Mina Yan,1,2 Zhaoguo Zhang,2 Shengmiao Cui,3 Ming Lei,2 Ke Zeng,2 Yunhui Liao,2 Weijing Chu,2 Yihui Deng,1 Chunshun Zhao2 1School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 2School of Pharmaceutical Sciences, Sun Yat-sen University, 3Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China Abstract: Layered double hydroxide (LDH) has attracted considerable attention as a drug carrier. However, because of its poor in vivo behavior, polyethylene glycolylated (PEGylated) phospholipid must be used as a coformer to produce self-assembled core–shell nanoparticles. In the present study, we prepared a PEGylated phospholipid-coated LDH (PLDH) (PEG-PLDH) delivery system. The PEG-PLDH nanoparticles had an average size of 133.2 nm. Their core–shell structure was confirmed by transmission electron microscopy and X-ray photoelectron spectroscopy. In vitro liposome-cell-association and cytotoxicity experiments demonstrated its ability to be internalized by cells. In vivo studies showed that PEGylated phospholipid membranes greatly reduced the blood clearance rate of LDH nanoparticles. PEG-PLDH nanoparticles demonstrated a good control of tumor growth and increased the survival rate of mice. These results suggest that PEG-PLDH nanoparticles can be a useful drug delivery system for cancer therapy. Keywords: lipid membrane, positive charge, delivery system, cancer therapy