In this study, Schiff-base copolymer coating and mesoporous silica nanoparticles (Polymer@MSN) were synthesized by ARGET ATRP and sol-gel method respectively. Imine bonds acted as the pH-cleavable linker between copolymer gatekeepers and MSN to promote the controlled-release performance of DOX. The DOX-loaded nanoparticles (Polymer@MSN-DOX) were spherical with a diameter of approximately 150 nm. At pH 5.0 (pH of intracellular environment), the cumulative release of DOX within 72 h was 45% higher than that at pH 7.4 (normal physiological environment) due to the cleavage of imine bonds, showing obvious pH-responsive drug release performance. Confocal microscopy studies and in vitro cytotoxicity results revealed that Polymer@MSN-DOX could smoothly enter HepG2 cells to release DOX and show a high cytotoxicity. Noted specially that molecular dynamics simulations were applied to investigate the microcosmic adsorption/diffusion interaction between drug molecules and MSN. Simulation results showed that the driving force of DOX adsorption in mesoporous channels was originated from hydrogen bonding interaction between the mesoporous wall and DOX molecules and π-π conjugated interaction between benzene rings in addition to concentration differences. The structural design of composite nanocarriers in this research could provide guidance for the application of pH-responsive MSN-based drug delivery system.