Stimuli-responsive polymer nanoparticles are playing an increasingly more important role in drug delivery applications. However, limited knowledge has been accumulated about processes which use stimuli-responsive polymer nanospheres (matrix nanoparticles whose entire mass is solid) to carry and deliver hydrophobic therapeutics in aqueous solution. In this research, pyrene was selected as a model hydrophobic drug and a pyrene-loaded core-shell structured nanosphere named poly(DEAEMA)-poly(PEGMA) was designed as a drug carrier where DEAEMA and PEGMA represent 2-(diethylamino)ethyl methacrylate and poly(ethylene glycol) methacrylate, respectively. The pyrene-loaded core-shell nanospheres were prepared via an in situ two-step semibatch emulsion polymerization method. The particle size of the core-shell nanosphere can be well controlled through adjusting the level of surfactant used in the polymerization where an average particle diameter of below 100 nm was readily achieved. The surfactant was removed via a dialysis operation after polymerization. Egg lecithin vesicles (liposome) were prepared to mimic the membrane of a cell and to receive the released pyrene from the nanosphere carriers. The in vitro release profiles of pyrene toward different pH liposome vesicles were recorded as a function of time at 37 degrees C. It was found that release of pyrene from the core-shell polymer matrix can be triggered by a change in the environmental pH. In particular the pyrene-loaded nanospheres are capable of responding to a narrow window of pH change from pH=5, 6, to 7 and can achieve a significant pyrene release of above 80% within 90 h. The rate of release increased with a decrease in pH. A first-order kinetic model was proposed to describe the rate of release with respect to the concentration of pyrene in the polymer matrix. The first-order rate constant of release k was thus determined as 0.049 h(-1) for pH=5; 0.043 h(-1) for pH=6; and 0.035 h(-1) for pH=7 at 37 degrees C. The release of pyrene was considered to follow a diffusion-controlled mechanism. The synthesis and encapsulation process developed herein provides a new approach to prepare smart nanoparticles for efficient delivery of hydrophobic drugs. (c) 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 4440-4450