Fig. 1

Schematic representation of DNA endocytosis, cytoskeletal trafficking, and nuclear entry. Description of figure from left to right: DNA complexes enter the cells via endocytosis, through clathrin-coated vesicles, through caveolae or through pinocytosis. Their entry is regulated by Rho proteins and mDia1, which control actin dynamics. Dynamin mediates both clathrin-dependent and caveola-dependent endocytosis, whereas Caveolin 1 and Filamin A only mediate caveolae internalisation. Endocytic vesicles are transported by dynein and move along the microtubules. DNA complexes escaping the endocytic trafficking enter the nucleus. Nuclear entry either happens during cellular mitosis or through the Nuclear Pore Complex. A small portion of lipoplexes can enter the cells through direct membrane fusion. Certain caveolar vesicles were instead shown to directly target the Golgi, preventing DNA from reaching the lysosomes. Similarly, despite mechanisms being still obscure, certain CPPs can either fuse with or destabilise the plasma membrane, allowing the DNA to directly reach the Golgi-Endoplasmic Reticulum network, avoiding the lysosomal degradation [32,33,34].