pH-responsive drug nanocarriers are widely applied for cancer treatment. However, the mechanistic details of drug loading and drug release from these micelles are unknown. Here, we reveal the mechanistic details of micelle formation, drug loading and drug release from pH-responsive polymeric micelles using computer simulations and experiments. A triblock amphiphilic copolymer, methoxy-poly(ethylene glycol) 2000-poly(2-(N,N-diethylamino)ethyl methacrylate)-polycaprolactone (mPEG-PDEA-PCL, PDC), was used to load paclitaxel (PTX), a hydrophobic anticancer agent, using an injection method. The micelles showed strong pH-responsive behavior, where the sizes and zeta potentials ranged from 51 nm and 19 mV at pH 4.5, respectively, to 22 nm and -5.5 mV at pH 8, respectively, with greater PTX release at pH 6.5 than that at pH 7.4. Furthermore, the PTX-loaded PDC micelles showed higher cytotoxicity to MCF-7 cells at pH 6.5 than that at pH 7.4 due to differential drug release. Molecular dynamics and the coarse-grained dissipative particle dynamic method were used to mimic micelle formation, drug loading and drug release. The pH-responsive segment, PDEA, transforms to its protonated form, PDEAH(+), in an acidic environment. PTX and PDC form micelles based on hydrophobic interactions, where PTX inserts into the hydrophobic PDEA-PCL core in a neutral environment. An acidic transition of the environment leads to rapid PTX release from the micelles due to the hydrophobic-hydrophilic transition of PDEA to PDEAlr, though some PTX molecules still remain in the PCL core. The pH-responsive PDC micelles are suitable for triggered drug release in an acidic tumor microenvironment. The PDC micelle is, therefore, a promising nanocarrier of anticancer agents for cancer treatment. (C) 2017 Elsevier B.V. All rights reserved.