The multifunctional envelope-type nano device (MEND) is a novel non-viral gene delivery system for plasmid DNA (pDNA) and oligodeoxynucleotides (ODN). We showed previously that octaarginine-modified MEND (R8-MEND) produces a high transfection activity without cytotoxicity via macropinocytosis and efficient release of a condensed DNA core to the cytosol. In the present study, we succeeded in developing an efficient method for packaging siRNA into the R8-MEND, and its silencing effect was compared with that of transfection reagent TransIT-TKO. A polycation able to condense siRNA was screened for by measuring the size and zeta-potential of complexes formed between siRNA and the polycations poly-l-lysine (PLL), stearyl octaarginine (STR-R8) and protamine. Only STR-R8 was able to condense siRNA to form nano particles (<100 nm), whereas all three polycations were able to condense pDNA or ODN. The siRNA packaged in R8-MEND inhibited luciferase activity by more than 80% in HeLa cells stably expressing luciferase. Much amount of siRNA was internalized into the cells as R8-MEND, and siRNA was effectively released from lipid envelope of MEND to cytoplasm near the nucleus. Consequently, R8-MEND can deliver condensed siRNA into cells to produce an efficient and persistent silencing effect with minimum cytotoxicity.