Arctigenin (ATG) is a broad-spectrum antitumor drug with an excellent inhibitory effect on malignant tumors such as breast cancer, glioblastoma, liver cancer, and colon cancer. However, the clinical application of ATG is limited by its poor water solubility and quick hydrolysis in the liver, intestine, and plasma, which might hinder its application. Sialic acid (SA) recognizes selectin receptors overexpressed on the surface of tumor-associated macrophages. In this study, SA was conjugated with octadecylamine (ODA) to prepare SA-ODA, which was employed to prepare SA functionalized nanoliposomes (SA-Lip) to achieve breast cancer targeting. The formulations were finely optimized using the Box–Behnken design to achieve higher ATG loading. The size, ζ potential, entrapment efficiency, drug loading, and release behavior of ATG@SA-Lip were fully investigated in comparison with conventional ATG@Lip. The ATG@SA-Lip displayed more potent cytotoxicity and higher cellular internalization compared to ATG@Sol and ATG@Lip in both MCF7 and 4T1 cells. Notably, ATG@SA-Lip showed the lowest impact on the immune system. Our study demonstrates that SA-Lip has strong potential as a delivery system for the targeted delivery of ATG.