Harashima group from Hokkaido University developed a hepatocyte-specific drug delivery system called multifunctional envelope-type nanodevice (MEND) which gives improved siRNA endosomal escape efficiency. The three generations of the pH-responsive ionizable lipid of the MEND system are YSK05 (2012 pKa 6.4) YSK13 (2016 pKa 6.45) and CL4H6 (2019 pKa 6.25). The ED50Â of Factor VII knockdown after the intravenous injection of YSK05 YSK13 and CL4H6 LNPs into mice were shown to be 60 ug/kg 15 ug/kg 2.5Â ug/kg respectively.