Malignant tumors remain a serious threat to human health and life and are a major public health problem globally. Herein, we designed and synthesized a novel nucleic acid nanomedicine AS1411-siRNA-LNPs (As@LNPs). Bmi-1 siRNA was coated with cationic liposomes, and a nucleic acid aptamer AS1411 with tumor cell-targeting ability was attached to the outermost layer of the liposomes. The average particle size of As@LNPs was 183 nm, and the polydispersion coefficient was 0.187. The encapsulation rate and drug loading of As@LNPs were 85% and 4.6%, respectively. The average electron mobility of the drug was 2.64 (μ/s)/(V/cm), and the zeta potential of As@LNPs was 33.79 ± 0.78 mV. The microstructure of the nanomedicine was evaluated via transmission electron microscopy. In vitro and in vivo experiments showed that As@LNPs significantly inhibited tumor growth and promoted tumor cell apoptosis. As@LNPs showed favorable biosafety with major tissues and organs, except glomerulus and renal epithelial cells.