To enhance the aqueous solubility and stability of etoposide preparation, the central composite design-response surface method was used to optimize the prescription technology of etoposide nano-mixed micelles (ETP mPEG-PLA/P123) and its physicochemical properties were investigated . The content of etoposide was determined by UPLC. The ETP mPEG-PLA/P123 micelles were synthesized by the thin film hydration method. Based on the results of single factor exploration, central composite design-response surface method of three factors and five levels was carried out to optimize the prescription technology with drug dosage, the mass ratio of mPEG-PLA and hydration volume as independent variables, and the entrapment efficiency, drug loading and particle size as dependent variables. Finally, chemical and physical characterization studies of micelles were evaluated. The results showed that the optimal prescription of ETP mPEG-PLA/P123 micelle preparation was that mPEG-PLA:P123=38:62, the drug dosage was 5 mg, and the hydration volume was 6 mL. After optimization, the entrapment efficiency and drug loading were 87.4 % and 4.19 %, the particle size was 115.6 nm, PDI was 0.216, and Zeta potential was -16.3 mV. The critical micelle concentration (CMC) was determined by fluorescence probe method, and the CMC value was 1.7×10-3 g?L-1, indicating that the mPEG-PLA/P123 micelles had high stability. In addition, in vitro release experiments showed that etoposide could be released from micelles slowly and continuously, up to 80 % within 48 h. The optimized ETP mPEG-PLA/P123 nano-mixed micelles were able to enormously improve the aqueous solubility of etoposide, and the micelle preparation had good stability and a certain slow-release effect.