Nucleic acid delivery to cells is an important therapeutic strategy that requires the transport of nucleic acids to intracellular compartments and their protection from enzymatic degradation. This can be achieved through the complexation of the nucleic acids with polycations. Poly(amidoamine) (PAMAM) dendrimers and peptide-conjugated dendrimers have been investigated as delivery vectors. Inspired by these studies and the role of flexible peptide domains in protein-DNA interactions, we studied the impact of conjugating two peptides (tails) to generation 2 (G2) PAMAM dendrimers on DNA condensation and polyplex formation. Using gel electrophoresis, dye exclusion assays, atomic force microscopy, and Monte Carlo simulations, it is shown that the steric impact of neutral peptide tails is to hinder the formation of DNA-G2 polyplexes composed of multiple DNA chains. If the tails are negatively charged, which results in overall neutral G2 conjugates, then the interaction of G2 with DNA is hindered. Increasing the net positive charge of the tails resulted in the complexation capacity of G2 with the DNA being restored. While DNA complexation is obtained for a similar net charge balance for G2 and G2 conjugates with positive tails, fewer of the latter are required to achieve a comparable condensation degree. Furthermore, it is shown that about 40% of the DNA remains accessible to binding by small molecules. Overall, this shows that tuning the net charge of peptide tails conjugated to PAMAM dendrimers offers a handle to control the complexation capacity of DNA, which can be explored as a novel route for optimization as gene delivery vehicles.
© 2023 The Authors. Published by American Chemical Society.