Nanoscale Metal-Organic Layer Isolates Phthalocyanines for Efficient Mitochondria-Targeted Photodynamic Therapy.

Zinc-phthalocyanine (ZnPc) photosensitizers (PSs) have shown great potential in photodynamic therapy (PDT) owing to their strong absorption at long wavelengths (650-750 nm), high triplet quantum yields, and biocompatibility. However, the clinical utility of ZnPc PSs is limited by their poor solubility and tendency to aggregate in aqueous environments. Here we report the design of a new nanoscale metal-organic layer (nMOL) assembly, ZnOPPc@nMOL, with ZnOPPc [ZnOPPc = zinc(II)-2,3,9,10,16,17,23,24-octa(4-carboxyphenyl)phthalocyanine] PSs supported on the secondary building units (SBUs) of a Hf12 nMOL for PDT. Upon irradiation, SBU-bound ZnOPPc PSs absorb 700 nm light and efficiently sensitize the formation of singlet oxygen by preventing aggregation-induced self-quenching of ZnOPPc excited states. With intrinsic mitochondria-targeting capability, ZnOPPc@nMOL showed exceptional PDT efficacy with >99% tumor growth inhibition and 40-60% cure rates on two mouse models of colon cancer.

Bifunctional Metal-Organic Layers for Tandem Catalytic Transformations Using Molecular Oxygen and Carbon Dioxide.

Tandem catalytic reactions improve atom- and step-economy over traditional synthesis but are limited by the incompatibility of the required catalysts. Herein, we report the design of bifunctional metal-organic layers (MOLs), HfOTf-Fe and HfOTf-Mn, consisting of triflate (OTf)-capped Hf6 secondary building units (SBUs) as strong Lewis acidic centers and metalated TPY ligands as metal active sites for tandem catalytic transformations using O2 and CO2 as coreactants. HfOTf-Fe effectively transforms hydrocarbons into cyanohydrins via tandem oxidation with O2 and silylcyanation whereas HfOTf-Mn converts styrenes into styrene carbonates via tandem epoxidation and CO2 insertion. Density functional theory calculations revealed the involvement of a high-spin FeIV (S = 2) center in the challenging oxidation of the sp3 C-H bond. This work highlights the potential of MOLs as a tunable platform to incorporate multiple catalysts for tandem transformations.

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 Zr6 secondary building units (SBUs) and 2,4,6-tris(4-carboxyphenyl)aniline (BTB-NH2) ligands was postsynthetically functionalized to afford NA@Zr-BTB/F/R by exchanging formate capping groups on the SBUs with glutathione(GSH)-selective (2E)-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-NH2 ligands. Cell imaging demonstrated NA@Zr-BTB/F/R as a ratiometric sensor for mitochondrial dysregulation and chemotherapy resistance via GSH and pH sensing.

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

We report the design of a bifunctional metal-organic layer (MOL), Hf12 -Ru-Co, composed of [Ru(DBB)(bpy)2 ]2+ [DBB-Ru, DBB=4,4'-di(4-benzoato)-2,2'-bipyridine; bpy=2,2'-bipyridine] connecting ligand as a photosensitizer and Co(dmgH)2 (PPA)Cl (PPA-Co, dmgH=dimethylglyoxime; PPA=4-pyridinepropionic acid) on the Hf12 secondary building unit (SBU) as a hydrogen-transfer catalyst. Hf12 -Ru-Co efficiently catalyzed acceptorless dehydrogenation of indolines and tetrahydroquinolines to afford indoles and quinolones. We extended this strategy to prepare Hf12 -Ru-Co-OTf MOL with a [Ru(DBB)(bpy)2 ]2+ photosensitizer and Hf12 SBU capped with triflate as strong Lewis acids and PPA-Co as a hydrogen transfer catalyst. With three synergistic active sites, Hf12 -Ru-Co-OTf competently catalyzed dehydrogenative tandem transformations of indolines with alkenes or aldehydes to afford 3-alkylindoles and bisindolylmethanes with turnover numbers of up to 500 and 460, respectively, illustrating the potential use of MOLs in constructing novel multifunctional heterogeneous catalysts.

