Lipid Membrane Interaction of Peptide/DNA Complexes Designed for Gene Delivery

Among gene delivery systems, peptide-based gene carriers have received significant attention because of their selectivity, biocompatibility, and biodegradability. Since cellular membranes function as a barrier toward exogenous molecules, cell-penetrating peptides (CPPs), which are usually cationic and/or amphiphilic, can serve as efficient carriers to deliver cargo into the cytosol. Here, we examined the interactions of carrier peptides and their DNA complexes with lipid membranes using a quartz crystal microbalance (QCM) and high-speed atomic force microscopy (HS-AFM). The carrier peptides are a 12-residue partial presequence of yeast cytochrome c oxidase subunit IV (Cytcox) and BP100, which are a mitochondria-targeting signal peptide and a CPP, respectively. QCM data showed that BP100 has a higher binding affinity than Cytcox to both plasma membrane- and mitochondrial membrane-mimicking lipid bilayers. The DNA complexes with either Cytcox or BP100 exhibited the same tendency. Furthermore, HS-AFM data demonstrated that the DNA complexes of either peptide can disrupt the lipid membranes, forming larger pores in the case of Cytcox. Our results suggest that the binding affinity of the peptide/DNA complex to the plasma membrane is more critical than its membrane disruption ability in enhancing the cellular uptake of DNA.