Triple-negative breast cancer is one of the intractable cancers that are not sensitive to treatment with existing molecular-targeted drugs. Recently, there has been much interest in RNA interference-mediated treatment of triple-negative breast cancer. In the present study, we have developed lipid nanoparticles encapsulating siRNA (LNP-siRNA) decorated with an Fab' antibody against heparin-binding EGF-like growth factor (αHB-EGF LNP-siRNA). αHB-EGF LNP-siRNA targeting polo-like kinase 1 (PLK1) was prepared and evaluated for its anticancer effect using MDA-MB-231 human triple-negative breast cancer cells overexpressing HB-EGF on their cell surface. Biodistribution data of radioisotope-labeled LNP and fluorescence-labeled siRNA indicated that αHB-EGF LNP effectively delivered siRNA to tumor tissue in MDA-MB-231 carcinoma-bearing mice. Expression of PLK1 protein in the tumors was clearly suppressed after intravenous injection of αHB-EGF LNP-siPLK1. In addition, tumor growth was significantly inhibited by treatment with this formulation of siRNA and an antibody-modified carrier. These findings indicate that αHB-EGF LNP is a promising carrier for the treatment of HB-EGF-expressing cancers, including triple-negative breast cancer.