Cationic dendron-bearing lipids: investigating structure-activity relationships for small interfering RNA delivery

A new family of cationic dendron-bearing lipids (CDLs) with poly(amidoamine) dendrons of first to third generation (named as A1, A2, and A3, respectively) was synthesized through a synthesis approach that permits facile variation of chemical structures. All CDLs could effectively bind small interfering RNA (siRNA) to form complexes confirmed by gel retardation analysis. In in vitro transfection experiments, A1/siRNA complexes exhibited significant gene silencing efficiency close to Lipofectamine 2000/siRNA complexes and much higher than A2/siRNA and A3/siRNA complexes. To reveal the underlying reason, we performed a series of experimental methods. The results suggested that the CDLs with smaller dendron sizes and higher proportion of hydrophobic segments could bind siRNA to form dendriplex aggregates with more compact structures and higher surface potentials. Therefore, they could be internalized via endocytosis more easily, which was believed to be the main reason for higher gene silencing efficiency. This paper provides an efficient CDL (A1) for siRNA delivery and indicates great potential for gene therapy.