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Abstract Background Drug resistance of paclitaxel (TAX), the first-line chemotherapy drug for breast cancer, was reported to develop in 90% of patients with breast cancer, especially metastatic breast cancer. Investigating the mechanism of TAX resistance of breast cancer cells and developing the strategy improving its therapeutic efficiency are crucial to breast cancer cure. Methods and Results We here report an elegant nanoparticle (NP)-based technique that realizes efficient breast cancer treatment of TAX. Using lentiviral vector-mediated gene knockdown, we first demonstrated that TAX therapeutic efficiency was closely correlated with metadherin (MTDH) gene expression in breast cancer cell lines. This finding was also supported by efficacy of TAX treatment in breast cancer patients from our clinical studies. Specifically, TAX treatment became more effective when MTDH expression was decreased in MCF-7 cancer cells by the blocking nuclear factor-kappa B (NF-κB) pathway. Based on these findings, we subsequently synthesized a polymeric NP that could co-deliver MTDH-small interfering RNA (MTDH–siRNA) and TAX into the breast cancer tumors in tumor-bearing mice. The NPs were composed of a cationic copolymer, which wrapped TAX in the inside and adsorbed the negatively charged siRNA on their surface with high drug-loading efficiency and good stability. Conclusions NP-based co-delivery approach can effectively knock down the MTDH gene both in vitro and in vivo, which dramatically inhibits breast tumor growth, achieving effective TAX chemotherapy treatment without overt side effects. This study provides a potential therapeutic strategy for the treatment of a wide range of solid tumors highly expressing MTDH.