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Breast cancer is the leading cause of mortality among all cancers. HER2, human epidermal growth factor receptors type 2, a receptor tyrosine kinase that induces interminable cell proliferation, is overexpressed in 20–25 percent of breast cancers. In spite of significant progress in nanomedicine in the past decade, being subjected to genetic drift that hides many paramount epitopes has rendered targeting HER2 as a big challenge. In the present study, we developed monovalent and bivalent monospecific along with bivalent bispecific VHH targeting different epitopes on HER2, and showed that bivalent bispecific VHH has the highest affinity among other tested modalities. Then we covalently coupled VHHs to the fluorescent labeled liposomal nanoparticle to produce targeted liposomes. Based on flow cytometry results, bivalent bispecific VHH targeted liposomes showed the highest fluorescent intensity, on HER2 breast cancer cells. Liposomes conjugated to bivalent monospecific VHH exhibited enhanced affinity toward HER2 positive cell lines compared to monovalent targeted liposomes, with bivalent bispecific liposomes appearing as the most robust probe.Nanobodies are small antibody fragments often with subnanomolar affinities against antigen.VHH are robust utility as targeting moiety for targeted delivery in cancer therapy.Genetic drift is the main cause that cancer cells develop resistance against antibody treatment.Bivalent-bispecific VHH reveal the highest affinity in comparison with bivalent-monospecifc- and monovalent VHHs.