Nanoscale Mixed-Ligand Metal-Organic Framework for X-ray Stimulated Cancer Therapy.

Concurrent localized radiotherapy and systemic chemotherapy are standards of care for many cancers, but these treatment regimens cause severe adverse effects in many patients. Herein, we report the design of a mixed-ligand nanoscale metal-organic framework (nMOF) with the ability to simultaneously enhance radiotherapeutic effects and trigger the release of a potent chemotherapeutic under X-ray irradiation. We synthesized a new functional quaterphenyl dicarboxylate ligand conjugated with SN38 (HQP-SN) via a hydroxyl radical-responsive covalent linkage.

Nanoscale Metal-Organic Framework with an X-ray Triggerable Prodrug for Synergistic Radiotherapy and Chemotherapy.

As heavy-metal-based nanoscale metal-organic frameworks (nMOFs) are excellent radiosensitizers for radiotherapy via enhanced energy deposition and reactive oxygen species (ROS) generation, we hypothesize that nMOFs with covalently conjugated and X-ray triggerable prodrugs can harness the ROS for on-demand release of chemotherapeutics for chemoradiotherapy. Herein, we report the design of a novel nMOF, Hf-TP-SN, with an X-ray-triggerable 7-ethyl-10-hydroxycamptothecin (SN38) prodrug for synergistic radiotherapy and chemotherapy. Upon X-ray irradiation, electron-dense Hf secondary building units serve as radiosensitizers to enhance hydroxyl radical generation for the triggered release of SN38 via hydroxylation of the 3,5-dimethoxylbenzyl carbonate followed by 1,4-elimination, leading to 5-fold higher release of SN38 from Hf-TP-SN than its molecular counterpart.

Zinc cyclic di-AMP nanoparticles target and suppress tumours via endothelial STING activation and tumour-associated macrophage reinvigoration.

The clinical utility of stimulator of interferon genes (STING) agonists has been limited due to poor tumour-targeting and unwanted toxicity following systemic delivery. Here we describe a robust tumour-targeted STING agonist, ZnCDA, formed by the encapsulation of bacterial-derived cyclic dimeric adenosine monophosphate (CDA) in nanoscale coordination polymers. Intravenously injected ZnCDA prolongs CDA circulation and efficiently targets tumours, mediating robust anti-tumour effects in a diverse set of preclinical cancer models at a single dose.

Monte Carlo Simulation-Guided Design of a Thorium-Based Metal-Organic Framework for Efficient Radiotherapy-Radiodynamic Therapy.

High-Z metal-based nanoscale metal-organic frameworks (nMOFs) with photosensitizing ligands can enhance radiation damage to tumors via a unique radiotherapy-radiodynamic therapy (RT-RDT) process. Here we report Monte Carlo (MC) simulation-guided design of a Th-based nMOF built from Th -oxo secondary building units and 5,15-di(p-benzoato)porphyrin (DBP) ligands, Th-DBP, for enhanced RT-RDT. MC simulations revealed that the Th-lattice outperformed the Hf-lattice in radiation dose enhancement owing to its higher mass attenuation coefficient.

Tumor-Activatable Nanoparticles Target Low-Density Lipoprotein Receptor to Enhance Drug Delivery and Antitumor Efficacy.

The binding of plasma proteins to nanomedicines is widely considered detrimental to their delivery to tumors. Here, the design of OxPt/SN38 nanoparticle containing a hydrophilic oxaliplatin (OxPt) prodrug in a coordination polymer core and a hydrophobic cholesterol-conjugated SN38 prodrug on the lipid shell for active tumor targeting is reported. OxPt/SN38 hitchhikes on low-density lipoprotein (LDL) particles, concentrates in tumors via LDL receptor-mediated endocytosis, and selectively releases SN38 and OxPt in acidic, esterase-rich, and reducing tumor microenvironments, leading to 6.

Dimensional Reduction Enhances Photodynamic Therapy of Metal-Organic Nanophotosensitizers.

Herein we report that dimensional reduction from three-dimensional nanoscale metal-organic frameworks (nMOFs) to two-dimensional nanoscale metal-organic layers (nMOLs) increases the frequency of encounters between photosensitizers and oxygen and facilitates the diffusion of singlet oxygen from the nMOL to significantly enhance photodynamic therapy. The nMOFs and nMOLs share the same M-oxo (M = Zr, Hf) secondary building units and 5,15-di--benzoatoporphyrin (DBP) ligands but exhibit three-dimensional and two-dimensional topologies, respectively. Molecular dynamics simulations and experimental studies revealed that the nMOLs with a monolayer morphology enhanced the generation of reactive oxygen species and exhibited over an order of magnitude higher cytotoxicity over the nMOFs.

