Design strategy of cell-penetrating copolymers for high efficient drug delivery.

Finding a highly effective drug delivery carrier with low cytotoxicity is essential for disease therapy. In this work, we design a cell-penetrating copolymer (CPC) carrier, in which the inspiration comes from cell-penetrating peptides that have both hydrophilic and hydrophobic residues and are capable of penetrating membranes without inducing membrane disruption. Further dissipative particle dynamics simulations indicate that the CPCs also have an effective penetration capacity. Importantly, we found that the penetration mechanism of the CPC is in a zipper way, i.e. the adjacent hydrophobic segments of the CPC could cross the membrane in a cooperative way. Moreover, we determine the optimal parameters for the CPC crossing lipid membrane, i.e. the hydrophobic segment length of the CPC is close to the membrane thickness, and the CPC has more segment number. Finally, by grafting the CPC with the optimal structure on the hydrophilic drug, we found that the CPCs can definitely help the hydrophilic drug penetrate the lipid membrane effectively, which is an excellent prototype of drug delivery carriers. It is expected that this work can provide the fundamental for further design of drug delivery carriers.