Abstract: In recent years, non-viral vectors, such as cationic polymers and liposomes, have attracted increasing attentions for their applications in gene delivery. However, reduced transfection efficiency inhibits their further use in the presence of serum. Therefore, it is necessary to develop serum-tolerant non-viral gene vectors. Herein, a novel Zn coordinated lipid is synthesized, which self-assembles with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine lipid (DOPE), forming cationic liposome (Zn-DTAc liposome). The experimental results demonstrate that Zn-DTAc liposomes can effectively condense pDNA into nanoparticles, which have high cellular uptake and effective endosomal escape and exhibit efficient gene transfection even in the presence of 50% fetal bovine serum.