Doxorubicin‐Loaded Metal–Organic Framework for Ferroptosis‐Enhanced Chemotherapy Through Sustained Zn Release and Glutathione Peroxidase Downregulation

TL;DR

A new zinc-based material delivers chemotherapy drugs and triggers cell death in cancer cells, improving treatment effectiveness.

Contribution

A novel ZnMOF nanoplatform combines chemotherapy delivery with ferroptosis induction to overcome drug resistance.

Findings

DOX@ZnMOF achieves tumor growth inhibition of 0.91 and 0.93 in CT26 and MC38 models.

ZnMOF effectively depletes glutathione and suppresses GPX4 to induce ferroptosis.

ZnMOF shows superior stability and pH-responsive drug release compared to ZIF-8.

Abstract

As a cornerstone of cancer treatment, chemotherapy is frequently hindered by poor tumor specificity, systemic toxicity, and the emergence of drug resistance. These limitations underscore the need for innovative therapeutic strategies that can circumvent resistance mechanisms and enhance cancer cell cytotoxicity. Herein, we report the development of a structurally robust zinc‐based metal–organic framework (ZnMOF) constructed from 4,4′‐di(pyrazol‐4‐yl)‐1,1′‐biphenyl ligands for simultaneous ferroptosis induction and chemotherapeutic delivery. Compared to the widely used ZIF‐8, the newly developed ZnMOF exhibits superior structural stability under physiological conditions, robust doxorubicin (DOX) loading, and pH‐responsive drug release in acidic tumor microenvironments. In addition to efficient DOX delivery, ZnMOF effectively promotes ferroptosis by elevating intracellular reactive oxygen species, depleting glutathione, and inducing lipid peroxidation. In vivo studies using CT26 and MC38 colon carcinoma models demonstrated potent antitumor efficacy of DOX‐loaded ZnMOF, achieving tumor growth inhibition values of 0.91 and 0.93, respectively. These results position ZnMOF as a promising multifunctional nanoplatform for overcoming chemoresistance and enhancing therapeutic outcomes through ferroptosis‐based combination cancer therapy.

A robust zinc‐based metal–organic framework (ZnMOF) enables dual functions of doxorubicin delivery and sustained Zn2+ release to trigger ferroptosis‐enhnaced chemotherapy. DOX@ZnMOF effectively depletes intracellular glutathione, suppresses GPX4, and elevates reactive oxygen species, leading to efficient oxidative DNA damage and apoptosis. In murine colorectal carcinoma models, DOX@ZnMOF achieves potent tumor growth inhibition and significantly prolongs survival, highlighting its potential as a promising nanoplatform for synergistic cancer therapy.

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