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Indolicidin (IL), a cationic peptide derived from bovine neutrophils, was grafted onto polyethylenimine (PEI) to investigate the potential of these conjugates as nonviral vectors. To specifically control the conjugation sites, a cysteine residue was added to the C or N terminus of IL, which was denoted as ILC or CIL, respectively. In addition, an IL-derived hydrophilic peptide, SAP10, was also applied for conjugation. Both PEI-ILC and PEI-CIL demonstrated higher transfection efficiency than unmodified PEI; however, PEI-SAP10 was unable to transfect cells. The confocal microscopy results indicated that only PEI-ILC and PEI-CIL successfully delivered DNA into cells. These internalized DNA should be released mainly through the proton sponge effect, whereas the grafted IL may also perturb the endosomal membrane to eventually cause membrane disruption. Finally, we used molecular dynamics simulations to clarify the mechanism of grafted peptides interacting with membranes. The results indicated that the hydrophobic domains of conjugated peptides were essential for gene transportation because the interaction between peptides and the cell membrane was enhanced when these hydrophobic domains entered the hydrocarbon zone of the lipid bilayer. Additionally, tryptophan residues played important roles in stabilizing the insertion of peptide sequences. This study not only developed an effective gene vehicle but also provided useful information for the design of peptide-conjugated carriers for drug delivery applications.
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