Design Principles for Smart Linear Polymer Ligand Carriers with Efficient Transcellular Transport Capabilities.

The surface functionalization of polymer-mediated drug/gene delivery holds immense potential for disease therapy. However, the design principles underlying the surface functionalization of polymers remain elusive. In this study, we employed computer simulations to demonstrate how the stiffness, length, density, and distribution of polymer ligands influence their penetration ability across the cell membrane. Our simulations revealed that the stiffness of polymer ligands affects their ability to transport cargo across the membrane. Increasing the stiffness of polymer ligands can promote their delivery across the membrane, particularly for larger cargoes. Furthermore, appropriately increasing the length of polymer ligands can be more conducive to assisting cargo to enter the lower layer of the membrane. Additionally, the distribution of polymer ligands on the surface of the cargo also plays a crucial role in its transport. Specifically, the one-fourth mode and stripy mode distributions of polymer ligands exhibited higher penetration ability, assisting cargoes in penetrating the membrane. These findings provide biomimetic inspiration for designing high-efficiency functionalization polymer ligands for drug/gene delivery.