The development of efficient gene delivery systems targeting the lung endothelium remains a serious challenge. This study reports on the design and optimization of a multifunctional envelope-type nanodevice (MEND) for an efficient siRNA delivery to the lung endothelium based on GALA-peptide targeting ability. The incorporation of a pH-sensitive lipid (YSK05) results in a dramatic improvement in silencing efficiency by enhancing endosomal escape, but this also causes a reduction in the lung selectivity. Contrary to the assumption that active targeting is largely dependent on the presence of a targeting ligand, the findings of the present study indicate that nanocarrier composition is critical for achieving the organ selectivity. Interestingly, helper lipids substantially mask the liver delivery resulting in optimum lung targeting. The optimized YSK05-MEND is 40-fold more efficient than a previously developed MEND, with a robust lung endothelium gene knockdown at small doses. The YSK05-MEND strongly inhibits a metastatic lung cancer model and exerts superior control over lung metastasis compared to chemotherapy or the previously developed MEND. The YSK05-MEND is well-tolerated in mice after acute or chronic administration. As far as it is known, YSK05-MEND achieves the most efficient lung endothelium gene silencing reported thus far with a median effective dose of 0.01 mg siRNA kg(-1) while minimally affecting the endothelium of other organs.