Metal-Organic Framework Coordinated with Single Fe Nanozymes and Gold Cluster for Biomedical Applications

Metal-organic frameworks (MOFs) have been extensively utilized as substrates for constructing single-atom catalysts (SACs) due to their abundant ligands, enabling nanozyme-mediated biomedical applications. However, the preparation of SACs using MOF substrates typically involves harsh calcination processes to stabilize the single metal atom catalysts, which can lead to uncertain changes in the oxidation state of the metal centers, impacting the overall catalytic reaction. In this study, we have developed ultrasmall MOF-based single iron (Fe) atom Fenton-like nanozymes (referred to as Fe/MOF) by employing a simple mixing method. These nanozymes were combined with a gold nanocluster-embedded MOF mimic of glucose oxidase (referred to as Au/MOF), enabling cascade enzymatic reactions within living systems. To harness the abundant porosity of MOF and enhance cell cytotoxicity, the anticancer drug doxorubicin (DOX) was loaded inside Fe/MOF (referred to as Fe/DOX/MOF). Additionally, Au/MOF was further modified with a mitochondrial targeting moiety (triphenylphosphonium, TPP) to target the mitochondria and disrupt the cellular redox system. Internalization of Au/MOF into mitochondria resulted in glutathione (GSH) depletion through thiol-gold interactions, leading to mitochondrial excess lipid peroxidation. The constructed Fe/MOF exhibited an oxidation state of 2+ with Fe-N coordination bonds, demonstrating well-established Fenton-like nanozymes characteristics. The overall cascade enzymatic activity effectively generated hydroxyl radicals from glucose as a substrate. The generated gluconic acid induced an acidic environment that further accelerated the overall Fenton reaction. In vitro, studies demonstrated effective cancer eradication through cascade glucose oxidation and hydroxyl radical generation. GSH depletion-mediated down-regulation of GPx4, along with the delivered Fe²⁺, induced Fenton reaction-mediated lipid peroxidation, indicating ferroptosis. In vivo, studies further confirmed the overall therapeutic effects of the cascade enzymatic activity of Fe/MOF and Au/MOF. Our novel and straightforward synthesis process for MOF-based single-atom nanozymes and metal clusters present a new paradigm for fabricating single-atom nanozymes for multimodal cancer treatment.