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

Sep 20, 2025Colloids and surfaces. B, Biointerfaces

Magnetic copper-based nanoparticles use gentle heating and cell stress to boost copper-triggered cell death

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Regenerative Health on OpenScience ↗PubMed ↗DOI ↗

Abstract

Engineered nanoparticles achieve significant tumor growth inhibition while enhancing cuproptosis therapy through precise copper accumulation.

Hyaluronic acid functionalized Cu-CuFe₂O₄ nanoparticles (CCIO@HA NPs) are designed to improve the effectiveness of cuproptosis therapy.
These nanoparticles release copper in response to pH and mild magnetic hyperthermia therapy (MMHT), promoting targeted cell death.
CCIO@HA NPs induce redox dyshomeostasis by utilizing enzyme activities that deplete protective molecules and produce reactive oxygen species.
The combination of MMHT with redox dyshomeostasis degrades heat shock protein 70 (HSP70), increasing susceptibility of tumors to copper-induced damage.
In vitro and in vivo results indicate high biocompatibility and effective tumor growth suppression.

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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.

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

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