High-Curvature Features Improve Targeting of Nanoconstructs with Small-Molecule Ligands

Small molecules are promising ligands because of their affinity for cancer targets, chemical stability, controlled synthesis, and ease of characterization. Under biological conditions, small-molecule ligands grafted to nanoconstructs become coated with nonspecific proteins, collectively known as a protein corona, which physically obstruct targeting interactions because of their orders of magnitude difference in size. Here, we investigated how nanoparticle shape affects folic-acid ligand (FA) binding to folate receptors on cancer cell membranes using ensemble and single-particle analysis. From dot blot assays, we determined that gold nanoconstructs with spiky cores (tip features < 5 nm) and FA ligands bind more folate receptors compared to spherical cores of similar surface areas. Single-nanoconstruct tracking showed a higher proportion of spiky constructs displayed confined motion, which we attributed to binding of folate receptors. Our findings reveal that nanoparticles with anisotropic nanofeatures can circumvent adverse protein corona effects and enhance targeting of nanoconstructs with small-molecule ligands.