Synergistic checkpoint-blockade and radiotherapy-radiodynamic therapy via an immunomodulatory nanoscale metal-organic framework.

Checkpoint blockade elicits durable responses in immunogenic cancers, but it is largely ineffective in immunologically 'cold' tumours. Here we report the design, synthesis and performance of a bismuth-based nanoscale metal-organic framework that modulates the immunological and mechanical properties of the tumour microenvironment for enhanced radiotherapy-radiodynamic therapy. In mice with non-immunogenic prostate and pancreatic tumours irradiated with low X-ray doses, the intratumoural injection of the radiosensitizer mediated potent outcomes via the repolarization of immunosuppressive M2 macrophages into immunostimulatory M1 macrophages, the reduction of the concentration of intratumoural transforming growth factor beta (TGF-β) and of collagen density, and the inactivation of cancer-associated fibroblasts.

A Substrate-Binding Metal-Organic Layer Selectively Catalyzes Photoredox Ene-Carbonyl Reductive Coupling Reactions.

Intermolecular photoredox ene-carbonyl reductive coupling reactions typically have low product selectivity owing to competing dimerization and/or reduction of ketyl radicals. Herein, we report a metal-organic layer (MOL), Hf-Ir-OTf, as a bifunctional photocatalyst for selective photoredox reductive coupling of ketones or aldehydes with electron-deficient alkenes. Composed of iridium-based photosensitizers (Ir-PSs) and triflated Hf clusters, Hf-Ir-OTf uses Lewis acidic Hf sites to bind and activate electron-deficient alkenes to accept ketyl radicals generated by adjacent Ir-PSs, thereby suppressing undesired dimerization and reduction of ketyl radicals to enhance the selectivity for the cross-coupling products.

Reprogramming of Neutrophils as Non-canonical Antigen Presenting Cells by Radiotherapy-Radiodynamic Therapy to Facilitate Immune-Mediated Tumor Regression.

Ineffective antigen cross-presentation in the tumor microenvironment compromises the generation of antitumor immune responses. Radiotherapy-radiodynamic therapy (RT-RDT) with nanoscale metal-organic frameworks (nMOFs) induces robust adaptive immune responses despite modest activation of canonical antigen presenting dendritic cells. Here, using transplantable and autochthonous murine tumor models, we demonstrate that RT-RDT induces antitumor immune responses early neutrophil infiltration and reprogramming.

Monte Carlo Simulations Reveal New Design Principles for Efficient Nanoradiosensitizers Based on Nanoscale Metal-Organic Frameworks.

Nanoscale metal-organic frameworks (nMOFs) have recently been shown to provide better radiosensitization than solid nanoparticles (NPs) when excited with X-rays. Here, a Monte Carlo simulation of different radiosensitization effects by NPs and nMOFs using a lattice model consisting of 3D arrays of nanoscale secondary building units (SBUs) is reported. The simulation results reveal that lattices outperform solid NPs regardless of radiation sources or particle sizes via enhanced scatterings of photons and electrons within the lattices.

Nanoscale Metal-Organic Framework Confines Zinc-Phthalocyanine Photosensitizers for Enhanced Photodynamic Therapy.

The performance of photodynamic therapy (PDT) depends on the solubility, pharmacokinetic behaviors, and photophysical properties of photosensitizers (PSs). However, highly conjugated PSs with strong reactive oxygen species (ROS) generation efficiency tend to have poor solubility and aggregate in aqueous environments, leading to suboptimal PDT performance. Here, we report a new strategy to load highly conjugated but poorly soluble zinc-phthalocyanine (ZnP) PSs in the pores of a Hf-QC (QC = 2″,3'-dinitro-[1,1':4',1";4″,1'"-quaterphenyl]-4,4'"-dicarboxylate) nanoscale metal-organic framework to afford ZnP@Hf-QC with spatially confined ZnP PSs.

Nanoscale Metal-Organic Layers Detect Mitochondrial Dysregulation and Chemoresistance via Ratiometric Sensing of Glutathione and pH.

Mitochondrial dysregulation controls cell death and survival by changing endogenous molecule concentrations and ion flows across the membrane. Here, we report the design of a triply emissive nanoscale metal-organic layer (nMOL), NA@Zr-BTB/F/R, for sensing mitochondrial dysregulation. Zr-BTB nMOL containing Zr secondary building units (SBUs) and 2,4,6-tris(4-carboxyphenyl)aniline (BTB-NH) ligands was postsynthetically functionalized to afford NA@Zr-BTB/F/R by exchanging formate capping groups on the SBUs with glutathione(GSH)-selective (2)-1-(2'-naphthyl)-3-(4-carboxyphenyl)-2-propen-1-one (NA) and covalent conjugation of pH-sensitive fluorescein (F) and GSH/pH-independent rhodamine-B (R) to the BTB-NH ligands.

