A facile and well-controlled pathway was introduced to obtain optimal pH-sensitive luteinizing hormone-releasing hormonefunctionalized poly(ethylene glycol)-block-poly(l-histidine) (LHRH-PEG-PHIS) micelles in this paper. The influence of block-selective solvent, the weight ratio of the selective solvent to common solvent and initial polymer concentration on the self-assembly of LHRH-PEG-PHIS micelles were studied. These factors exerted remarkable influence on the morphology of the resulting micelles. The micelles showed a spherical geometry and an uniform appearance under the following optimal experimental conditions: LHRH-PEG/PHIS ratio of 1.0 by molar, DMF as the selective solvent and 3.0 mg/mL as initial concentration, 100 W of ultrasonic power. These micelles had a small diameter (about 90 nm), low CMC (10 g/mL), and pH-sensitive switch in surface charge and micelles' size. As the pH of the micellar solution decreased from pH 7.4 to 5.5, the zeta potential of the LHRH-PEG-PHIS micelles increased from -0.02 mV to 20.7 mV and the diameter of the nanoparticles decreased from 137 nm to 76 nm. After 30 h of incubation at pH 5.0, 6.0, and 7.4 the released free Doxorubicin (DOX) was about 83.18%, 81.26%, and 30.35%, respectively. The LHRH-PEG-PHIS micelles could combine the characteristics of active targeting with pH-triggered drug release promising as intracellular drug delivery carriers. POLYM. ENG. SCI., 55:277-286, 2015. (c) 2014 Society of Plastics Engineers