Abstract: The aim of the study was to optimize the preparation parameters of blank bovine serum albumin (BSA) nanoparticles with adsorbed breviscapine by central composite design (CCD)-response surface methodology (RSM).In the formulation design using CCD-RSM,independent variables were the concentrations of breviscapine and blank BSA nanoparticles and the amount of added breviscapine;dependent variables were the entrapment efficiency,the drug loading,and the increase of particle size after drug loading.Multilinear and quadratic models were used to estimate the relationship between the dependent and the independent variables.Response surface was delineated according to the mathematical models.The best-fit formulation was predicted and vali-dated.Particle size,polydispersity index,Zeta potential and in vitro release of the product were investigated.The results showed that the quantitative relationships between three factors and three evaluation indexes were characterized with high reliability.The determined values were very close to the predicted ones.In the optimized formulation,the concentrations of breviscapine and blank BSA nanoparticles were 1.45 mg/mL and 30 mg/mL respectively;and the volume of the former was 2.4 times of the latter.The optimized formulation had a drug-loading of 6.73%,encapsulation efficiency of 80.08%, and particle size increase of 22.7 nm,the average diameter of 283.4 nm with a polydispersity index of 0.117,Zeta potential of 17.95 mV,and 24 h-accumulated release ratio of 79.19%.The novel preparation method for breviscapine adsorbed-BSA nanoparticle was successfully developed and optimized.