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Zhaoqiang Dong,1 Yuzhen Wang,2 Jing Guo,3 Chuan Tian,4 Wengu Pan,4 Hongwei Wang,4 Jieke Yan4 1Department of Cardiology, The Second Hospital of Shandong University, Ji’nan, 250033, People’s Republic of China; 2Clinical Department, Jinan Vocation College of Nursing, Ji’nan, 250033, People’s Republic of China; 3Department of Gynaecology, The Second Hospital of Shandong University, Ji’nan, 250033, People’s Republic of China; 4Department of Renal Transplantation, The Second Hospital of Shandong University, Ji’nan, 250033, People’s Republic of ChinaCorrespondence: Jieke Yan, Department of Renal transplantation, The Second Hospital of Shandong University, No. 247 Beiyuan Street, Ji’nan, 250355, People’s Republic of China, Email yanjiekesdu@163.comObjective: To evaluate the prostate cancer therapy efficiency of the synergistic combination docetaxel (DTX) and formononetin (FMN) in one nano-sized drug delivery system. Hyaluronic acid (HA) and epidermal growth factor receptor-targeted peptide (GE11) dual ligands were applied to modify the nano-systems.Methods: In this study, GE11-modified nanoparticles (GE-NPs) were applied for the loading of DTX, and HA-decorated NPs (HA-NPs) were used to encapsulate FMN. HA and GE11 dual ligand-modified binary nanoparticles (HAGE-DTX/FMN-NPs) were constructed by the self-assembling of GE-NPs and HA-NPs. The anti-PCa ability of the system was evaluated in vitro on PC-3 human prostate carcinoma cells (PC3 cells) and in vivo on PC3 tumor-bearing mice in comparison with single NPs and free drugs formulations.Results: HA/GE-DTX/FMN-NPs were nano-sized particles with smaller particles coating on the inner core and achieved a size of 189.5 nm. HA/GE-DTX/FMN-NPs showed a cellular uptake efficiency of 59.6%, and a more efficient inhibition effect on PC3 cells compared with single ligand-modified NPs and free drugs. HA/GE-DTX/FMN-NPs showed significantly higher tumor inhibition efficiency than their single drug-loaded counterparts and free drugs.Conclusion: HA/GE-DTX/FMN-NPs have a synergistic anti-tumor effect and also could the reduce unexpected side effects during the cancer therapy. It could be used as a promising anti-PCa system.Keywords: prostate cancer, docetaxel, formononetin, hyaluronic acid, epidermal growth factor receptor, binary nanoparticles