Metal-Organic Layers for Synergistic Lewis Acid and Photoredox Catalysis.

We report the design of a new multifunctional metal-organic layer (MOL), Hf12-Ir-OTf, comprising triflate (OTf)-capped Hf12 secondary building units (SBUs) and photosensitizing Ir(DBB)[dF(CF3)ppy]2+ [DBB-Ir-F, DBB = 4,4'-di(4-benzoato)-2,2'-bipyridine; dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine] bridging ligands. Hf12-Ir-OTf effectively catalyzed dehydrogenative cross-couplings of heteroarenes with ethers, amines, and unactivated alkanes with turnover numbers of 930, 790, and 950, respectively. Hf12-Ir-OTf also competently catalyzed late-stage functionalization of bioactive and drug molecules such as caffeine, Fasudil, and Metyrapone. The superior catalytic performance of Hf12-Ir-OTf over a mixture of photoredox catalyst and stoichiometric amounts of Brønsted acids or substoichiometric amounts (20 mol %) of Lewis acids is attributed to the close proximity (1.2 nm) between photoredox and Lewis acid catalysts in Hf12-Ir-OTf, which not only facilitates the reaction between the carbon radical and the activated heteroarene but also accelerates the electron transfer from the nitrogen radical intermediate to the Ir(IV) species in the catalytic cycle.

Nanoscale Metal-Organic Frameworks Stabilize Bacteriochlorins for Type I and Type II Photodynamic Therapy.

Herein we report the design of a bacteriochlorin-based nanoscale metal-organic framework, Zr-TBB, for highly effective photodynamic therapy via both type I and type II mechanisms. The framework of Zr-TBB stabilizes 5,10,15,20-tetra(p-benzoato)bacteriochlorin (TBB) ligands toward oxygen and light via geometrical constraint. Upon 740 nm light irradiation, Zr-TBB efficiently generates various reactive oxygen species, including singlet oxygen, superoxide anion, hydrogen peroxide, and hydroxyl radicals, to afford superb antitumor efficacy on mouse models of breast and colon cancers, with cure rates of 40% and 60%, respectively.

A Nanoscale Metal-Organic Framework to Mediate Photodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Enhance Antigen Presentation and Cancer Immunotherapy.

Checkpoint blockade immunotherapy (CBI) awakes a host innate immune system and reactivates cytotoxic T cells to elicit durable response in some cancer patients. Now, a cationic nanoscale metal-organic framework, W-TBP, is used to facilitate tumor antigen presentation by enabling immunogenic photodynamic therapy (PDT) and promoting the maturation of dendritic cells (DCs). Comprised of dinuclear WVI secondary building units and photosensitizing 5,10,15,20-tetra(p-benzoato)porphyrin (TBP) ligands, cationic W-TBP mediates PDT to release tumor associated antigens and delivers immunostimulatory CpG oligodeoxynucleotides to DCs. The enhanced antigen presentation synergizes with CBI to expand and reinvigorate cytotoxic T cells, leading to superb anticancer efficacy and robust abscopal effects with >97 % tumor regression in a bilateral breast cancer model.

Multifunctional Nanoscale Metal-Organic Layers for Ratiometric pH and Oxygen Sensing.

