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Purpose: Nanoencapsulation of chemotherapeutics is an established method to target breast tumors and has been shown to enhance the efficacy of therapy in various animal models. During the past two decades, the nucleoside analog Gemcitabine has been under investigation to treat both recalcitrant and localized breast cancer, often in combination with other chemotherapeutics. In this study, we investigated the chemotherapeutic efficacy of a novel Gemcitabine-encapsulated liposome previously formulated by our group, GemPo, on both sensitive (4T1) and recalcitrant (MDA-MB-231) breast cancer cell lines., Methods: Gemcitabine free drug and liposomal Gemcitabine were compared both in vitro and in vivo using breast cancer models., Results: We demonstrated that GemPo differently hindered the growth, survival and migration of breast cancer cells, according to their drug sensitivities. Specifically, whereas GemPo was a more potent cytotoxic and apoptotic agent in sensitive breast cancer cells, it more potently inhibited cell migration in the resistant cell line. However, GemPo still acted as a more potent inhibitor of migration, in comparison with free Gemcitabine, irrespective of cell sensitivity. Administration of GemPo in a 4T1-bearing mouse model inhibited tumor growth while increasing mice survival, as compared with free Gemcitabine and a vehicle control. Interestingly, the inclusion of a mitotic inhibitor, Paclitaxel, synergized only with free Gemcitabine in this model, yet was as effective as GemPo alone. However, inclusion of Paclitaxel with GemPo significantly improved mouse survival., Conclusions: Our study is the first to demonstrate the pleiotropic effects of Gemcitabine and Gemcitabine-loaded nanoparticles in breast cancer, and opens the door for a novel treatment for breast cancer patients.