A Hyaluronic Acid Modified Copper-based Metal-organic Framework Overcomes Multidrug Resistance Via Two-way Redox Dyshomeostasis Under Hypoxia

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 and electrophilic ligands, and generate •OH via a Fenton-like reaction. In vitro experiments suggested that the nanoparticles had good targetability to cancer cells and biocompatibility to normal cells. HA-CuMOF@DOX was successfully internalized by drug-resistant human hepatoma carcinoma cell line (HepG2-ADR). It aggravated redox dyshomeostasis via dual regulation, inducing mitochondrial damage, reducing intracellular adenosine triphosphate (ATP) levels, and downregulating P-gp to overcome HepG2-ADR drug resistance. More importantly, in vivo experiments demonstrated an 80.69 % tumor growth inhibition in nude mice bearing HepG2-ADR cells. This work represents a significant advancement in the development of effective treatments for drug-resistant tumors.