Efficient systemic delivery of siRNA by using high-density lipoprotein-mimicking peptide lipid nanoparticles

The main challenge for RNAi therapeutics lies in systemic delivery of siRNA to the correct tissues and transporting them into the cytoplasm of targeted cells, at safe, therapeutic levels. Recently, we developed a high-density lipoprotein-mimicking peptide phospholipid scaffold (HPPS) and demonstrated its direct cytosolic delivery of siRNA in vitro, thereby bypassing endosomal trapping. Aim: We investigate the in vivo implementation of HPPS for siRNA delivery. Method & results: After systemic administration in KB tumor-bearing mice, HPPS prolonged the blood circulation time of cholesterol-modified siRNA (chol-siRNA) by a factor of four, improved its biodistribution and facilitated its uptake in scavenger receptor class B type I overexpressed tumors. For therapeutic targeting to the bcl-2 gene, the HPPS-chol-si-bcl-2 nanoparticles downregulated Bcl-2 protein, induced enhanced apoptosis (2.5-fold) in tumors when compared with controls (saline, HPPS, HPPS-chol-si-scramble and chol-si-bcl-2) and significantly inhibited tumor growth with no adverse effect. Conclusion: HPPS is a safe, efficient nanocarrier for RNAi therapeutics in vivo. Original submitted 2 December 2011; Revised submitted 19 April 2012; Published online 26 July 2012