DNA-conjugated layered double hydroxides penetrating into a plasma membrane: Layer size, thickness and DNA grafting density matter

Abstract

Layered double hydroxides (LDHs) are promising as carriers delivering active molecules into cells via endocytosis which, however, is disadvantageous because contents are easily digested by the acid hydrolase upon entering the lysosomal system. Our earlier experiments have demonstrated that, when conjugated with DNA molecules on the LDH surface, the DNA-LDH-DNA nanocomposite can be formed and effectively enter cells via a non-endocytic pathway. Here, we combine dissipative particle dynamics simulations and free energy analysis to reveal the pathway and mechanism of DNA-LDH-DNA nanocomposites penetrating into a plasma membrane, and answer how the translocation is influenced by properties including the LDH size, thickness, and DNA grafting density. First, membrane anchorage is a spontaneous leading step of penetration via gaining favorable contacts with lipid headgroups and tails respectively by LDH and grafted DNA. Further insertion creates unfavorable contacts between LDH and lipid tails, generating a finite energy barrier with the magnitude depending on the LDH lateral size. Increasing the layer thickness can ease tilting of small nanocomposites to facilitate translocation, while for laterally larger nanocomposites especially than the membrane thickness, increase of the thickness contrarily makes translocation more difficult due to the enhanced membrane perturbation. Grafting more DNA molecules increases the LDH surface hydrophobicity to promote translocation into a membrane.