Disulfide modified self-assembly of lipopeptides with arginine-rich periphery achieve excellent gene transfection efficiency at relatively low nitrogen to phosphorus ratios.

Integrating the advantages of artificial vectors with bioinspired strategies has opened interesting perspectives in the design of gene delivery systems. Herein, disulfide modified, self-assembled lipopeptides with arginine-rich periphery are demonstrated as gene vectors (RLS). It is surprising that these carriers achieved excellent gene transfection efficacy (up to 380-fold higher than PEI) in different cell lines (HeLa and B16 cells) at relatively low N/P (∼10) ratios, compared to the analog lipopeptides without disulfide bonds (RL, N/P 40). As shown from the morphologies observed by transmission electronic microscopy and surface charge detection by dynamic light scattering, the existence of disulfide bonds may influence the configuration/conformation of the RLS assembly with decreased zeta potential (+27.2 mV), compared to that of the analogs, RL (+46.5 mV). Correspondingly, RLS/DNA complexes showed relatively lower zeta potentials than those of RL/DNA complexes at different N/P ratios. Under the transfection conditions, RLS/DNA complexes (N/P 10) showed even less cellular uptake than that of RL/DNA complexes (N/P 40), and no difference was detected in buffering effect and endosomal escape between RLS and RL complexes. Examination by gel electrophoresis and fluorescence resonance energy transfer (FRET) images in cell culture conditions confirmed that RLS lipoplexes could effectively liberate DNA. Thus, the higher gene transfection efficiency of disulfide modified vectors might be mainly attributed to the cleavage of disulfide bonds; the rapid release of DNA and the superiority of the design was closely related to the reductive conditions in the cells.