the importance of nanoconstruct ligand density for the selective targeting of membrane receptors in live cells.