Rational Construction of an Artificial Binuclear Copper Monooxygenase in a Metal-Organic Framework.

Artificial enzymatic systems are extensively studied to mimic the structures and functions of their natural counterparts. However, there remains a significant gap between structural modeling and catalytic activity in these artificial systems. Herein we report a novel strategy for the construction of an artificial binuclear copper monooxygenase starting from a Ti metal-organic framework (MOF).

Sequential Treatment of Bioresponsive Nanoparticles Elicits Antiangiogenesis and Apoptosis and Synergizes with a CD40 Agonist for Antitumor Immunity.

The combination of antiangiogenesis and chemotherapy regimens with cancer immunotherapy has the potential to synergistically boost antitumor immunity. Herein, we report the construction of two bioresponsive nanoparticles, namely, Podo-NP and CbP-NP, comprising prodrugs of podophyllotoxin (Podo) and carboplatin, respectively. Sequential treatment with esterase-responsive Podo-NP, redox-sensitive CbP-NP, and a CD40 agonist promotes antitumor T cell response.

Metal-Organic Layers Hierarchically Integrate Three Synergistic Active Sites for Tandem Catalysis.

We report the design of a bifunctional metal-organic layer (MOL), Hf -Ru-Co, composed of [Ru(DBB)(bpy) ] [DBB-Ru, DBB=4,4'-di(4-benzoato)-2,2'-bipyridine; bpy=2,2'-bipyridine] connecting ligand as a photosensitizer and Co(dmgH) (PPA)Cl (PPA-Co, dmgH=dimethylglyoxime; PPA=4-pyridinepropionic acid) on the Hf secondary building unit (SBU) as a hydrogen-transfer catalyst. Hf -Ru-Co efficiently catalyzed acceptorless dehydrogenation of indolines and tetrahydroquinolines to afford indoles and quinolones. We extended this strategy to prepare Hf -Ru-Co-OTf MOL with a [Ru(DBB)(bpy) ] photosensitizer and Hf SBU capped with triflate as strong Lewis acids and PPA-Co as a hydrogen transfer catalyst.

Metal-Organic Frameworks Integrate Cu Photosensitizers and Secondary Building Unit-Supported Fe Catalysts for Photocatalytic Hydrogen Evolution.

We report here the synthesis of a series of metal-organic frameworks (MOFs), , comprising cuprous photosensitizing linkers (Cu-PSs) and catalytically active Fe centers supported on secondary building units (SBUs) for photocatalytic H evolution. Close proximity (∼1 nm) between Cu-PS and SBU-supported Fe sites and stabilization of Fe sites by periodically ordered SBUs led to exceptionally high H evolution activity for , with turnover numbers of up to 33 700 and turnover frequencies of up to 880 h. Photocatalytic H evolution activities of correlate with the lability of X counteranions, suggesting that open coordination environments of Fe sites generated by labile X groups facilitate the formation of Fe-hydride intermediates before hydrogen evolution.

Metal-Organic Framework with Dual Active Sites in Engineered Mesopores for Bioinspired Synergistic Catalysis.

Here we report the design of an enzyme-inspired metal-organic framework (MOF), -OTf-Ir, by installing strong Lewis acid and photoredox sites in engineered mesopores. Al-MOF (), with mixed 2,2'-bipyridyl-5,5-dicarboxylate (dcbpy) and 1,4-benzenediacrylate (pdac) ligands, was oxidized with ozone and then triflated to generate strongly Lewis acidic Al-OTf sites in the mesopores, followed by the installation of [Ir(ppy)(dcbpy)] (ppy = 2-phenylpyridine) sites to afford -OTf-Ir with both Lewis acid and photoredox sites. -OTf-Ir effectively catalyzed reductive cross-coupling of -hydroxyphthalimide esters or aryl bromomethyl ketones with vinyl- or alkynyl-azaarenes to afford new azaarene derivatives.

Cerium-Based Metal-Organic Layers Catalyze Hydrogen Evolution Reaction through Dual Photoexcitation.

