Recently, interest in stimuli-responsive core–shell nanogels as drug delivery systems for tumor therapy has increased. Here, a temperature-activated drug locking and glutathione-triggered drug unlocking nanogel is designed, which is composed of hyaluronic acid (HA) conjugated with poly(N-isopropylacrylamide) (PNIPAAm) using a disulfide bond as the linker (HA–SS–PNIPAAm, H–SS–P). After injection into the systemic circulation, these synthetic copolymers endure temperature-motivated “lock” behaviors to form nanogels due to the thermosensitive lipophilic transformation of PNIPAAm, accompanied by doxorubicin (DOX) locking into the cavities of the nanogels. When they reach tumor cells, these nanogels exhibit glutathione (GSH)-triggered “opening” behavior to unlock the drugs for tumor therapy. The transmission electron microscopy (TEM) results demonstrate that the H–SS–P copolymer solutions are irregular at room temperature, while spherical structures (∼30 nm) can be observed below 37 °C, but dissociate in the presence of 40 mM GSH. Based on flow cytometry and fluorescence microscopy analyses, observations reveal that H–SS–P@DOX nanogels are intracellularly taken up into human lung cancer cells (A549) via HA-receptor mediated endocytosis. More importantly, these nanogels possess much higher tumor targeting capacity than free DOX and efficiently enhance the antitumor effect with reduced systemic toxicity in 4T1 tumor-bearing mice.