Objective To develop an efficient exosome-based delivery method to effectively transport therapeutic nucleic acid to liver cancer tissue for the treatment of primary hepatic cancer. Methods HEK293T cells were transfected with a recombinant plasmid expressing SP94 and CD47, and the exosomes were extracted and isolated. Exosomes were identified by transmission electron microscope, nanometer particle tracking analysis, and Western blotting. The mice were injected with 200 μg DiD labeled unmodified exosomes and SP94 modified exosomes via tail vein, and the targeting effect of exosomes on liver cancer tissue was detected and analyzed using small animal in vivo imaging. The unmodified exosomes and CD47 modified exosomes were incubated with macrophages (RAW264.7) and mouse hepatoma cells (Hepa1-6) to verify the phagocytosis of the modified exosomes by the cells. Polo-like kinase 1 (PLK1) small interfering RNA (siRNA) was loaded into different modified exosomes by electroporation and then the exosomes were co-incubated with Hepal-6 cells, and the cell apoptosis was detected by flow cytometry. The modified exosomes loaded with PLK1 siRNA were injected into the tail vein to systematically study and analyze the therapeutic effect of PLK1 siRNA on primary hepatic cancer in mice. Results SP94 modification enhanced the targeting effect of exosomes on liver cancer tissue, and CD47 modification reduced the phagocytosis of exosomes by macrophages. PLK1 siRNA delivered by SP94 and CD47 double-modified exosomes increased the apoptosis of hepatoma cells. In the primary hepatic cancer mice, SP94 and CD47 double-modified exosomes loaded with PLK1 siRNA could effectively inhibit the growth of liver cancer nodules and prolong the survival time of tumor-bearing mice. Conclusion SP94 and CD47 double-modified exosomes can efficiently deliver therapeutic nucleic acid PLK1 siRNA to target liver cancer and effectively inhibit the growth of liver cancer.