Abstract In this study, a novel pH-responsive nanogel composed of glycol chitosan (GCS) grafted with functional 3-diethylaminopropyl (DEAP) groups (denoted as GCS- g-DEAP hereafter) was fabricated. The GCS- g-DEAP was designed to have a self-assembled arrangement consisting of hydrophilic block (GCS) and hydrophobic block (DEAP) at physiological pH. As the pH decreased to tumor extracellular pH (pH e), the nanogel was destabilized due to the protonation of DEAP. The pH-responsive property of the nanogel at tumor extracellular pH (pH e) was characterized in drug-release kinetic studies. The release of doxorubicin (DOX) from DOX-loaded nanogels was significantly accelerated at lower pH values, which allowed for increased DOX uptake by non-small lung carcinoma A546 cells under a slightly acidic pH condition, as in tumor pH e.