Fe 3 O 4 -Incorporated Metal-Organic Framework for Chemo/Ferroptosis Synergistic Anti-Tumor via the Enhanced Chemodynamic Therapy.

Metal-organic framework (MOF)-based drug delivery nanomaterials for cancer therapy have attracted increasing attention in recent years. Here, we propose an enhanced chemodynamic anti-tumor therapy strategy by promoting the Fenton reaction by using core-shell zeolitic imidazolate framework-8 (ZIF-8)@Fe 3 O 4 as a therapeutic platform. Carboxymethyl cellulose (CMC) was used as a stabilizer of Fe 3 O 4 , which then decorated on the surface of ZIF-8 via the electrostatic interaction and served as an efficient Fenton reaction trigger. Meanwhile, the pH-responsive ZIF-8 scaffold acted as a container to encapsulate the chemotherapeutic drug doxorubicin (DOX). The obtained DOX-ZIF-8@Fe 3 O 4 /CMC nanoparticles concomitantly accelerated DOX release and generated more hydroxyl radicals by targeting the lysosomes in cancer cells. In vitro and in vivo studies verify that the DZFC nanoparticles trigger GPX4-dependent ferroptosis via the activation of the c-Jun N-terminal kinases (JNK) signaling pathway, following to achieve the chemo/ferroptosis synergistic anti-tumor efficacy. No marked toxic effects were detected during DZFC treatment in a tumor-bearing mouse model. This composite nanoparticle remarkably suppressed the tumor growth with minimized systemic toxicity, opening new horizons for the next generation of theragnostic nanomedicines. This article is protected by copyright. All rights reserved.