As a monolayered version of nanoscale metal-organic frameworks (nMOFs), nanoscale metal-organic layers (nMOLs) represent an emerging class of highly tunable two-dimensional materials for hierarchical functionalization and with facile access to analytes. Here we report the design of the first nMOL-based biosensor for ratiometric pH and oxygen sensing in mitochondria. Cationic Hf12-Ru nMOL was solvothermally synthesized by laterally connecting Hf12 secondary building units (SBUs) with oxygen-sensitive Ru(bpy)32+-derived DBB-Ru ligands (bpy = 2,2'-bipyridine). The Hf12-Ru nMOL was then covalently functionalized with pH-sensitive fluorescein isothiocyanate and pH/oxygen-independent Rhodamine-B isothiocyanate through thiourea linkages to afford Hf12-Ru-F/R as a mitochondria-targeted ratiometric sensor for pH and O2 in live cells. High-resolution confocal microscope imaging with Hf12-Ru-F/R revealed a positive correlation between pH and local O2 concentration in mitochondria. Our work shows the potential of nMOL-based ratiometric biosensors in sensing and imaging of biologically important analytes in live cells.

Nanoscale Metal-Organic Framework Hierarchically Combines High-Z Components for Multifarious Radio-Enhancement.

With tunability and porosity, nanoscale metal-organic frameworks (nMOFs) can incorporate multiple components to realize complex functions for biomedical applications. Here we report the synthesis of W18@Hf12-DBB-Ir, a new nMOF assembly hierarchically incorporating three high-Z components-Hf-based metal-oxo clusters, Ir-based bridging ligands, and W-based polyoxometalates (POMs)-as a multifarious radioenhancer. Cationic Hf12-DBB-Ir was built from Hf12 secondary building units (SBUs) and [Ir(bpy)2(ppy)]+ (bpy = 2,2'-bipyridine, ppy = 2-phenylpyridine) derived dicarboxylate ligands (DBB-Ir) and then loaded with Wells-Dawson-type [P2W18O62]6- (W18) POMs to afford W18@Hf12-DBB-Ir. Upon X-ray irradiation, W18@Hf12-DBB-Ir significantly enhances hydroxyl radical generation from Hf12 SBUs, singlet oxygen generation from DBB-Ir ligands, and superoxide generation from W18 POMs, respectively. Through synergistic cell killing by these distinct reactive oxygen species, W18@Hf12-DBB-Ir elicited superb anticancer efficacy with >98% tumor regression at a low X-ray dose of 5 × 1 Gy.

Metal-Organic Layers as Multifunctional Two-Dimensional Nanomaterials for Enhanced Photoredox Catalysis.

Metal-organic layers (MOLs) have recently emerged as a novel class of molecular two-dimensional (2D) materials with significant potential for catalytic applications. Herein we report the design of a new multifunctional MOL, Hf12-Ir-Ni, by laterally linking Hf12 secondary building units (SBUs) with photosensitizing Ir(DBB)[dF(CF3)ppy]2+ [DBB-Ir-F, DBB = 4,4'-di(4-benzoato)-2,2'-bipyridine; dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine] bridging ligands and vertically terminating the SBUs with catalytic Ni(MBA)Cl2 [MBA = 2-(4'-methyl-[2,2'-bipyridin]-4-yl)acetate] capping agents. Hf12-Ir-Ni was synthesized in a bottom-up approach and characterized by TEM, AFM, PXRD, TGA, NMR, ICP-MS, UV-vis, and luminescence spectroscopy. The proximity between photosensitizing Ir centers and catalytic Ni centers (∼0.85 nm) in Hf12-Ir-Ni facilitates single electron transfer, leading to a 15-fold increase in photoredox reactivity. Hf12-Ir-Ni was highly effective in catalytic C-S, C-O, and C-C cross-coupling reactions with broad substrate scopes and turnover numbers of ∼4500, ∼1900, and ∼450, respectively.

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. Upon light irradiation, Ti-TBP not only sensitizes singlet oxygen production, but also transfers electrons from excited TBP* species to Ti4+-based SBUs to afford TBP•+ ligands and Ti3+ centers, thus propagating the generation of superoxide, hydrogen peroxide, and hydroxyl radicals. By generating four distinct ROSs, Ti-TBP-mediated PDT elicits superb anticancer efficacy with >98% tumor regression and 60% cure rate.

Nanoscale Metal-Organic Frameworks for Phototherapy of Cancer.

