OICC Press Journal of Nanostructure in Chemistry 2193-8865 15 6 2025 12 31 Chitosan Nanoparticle-Mediated Dual Delivery of Quercetin and Paclitaxel Attenuates EMT and Angiogenesis Via ZEB1 and TIMP-3 Regulation in Triple-Negative Breast Cancer 10.57647/jnsc.2025.1506.22 EN Hamed Dadashi Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran Amirreza Nazemiyeh Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran Niloufar Ahdeno Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran Parniya Kehtari Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran Samar Mahari Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran Yadollah Omidi Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, United States Somayeh Vandghanooni Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Morteza Eskandani Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran Journal Article 2025 12 31 This study investigates the therapeutic potential of chitosan nanoparticles (Cs NPs) loaded with quercetin (Que) and paclitaxel (PTX) against triple-negative breast cancer (TNBC), focusing on their impact on epithelial-mesenchymal transition (EMT), a critical driver of metastasis, using MDA-MB-231 cells in vitro and in vivo models. Characterized by an average size of 82–91 nm, a positive zeta potential (+21–27 mV), and high encapsulation efficiencies, the Cs NPs demonstrated potent anti-tumor efficacy. Que-/PTX-loaded NPs significantly enhanced in vitro cytotoxicity by inducing late apoptosis. Furthermore, they suppressed cell migration and inhibited mammosphere formation in 3D cultures, effectively countering the invasiveness associated with EMT. Notably, the NPs downregulated ZEB1, a key EMT-promoting transcription factor, and upregulated TIMP-3, an inhibitor of extracellular matrix degradation, thereby attenuating EMT-driven metastasis. The chorioallantoic membrane (CAM) assay revealed a significant reduction in angiogenesis, further supporting their anti-metastatic potential. In vivo, BALB/c nude mice with MDA-MB-231 xenografts treated with Que-/PTX-Cs NPs exhibited 71.79% tumor growth inhibition and reduced metastatic spread, with 64.27% NP accumulation in tumors. These results underscore Que-/PTX-Cs NPs as a promising nanotherapeutic strategy for TNBC, effectively targeting tumor growth, EMT-driven metastasis, and angiogenesis through ZEB1 and TIMP-3 regulation.