Multidrug resistance (MDR) has become a major challenge in tumor chemotherapy, primarily associated with the overexpression of P-glycoprotein (P-gp). Inhibiting P-gp expression and function through redox dyshomeostasis has shown great potential for reversing MDR. Here, a nanoscale system of copper-based metal-organic framework (HA-CuMOF@DOX) modified with hyaluronic acid (HA) was constructed to overcome MDR via two-way regulation of redox homeostasis under hypoxia. HA-CuMOF@DOX is a spherical glutathione (GSH) responsive nanoparticle with a drug loading capacity of 20.69 %, which could deplete GSH through Cu