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• Novel Lip-PTX/BSA NPs were fabricated via modified thin-film method. • The fabrication process avoided direct contact of BSA with toxic organic solvents. • The fabrication process eliminated organic solvent residual. • The NPs exhibited excellent colloidal stability and sustained release manner. • The NPs showed effective in vitro/vivo antitumor efficacy. Organic solvents have been reported to exert certain influence on the structure and drug loading efficiency of albumin. It is urgent to develop organic solvent-free albumin-based paclitaxel nanoparticles for effective anticancer therapy. In this study, novel PTX liposome-albumin composite nanoparticles (Lip-PTX/BSA NPs) aimed at avoiding the direct contact of albumin with toxic organic solvents and enhancing the colloidal stability of the formulation were prepared. To methodically evaluate the impacts of multifarious factors on the critical characteristics of the nanoparticles, Box-Behnken design was applied in the formulation optimized process. Ratio of drug-phosphatidylcholine (EPC), ratio of drug-BSA and pH of the media were chosen as the independent variables, while particle size and drug-loading content (DLC) loss rate were applied as the selected response variables. A quadratic model fitted best to describe the data with maximal lack-of-fit p-value and minimum sequential p-value. Three-dimension surface figures were utilized to describe the correlation of independent variables with response variables. Optimized formulation of the nanoparticles with size of 116.2 ± 2.0 nm and zeta potential of -18.4 ± 1.01 mV were obtained with a high encapsulation efficiency of 99.8%. PTX was involved physical interaction with the excipient during the preparation process of the nanoparticles. The release of PTX from Lip-PTX/BSA NPs exhibited a sustained release manner compared to albumin-bound PTX (nab-PTX) and Taxol. Besides, Lip-PTX/BSA NPs presented enhanced in vitro cytotoxicity against 4T1 cells due to highly nonspecific internalization in the cytoplasm. Simultaneously, Lip-PTX/BSA NPs showed effective in vivo antitumor efficacy against 4T1 bearing BALB/c mice, while no apparent adverse effect was observed by histological section and blood biochemical analysis. In conclusion, the novel Lip-PTX/BSA NPs could be applied as a promising drug delivery system for PTX to exert efficient cancer curative effects in clinic. [ABSTRACT FROM AUTHOR]