Phototherapy involves the irradiation of tissues with light, and is commonly implemented in the forms of photodynamic therapy (PDT) and photothermal therapy (PTT). Photosensitizers (PSs) are often needed to improve the efficacy and selectivity of phototherapy via enhanced singlet oxygen generation in PDT and photothermal responses in PTT. In both cases, efficient and selective delivery of PSs to the diseased tissues is of paramount importance. Nanoscale metal-organic frameworks (nMOFs), a new class of hybrid materials built from metal connecting points and bridging ligands, have been examined as nanocarriers for drug delivery due to their compositional and structural tunability, highly porous structures, and good biocompatibility. This review summarizes recent advances on using nMOFs as nanoparticle PSs for applications in PDT and PTT.

Efficient Electrocatalytic Proton Reduction with Carbon Nanotube-Supported Metal-Organic Frameworks.

Hydrogen production from Earth-abundant catalysts remains an important but difficult challenge. Here we report the growth of Hf12-porphyrin metal-organic frameworks (MOFs) on carbon nanotubes (CNTs) for electrocatalytic proton reduction. Covalent attachment of MOF nanoplates to conductive CNTs improves electron transfer from the electrode to Co-porphyrin active sites, which leads to effective proton reduction via protonation of a CoI-H intermediate. The Hf12-CoDBP/CNT assembly afforded a turnover number of 32 000 in 30 min with a turnover frequency of 17.7 S-1, placing it among the most active Co-based molecular electrocatalysts.

Nanoscale Metal-Organic Layers for Radiotherapy-Radiodynamic Therapy.

Nanoscale metal-organic layers (nMOLs) are an emerging class of 2D crystalline materials formed by reducing the dimensionality of nanoscale metal-organic frameworks (nMOFs). nMOLs hold significant potential in biomedical applications by combining the structural and compositional tunability of nMOFs and anisotropic properties of 2D nanomaterials. Here we report two novel nMOLs, Hf12-Ir and Hf6-Ir, based on Hf12 and Hf6 secondary building units (SBUs) and photosensitizing Ir(bpy)[dF(CF3)ppy]2+ derived ligands [bpy = 2,2'-bipyridine; dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine] for radiotherapy (RT) and radiodynamic therapy (RDT). Upon X-ray irradiation, the Hf12 or Hf6 SBUs in the nMOLs efficiently absorb X-rays to enhance RT by producing hydroxyl radicals and to elicit RDT through the excitation of Ir(bpy)[dF(CF3)ppy]2+ derived ligands to generate singlet oxygen and superoxide anions. Hf12-Ir and Hf6-Ir promoted effective cell instant death through RDT and cell reproductive death through RT to elicit superb anticancer efficacy, resulting in >99% tumor regression at low X-ray doses of 0.5 × 5 Gy.

Electron Injection from Photoexcited Metal-Organic Framework Ligands to Ru2 Secondary Building Units for Visible-Light-Driven Hydrogen Evolution.

We report the design of two new metal-organic frameworks (MOFs), Ru-TBP and Ru-TBP-Zn, based on Ru2 secondary building units (SBUs) and porphyrin-derived tetracarboxylate ligands. The proximity of Ru2 SBUs to porphyrin ligands (∼1.1 nm) facilitates multielectron transfer from excited porphyrins to Ru2 SBUs to enable efficient visible-light-driven hydrogen evolution reaction (HER) in neutral water. Photophysical and electrochemical studies revealed oxidative quenching of excited porphyrin by Ru2 SBUs as the initial step of the HER process and the energetics of key intermediates in the catalytic cycle. Our work provides a new strategy to building multifunctional MOFs with synergistic ligands and SBUs for efficient photocatalysis.

Nanoscale Metal-Organic Framework Overcomes Hypoxia for Photodynamic Therapy Primed Cancer Immunotherapy.

