Stealth PLGA/Liposome nanoparticles (NPs) modified with tumor-targeting PD-L1 antibody for systemic delivery of luteolin for liver cancer were prepared. The morphologies and therapeutic effects of luteolin-loaded PD-L1 targeted stealth PLGA/Liposomes (L-PD-SP/Ls) in vitro were analyzed. Functional L-PD-P/L NPs composed of PLGA, DOPC and DSPE-PEG display low cell cytoxicity in HepG2 cells, and has more cell uptake ability than P/Ls NPs. L-PD-SP/Ls was more effective in inhibiting HepG2 cell proliferation than free luteolin in solution (p < 0.05) and luteolin-loaded P/Ls (p < 0.05). Compared with the cell control group and the non-PD-L1 targeted group, the mediated effect of PD-L1 can significantly enhance the uptake of drugs by cells, and L-PD-SP/Ls can significantly reduce the expression of Bcl-2 and increase the level of LDH in cells. Our findings collectively support the utility of PD-L1-targeted P/L NPs as a potentially effective drug delivery system.