As a first-line drug widely used in the treatment of leukemia, 6-MP has obvious effects on leukemia. However, 6-MP disadvantages such as poor solubility in water, easy binding with serum proteins, short circulation time, and large toxic and side effects greatly limit the application of 6-MP. For this reason, various 6-MP nano drug-loading systems have been designed to increase the water solubility of 6-MP, extend the circulation time, and increase the bioavailability of 6-MP to a certain extent, reducing its toxic and side effects. However, its therapeutic effect in vivo and in vitro is still far from expectations, and there is a lot of room for improvement. In order to solve the above problems encountered in the clinical application of 6-MP, we have tried two ways of polymer prodrugs and drug-loaded vesicles to achieve efficient targeted delivery and treatment of 6-MP. We designed hyaluronic acid (HA)-based gluteal-skin-responsive 6-MP polymer prodrug (HA-GS-MP) for highly effective targeted therapy of acute myeloid leukemia. Hyaluronic acid is a natural polysaccharide, which has excellent biocompatibility and biodegradability, and has a good ability to actively target malignant tumor cells overexpressing the CD44 receptor. 6-MP is connected to the HA chain through a vinyl sulfide bond, which is stable under physiological conditions (no drug release), and under intracellular reducing conditions, the connection bond is broken and 6-MP is quickly released. HA-GS-MP has a simple preparation process, good water solubility, long cycle time, and strong targeting ability. This GSH-responsive CD44 targeted 6-MP polymer prodrug is expected to improve the therapeutic effect on acute myeloid leukemia cells.