Can dual-ligand targeting enhance cellular uptake of nanoparticles?

Dual ligand targeting to different types of over-expressed receptors on cell surfaces is a promising strategy in nanomedicine. Here, by using dissipative particle dynamics simulations, the effect of the surface distribution and physicochemical properties of dual ligands on the cellular uptake of nanoparticles is systematically studied. It is found that the spontaneous rearrangement of dual ligands (from random to patterned distribution) on the nanoparticle surface can enhance the cellular uptake of nanoparticles. While the short length of ligands may restrict the ligand rearrangement, nanoparticles coated with short dual ligands cannot be fully wrapped by cell membranes unless the dual ligands are initially separated on the nanoparticle surface. Besides, when there exists a length mismatch or non-specific interaction between the dual ligands, dual-ligand targeting cannot enhance the uptake efficiency, either. Further, we also provide the design guidelines for surface decoration, and find that the Janus nanoparticle can make the most of dual-ligand targeting. These results can help understand how to better use dual ligands to achieve efficient cellular uptake, which may provide significant insights into the optimal design of future nanomaterials in drug delivery.