Dual-responsive magnetic nanozyme Cu-CuFe₂O₄ leverages mild magnetic hyperthermia and redox dyshomeostasis to potentiate cuproptosis

Abstract

Cuproptosis, a copper-dependent programmed cell death pathway, has shown limited antitumor efficacy due to the tumor responsiveness and copper bioavailability. To address these challenges, we engineered hyaluronic acid functionalized Cu-CuFe₂O₄ nanoparticles (CCIO@HA NPs) that enhance cuproptosis therapy through synergistic exploitation of mild magnetic hyperthermia therapy (MMHT)-induced mitochondrial copper overload and multiple enzyme activities-driven redox dyshomeostasis (RDH). Specifically, the system ensures precise copper accumulation to initiate cuproptosis by coupling pH/MMHT triggered Cu²⁺ release. Simultaneously, CCIO@HA NPs induce RDH via multiple enzyme activities: glutathione oxidase (GSHOx)-like activity depletes GSH to inhibit copper chelation, thereby amplifying mitochondrial copper overload; catalase (CAT)-like activity generates O₂ to alleviate hypoxia, which enhances mitochondrial respiration-driven cuproptosis; and peroxidase (POD)/Fenton like-derived activity produces hydroxyl radical (·OH), driving irreversible RDH. Crucially, MMHT synergizes with RDH to degrade heat shock protein 70 (HSP70), thereby sensitizing tumors to copper cytotoxicity. Furthermore, CCIO@HA NPs enable precise photoacoustic/magnetic resonance imaging-guided therapy. In vitro and in vivo experiments demonstrate an excellent tumor growth inhibition with high biocompatibility. This work establishes a paradigm-shifting strategy that coordinate MMHT with RDH, effectively addressing the dual bottlenecks of cuproptosis in solid tumor therapy.