Choriocarcinoma is a highly aggressive and vascular cancer. The main treatment for choriocarcinoma is the chemotherapy associated with severe side effects. Therefore, the development of novel strategies to eliminate choriocarcinoma is crucial for increasing the health of women. SATB1 (special AT-rich sequence binding protein 1) participates in tissue-specific gene expression and higher-order chromatin organization, and could promote cancer progression and invasion. For the first time, we hereby demonstrated that the expression of SATB1 was increased by 19 folds in choriocarcinoma cells compared with the normal chorionic cell line, and inhibition of SATB1 expression could markedly inhibit the proliferation of choriocarcinoma cells. Then we developed the gene drug delivery system EGFR-LPDS (epidermal growth factor receptor aptamer-conjugated liposome-polycation-DNA complex loaded with SATB1 siRNA) to increase the delivery and therapeutic effect of SATB1 siRNA against choriocarcinoma cells. The results showed that EGFR-LPDS could specifically target choriocarcinoma cells, resulting in significant inhibition of SATB1 expression, growth inhibitory effect and apoptosis in EGFR over-expressing choriocarcinoma cells in vitro. Notably, EGFR-LPDS could inhibit the expression of SATB1 in choriocarcinoma xenograft in mice, and exhibited the best therapeutic efficacy against mice bearing choriocarcinoma xenograft compared with other controls. Notably, EGFR-LPDS achieved a striking tumor weight inhibitory rate of 81.4%. This is the first report of the therapeutic efficacy of SATB1 siRNA towards choriocarcinoma, and the increased SATB1 siRNA delivery by nanoparticles to choriocarcinoma cells using EGFR aptamers. Thus, EGFR-LPDS represents an up-and coming approach for choriocarcinoma therapy. Considering that there are still limited treatment strategies for choriocarcinoma therapy, patients with choriocarcinoma may be beneficial from this gene therapy.