A novel method for preparing the PLGA nanospheres with hydrophilic surface has been designed and characterized. Because of good solubility of tetraglycol in water, PLGA (poly(lactide-co-glycolide)) nanospheres were formed by spraying the PLGA/tetraglycol solution into water. The size of PLGA nanospheres was manipulated by changing the concentration of PLGA/tetraglycol solution. Based on the hydrophobic interaction between PLGA and poly(propylene oxide) domain of F-127 (one of Pluronics, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer, F-127-coated PLGA nanospheres was prepared to enhance the stability of PLGA nanospheres in the aqueous media. For the application as a drug delivery vehicle, it was characterized by measuring the loading amount, the encapsulation efficiency and the release pattern of drug. Paclitaxel used as a potent anti-cancer drug was selected as a model drug.