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The ABC phenomenon is described as a syndrome of accelerated blood clearance which the repeated injection of polyethyleneglycol-modified (PEGylated) liposomes could cause a rapid clearance of them from the bloodstream, while an increased accumulations in the liver and spleen. In this research, to solve this immune response phenomenon, a novel modified pH-sensitive liposomes with the cleavable double smart PEG-lipid derivative (mPEG-Hz-CHEMS ) was evaluated. The results indicated that the ABC phenomenon in mice was brought about by repeated injection of conventional PEG-PE-liposomes and was accompanied by a greatly uptake in the liver. However, a slight ABC phenomenon was brought about by repeated injection of mPEG-CHEMS-liposomes and was accompanied by a slightly increased uptake in the liver. While repeated injection of mPEG-Hz-CHEMS-liposomes did not induce the ABC phenomenon and there was not an increase in liver accumulation. This finding indicates that the cleavable mPEG-Hz-CHEMS derivative could lessen or eliminate the ABC phenomenon induced by repeated injection of PEGylated liposomes. These studies have shed some light on a solution to the ABC phenomenon of cleavable PEG-Hz-Cholesterol derivative in nanoparticles.