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The signal transduction of human programmed death ligand 1 (PD-L1), as an important checkpoint gene in the immune system, plays a key role in the internal function and survival of cancer cells. In this paper, PD-L1-siRNA and immunostimulatory IL-2 encoding plasmid DNA loaded by polyethylenimine (PEI) lipid nanoparticles (PEI-LNPs) were constructed. Its therapeutic effect on lung cancer was evaluated, and its physical parameters such as particle size and potential were measured. The binding capacity, cytotoxicity, apoptosis, and cell uptake capacity of PD-L1-siRNA/IL-2 DNA-PEI-LNPs were tested by in vitro experiments. The down-regulation effect of PD-L1 in A549 cancer cells and the cytokine level of co-cultured T cells were also examined. The study indicated that the PD-L1-siRNA/IL-2-PEI-LNP complexes can provide effective treatment for lung cancer cells; the significant increase in IFN-γ and TNF-α levels and the decrease in the IL-10 level confirmed the change in secreted cytokines. The lipid NPs combined with the tumor-targeting therapeutic gene siRNA/pDNA constructed in this study had the ability to target cells in vitro and down-regulate the expression of PD-L1, which realized the tumor-specific expression of immunostimulatory cytokines, and were considered to be highly effective and safe nanocarriers for targeted therapy. [ABSTRACT FROM AUTHOR]