A Cell Selective Fluoride-Activated MOF Biomimetic Platform for Prodrug Synthesis and Enhanced Synergistic Cancer Therapy. ACS nano As a burgeoning bioorthogonal reaction, the fluoride-mediated desilylation is capable of prodrug activation. However, due to the reactions lack of cell selectivity and unitary therapy modality, this strongly impedes their biomedical applications. Herein, we construct a cancer cell-selective biomimetic metal-organic framework (MOF)-F platform for prodrug activation and enhanced synergistic chemodynamic therapy (CDT). With cancer cell membranes camouflage, the designed biomimetic nanocatalyst displays preferential accumulation to homotypic cancer cells. Then, pH-responsive nanocatalyst releases fluoride ions and ferric ions. For activation of our designed prodrug -butyldimethyl silyl (TBS)-hydroxycamptothecin (TBSO-CPT), fluoride ions can desilylate TBS and cleave the designed silyl ether linker to synthesize the OH-CPT (10-hydroxycamptothecin) drug molecule, which effectively kills cancer cells. Intriguingly, the bioorthogonal-synthesized OH-CPT drug upregulates intracellular HO by activating nicotinamide adenine dinucleotide phosphate oxidase (NOX), amplifying the released iron induced Fenton reaction for synergistic CDT. Both and studies demonstrate our strategy presents a versatile fluoride-activated bioorthogonal catalyst for cancer cell-selective drug synthesis. Our work may accelerate the biomedical applications of fluoride-activated bioorthogonal chemistry. 10.1021/acsnano.2c08604

Coordination Self-Assembled AuTPyP-Cu Metal-Organic Framework Nanosheets with pH/Ultrasound Dual-Responsiveness for Synergistically Triggering Cuproptosis-Augmented Chemotherapy. ACS nano Reactive oxygen species (ROS) mediated tumor cell death is a powerful anticancer strategy. Cuproptosis is a copper-dependent and ROS-mediated prospective tumor therapy strategy. However, the complex tumor microenvironment (TME), low tumor specificity, poor therapy efficiency, and lack of imaging capability impair the therapy output of current cuproptosis drugs. Herein, we designed a dual-responsive two-dimensional metal-organic framework (2D MOF) nanotheranostic via a coordination self-assembly strategy using Au(III) tetra-(4-pyridyl) porphine (AuTPyP) as the ligand and copper ions (Cu) as nodes. The dual-stimulus combined with the protonation of the pyridyl group in AuTPyP and deep-penetration ultrasound (US) together triggered the controlled release in an acidic TME. The ultrathin structure (3.0 nm) of nanotheranostics promoted the release process. The released Cu was reduced to Cu by depleting the overexpressed glutathione (GSH) in the tumor, which not only activated the Ferredoxin 1 (FDX1)-mediated cuproptosis but also catalyzed the overexpressed hydrogen peroxide (HO) in the tumor into reactive oxygen species via Fenton-like reaction. Simultaneously, the released AuTPyP could specifically bind with thioredoxin reductase and activate the redox imbalance of tumor cells. These together selectively induced significant mitochondrial vacuoles and prominent tumor cell death but did not damage the normal cells. The fluorescence and magnetic resonance imaging (MRI) results verified this nanotheranostic could target the HeLa tumor to greatly promote the self-enhanced effect of chemotherapy/cuproptosis and tumor inhibition efficiency. The work helped to elucidate the controlled assembly of multiresponsive nanotheranostics and the high-specificity ROS regulation for application in anticancer therapy. 10.1021/acsnano.3c13225

"Three-in-One" Nanozyme Composite for Augmented Cascade Catalytic Tumor Therapy. Advanced materials (Deerfield Beach, Fla.) Cascade catalytic reaction exhibits simple procedure and high efficiency, such as that from the orderly assembly of different enzymes in biological systems. Mimicking of the natural cascade procedure becomes critical, but the orderly assembly of different enzymes is still challenging. Herein, single Au-Pt nanozyme is reported with "three-in-one" functions to initiate cascade conversions for O supply as mimic catalase, H O production with its glucose oxidase-like property, and OH generation as mimic peroxidase for chemodynamic therapy (CDT). Thus, the complex assembly and cross-talk among the different enzymes are avoided. To this end, metastable Cu O NPs, as scaffolds, are used to anchor ultrasmall Au-Pt nanozyme, while metal-organic framework (MOF) is used to encapsulate the nanozyme for tumor microenvironment response and shielding protein adsorption. Pluronic F127 is then modified on the surface to improve hydrophilicity and biocompatibility of the composite. The endogenous acidity and glutathione in tumor degrade MOF to expose nanozyme for cascade catalytic CDT. The high photothermal conversion ability also enhances the CDT, while Cu ions consume GSH to further improve CDT efficiency as augmented cascade catalytic tumor therapy. Thus, a new paradigm is provided with drug-free single nanozyme for improving tumor therapeutic efficacy and minimizing side effects. 10.1002/adma.202308033

Cu-MOF chemodynamic nanoplatform via modulating glutathione and HO in tumor microenvironment for amplified cancer therapy. Tian Hailong,Zhang Mengzhu,Jin Guoxia,Jiang Yue,Luan Yuxia Journal of colloid and interface science Chemodynamic therapy (CDT) utilizes Fenton catalysts to convert intracellular hydrogen peroxide (HO) into cytotoxic hydroxyl radical (OH∙) for tumor therapy, but endogenous HO is usually insufficient to achieve satisfactory tumor therapy effect. Engineering an efficient CDT nanoplatform for satisfactory cancer therapy remains a challenge. Herein, we rationally designed a Cu-based metal-organic framework-199 (MOF-199) nanoplatform integrating vitamin k3 (Vk3) for amplified CDT-mediated cancer therapy, which could accumulate efficiently in tumor tissues through enhanced permeability and retention (EPR) effect. The MOF-199 nanoparticles (MOF-199 NPs) were dissociated by glutathione (GSH) into MOF-199 fragments, which triggered Fenton-like reaction for CDT. On the one hand, Vk3 was catalyzed by NAD(P)H quinone oxidoreductase-1 (NQO1) to produce sufficient HO to activate Fenton-like reaction. On the other hand, GSH was largely consumed in the tumor microenvironment. Thus, this nanoplatform enabled sufficient cytotoxic reactive oxygen species (ROS) for amplified CDT effect, demonstrating effective tumor growth inhibition with minimal side-effect in vivo. Our work provides an innovative strategy to modulate GSH and HO levels for amplified CDT. 10.1016/j.jcis.2020.12.028