Charge Regulation in Polyelectrolyte Complexation

Non-viral nucleic acid delivery to cells has become increasingly important in modern medicine. Several barriers must be overcome to achieve efficient delivery into cells. The nuclei acids must be packed into complexes that protects them from enzymatic digestion and clearance. Here, cationic agents are needed for complexation with the nucleic acids but, these are often cytotoxic.

Further, due to the dimensions of such particles, the complexes enter the cells via endocytosis, becoming enclosed in endosomes. As endosomes mature and merge with other compartments, the pH drops from approximately 7.4 to 4.7 in the late lysosomes, which activates enzymes and leads to degradation of the biological material. Endosomal escape is thus another bottleneck in nucleic acid delivery.

The complexation of DNA with poly(amidoamine) (PAMAM) dendrimers and peptide-conjugated PAMAM is investigated using a combination of molecular modelling and experimental techniques.

By varying the solution pH in the range relevant for endosomal maturation, we observed how differences in peptide composition led to significant changes in condensation behavior. Incorporating histidine residues in the peptide tails lead to a stronger pH dependency of the DNA condensation, compared to tails with lysine residues, suggesting a stronger effect of endosome maturation on the dendriplex behavior.

This can be used to fine tune the DNA condensation by PAMAM-peptide conjugates and to achieve efficient endosomal escape, a basis needed for successful non-viral nucleic acid delivery.