<p>Breast cancer is one of the leading causes of cancer-related death among women, and nanoparticle (NPs)-based delivery of chemotherapeutic agents has emerged as a promising strategy to improve treatment outcomes. Here, we designed Doxorubicin (Dox) and Minocycline (Min) loaded polyvinyl-pyrrolidone nanoparticles coated with β-cyclodextrin (β-CD) (DM/NPs-CD) and evaluated their chemotherapeutic efficiency in breast cancer cells, in vitro and in vivo. DM/NPs-CD were successfully prepared and evaluated against breast cancer. In vitro studies were performed to assess cytotoxicity, cellular uptake, and apoptosis in breast cancer cells. In vivo studies were conducted using a breast cancer xenograft model to evaluate tumor growth inhibition and inhibition of lung metastasis. The synthesized DM/NPs-CD possessed approximately ⁓143&#xa0;nm particle size with slightly negative zeta-potential, excellent physicochemical properties including drugs release. DM/NPs-CD exhibited enhanced cytotoxicity with synergistic ratio of Dox: Min (1:1), improved cellular uptake, and increased apoptosis in breast cancer cells. In vivo studies demonstrated significant tumor growth inhibition and marked inhibition of lung metastasis in mice treated with DM/NPs-CD. Furthermore, immunohistochemistry (IHC) of tumors and lungs also declared their efficiency in murine tumor model. The safety and systemic compatibility were also confirmed by H&amp;E staining of major organs and liver functional tests. Current research demonstrates the potential of DM/NPs-CD as a novel and effective therapeutic strategy for breast cancer treatment. The results highlight the synergistic anti-tumor effects of Dox and Min, and the improved delivery of Dox to the tumor site using the designed nanoparticles.</p>