Cerium-based materials such as ceria are increasingly used in catalytic reactions. We report here the synthesis of the first Ce-based metal-organic layer (MOL), Ce-BTB, comprising Ce secondary building units (SBUs) and 1,3,5-benzenetribenzoate (BTB) linkers, and its functionalization for photocatalytic hydrogen evolution reaction (HER). Ce-BTB was postsynthetically modified with photosensitizing [(MBA)Ir(ppy)]Cl or [(MBA)Ru(bpy)]Cl (MBA = 2-(5'-methyl-[2,2'-bipyridin]-5-yl)acetate, ppy = 2-phenylpyridine, bpy = 2,2'-bipyridine) to afford Ce-BTB-Ir or Ce-BTB-Ru MOLs, respectively.

Multistep Engineering of Synergistic Catalysts in a Metal-Organic Framework for Tandem C-O Bond Cleavage.

Cleavage of strong C-O bonds without breaking C-C/C-H bonds is a key step for catalytic conversion of renewable biomass to hydrocarbon feedstocks. Herein we report multistep sequential engineering of orthogonal Lewis acid and palladium nanoparticle (NP) catalysts in a metal-organic framework (MOF) built from (Al-OH) secondary building units and a mixture of 2,2'-bipyridine-5,5'-dicarboxylate (dcbpy) and 1,4-benzenediacrylate (pdac) ligands () for tandem C-O bond cleavage. Ozonolysis of selectively removed pdac ligands to generate Al(OH)(OH) sites, which were subsequently triflated with trimethylsilyl triflate to afford strongly Lewis acidic sites for dehydroalkoxylation.

Metal-Organic Frameworks Significantly Enhance Photocatalytic Hydrogen Evolution and CO Reduction with Earth-Abundant Copper Photosensitizers.

We report here the design of two multifunctional metal-organic frameworks (MOFs), and comprising cuprous photosensitizers (Cu-PSs) and molecular Co or Re catalysts for photocatalytic hydrogen evolution (HER) and CO reduction (CORR), respectively. Hierarchical organization of Cu-PSs and Co/Re catalysts in these MOFs facilitates multielectron transfer to drive HER and CORR under visible light with an HER turnover number (TON) of 18 700 for and a CORR TON of 1328 for , which represent a 95-fold enhancement over their homogeneous controls. Photophysical and electrochemical investigations revealed the reductive quenching pathway in HER and CORR catalytic cycles and attributed the significantly improved performances of MOFs over their homogeneous counterparts to enhanced electron transfer due to close proximity between Cu-PSs and active catalysts and stabilization of Cu-PSs and molecular catalysts by the MOF framework.

Metal-Organic Framework Stabilizes a Low-Coordinate Iridium Complex for Catalytic Methane Borylation.

Catalytic borylation has recently been suggested as a potential strategy to convert abundant methane to fine chemicals. However, synthetic utility of methane borylation necessitates significant improvement of catalytic activities over original phenanthroline- and diphosphine-Ir complexes. Herein, we report the use of metal-organic frameworks (MOFs) to stabilize low-coordinate Ir complexes for highly active methane borylation to afford the monoborylated product.

Titanium-Based Nanoscale Metal-Organic Framework for Type I Photodynamic Therapy.

Nanoscale metal-organic frameworks (nMOFs) have shown great potential as nanophotosensitizers for photodynamic therapy (PDT) owing to their high photosensitizer loadings, facile diffusion of reactive oxygen species (ROSs) through their porous structures, and intrinsic biodegradability. The exploration of nMOFs in PDT, however, remains limited to an oxygen-dependent type II mechanism. Here we report the design of a new nMOF, Ti-TBP, composed of Ti-oxo chain secondary building units (SBUs) and photosensitizing 5,10,15,20-tetra( p-benzoato)porphyrin (TBP) ligands, for hypoxia-tolerant type I PDT.

Photosensitizing Metal-Organic Layers for Efficient Sunlight-Driven Carbon Dioxide Reduction.

Metal-organic layers (MOLs), a free-standing monolayer version of two-dimensional metal-organic frameworks (MOFs), have emerged as a new class of 2D materials for many potential applications. Here we report the design of a new photosensitizing MOL, Hf-Ru, based on Hf secondary building units (SBUs) and [Ru(bpy)] (bpy = 2,2'-bipyridine) derived dicarboxylate ligands. After modifying the SBU surface of Hf-Ru with M(bpy)(CO)X (M = Re and X = Cl or M = Mn and X = Br) derived capping molecules through carboxylate exchange reactions, the resultant Hf-Ru-Re and Hf-Ru-Mn MOLs possess both [Ru(bpy)] photosensitizers and M(bpy)(CO)X catalysts for efficient photocatalytic CO reduction.