Design of Peptide Dendrimer–Liposome Nanocomplexes for Efficient Nucleic Acid Delivery

Nucleic acid drugs have attracted attention due to their high specificity and therapeutic potential. Still, their poor stability and limited cellular uptake hinder practical applications. As a reagent, peptide dendrimers exhibit well-defined architectures. They can form well-defined nanostructures by complexing with DNA, RNA, and other nucleic acids while enhancing membrane interaction and intracellular delivery. Here, we designed peptide dendrimers (KEL-G1 and KEL-G2) and compounded them with liposome DOTAP to obtain KEL-G@DOTAP nanocomplexes. The resulting peptide dendrimer–liposome nanocomplexes exhibited uniform nanoscale sizes (∼100–250 nm) and positive surface charge, facilitating efficient cellular uptake and gene delivery. KEL-G@DOTAP can successfully carry mRNA across the cell membrane and be converted into protein and siRNA-mediated gene regulation (7–10 times that of Lipo2000 in some cells). The KEL-G2/DOTAP/KE system enabled targeted delivery of mRNA to the mouse lung with high protein expression. This peptide dendrimer–liposome delivery system demonstrates broad applicability and good biosafety, providing a platform to improve nucleic acid delivery efficiency for gene therapy.