Fig. (1).

Simplistic scheme of peptide-based nucleic acid delivery systems (A). Interaction of CPP and cargo is either achieved by covalent attachment or by non-covalent complexation through mainly ionic interactions. In case of non-covalent complex formation, a further assembly of cargo/carrier complexes occurs, leading to the formation of large nanoparticles (confer Fig. (2)). In case of covalently joined molecules a similar scenario is less likely, yet cannot be excluded. Prior to the translocation process the particles attach to the cell surface by ionic interactions of positively charged CPP residues with negatively charged membrane components. Subsequently, complexes are taken up via an endocytotic pathway. Although less likely, direct penetration cannot be excluded and may occur simultaneously. Once inside the cell, the cargo has to escape from vesicular compartments, otherwise it eventually gets degraded in the lysosome. Red: negative charges, blue: positive charges, green: hydrophobic domains.

Three-dimensional model of MPGα/siRNA interactions (B). The model was generated by iterative rigid body docking cycles of siRNA (PDB 1R9F) and peptide using the program Hex 4.2 [201]. The PDB file of MPGα was generated with the program ICM (Molsoft LLC) taking into consideration different secondary structure predictions and energy minimization protocols. Out of many docking solutions particular ones were picked for illustration purposes using the program Chimera [202]. The phosphate backbone of the siRNA is shown in red, the nucleobases in light gray. Aliphatic, aromatic and hydrophobic residues of the peptide are shown in green, positive charged residues in blue and the remaining amino acids in gray. It is assumed that formation of larger particles is driven by hydrophobic peptide/peptide interactions generating free positive charges where other siRNA molecules can interact. This eventually drives complex formation in a sandwich or mesh like assembly reaction. In principle such a scenario holds true for any given nucleic acid cargo.