Immunotherapy has become a promising cancer therapy, but only works for a subset of cancer patients. Immunogenic photodynamic therapy (PDT) can prime cancer immunotherapy to increase the response rates, but its efficacy is severely limited by tumor hypoxia. Here we report a nanoscale metal-organic framework, Fe-TBP, as a novel nanophotosensitizer to overcome tumor hypoxia and sensitize effective PDT, priming non-inflamed tumors for cancer immunotherapy. Fe-TBP was built from iron-oxo clusters and porphyrin ligands and sensitized PDT under both normoxic and hypoxic conditions. Fe-TBP mediated PDT significantly improved the efficacy of anti-programmed death-ligand 1 (α-PD-L1) treatment and elicited abscopal effects in a mouse model of colorectal cancer, resulting in >90% regression of tumors. Mechanistic studies revealed that Fe-TBP mediated PDT induced significant tumor infiltration of cytotoxic T cells.

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, Hf12-Ru, based on Hf12 secondary building units (SBUs) and [Ru(bpy)3]2+ (bpy = 2,2'-bipyridine) derived dicarboxylate ligands. After modifying the SBU surface of Hf12-Ru with M(bpy)(CO)3X (M = Re and X = Cl or M = Mn and X = Br) derived capping molecules through carboxylate exchange reactions, the resultant Hf12-Ru-Re and Hf12-Ru-Mn MOLs possess both [Ru(bpy)3]2+ photosensitizers and M(bpy)(CO)3X catalysts for efficient photocatalytic CO2 reduction. The proximity of the MOL skeleton to the capping ligands (1-2 nm) facilitates electron transfer from the reduced photosensitizer [Ru(bpy)3]+ to MI(bpy)(CO)3X (M = Re, Mn) catalytic centers, resulting in CO2 reduction turnover numbers of 8613 under artificial visible light and of 670 under sunlight. MOLs thus represent a novel platform to assemble multifunctional materials for studying artificial photosynthesis.

Metal-Organic Layers Catalyze Photoreactions without Pore Size and Diffusion Limitations.

Metal-organic frameworks (MOFs) have emerged as promising single-site solid catalysts for organic reactions. However, MOF catalysts suffer from pore size limitation and slow diffusion, which are detrimental for photoreactions. Metal-organic layers (MOLs) have unique ultrathin 2D monolayer structures and overcome pore size and diffusion limitations. Here, the synthesis of photoactive Zr-RuBPY MOL based on Zr-oxo clusters and [Ru(bpy)3 ]2+ -containing linkers is reported as well as its application in photocatalytic [2+2] cyclizations of enones and Meerwein addition reactions between aryl diazonium salts, styrenes, and nitriles.

Metal-Organic Layers Efficiently Catalyze Photoinduced Polymerization under Visible Light.

A photosensitizing metal-organic layer (MOL), IrBPY-MOL, based on hafnium-oxo clusters and cyclometalated iridium-complex-derived organic linkers, was synthesized and used as an efficient catalyst for photopolymerization of methyl methacrylate and other monomers to afford polymers with high-number-averaged molar masses and low polydispersity indices. The corresponding metal-organic framework (MOF) failed to photopolymerize or exhibited low catalytic efficiency under identical conditions. This work highlights the advantages of MOLs over their MOF counterparts in overcoming pore-size and diffusion limitations in photopolymerization reactions.

Merging Photoredox and Organometallic Catalysts in a Metal-Organic Framework Significantly Boosts Photocatalytic Activities.

Metal-organic frameworks (MOFs) have been extensively used for single-site catalysis and light harvesting, but their application in multicomponent photocatalysis is unexplored. We report here the successful incorporation of an IrIII photoredox catalyst and a NiII cross-coupling catalyst into a stable Zr12 MOF, Zr12 -Ir-Ni, to efficiently catalyze C-S bond formation between various aryl iodides and thiols. The proximity of the IrIII and NiII catalytic components to each other (ca. 0.6 nm) in Zr12 -Ir-Ni greatly facilitates electron and thiol radical transfers from Ir to Ni centers to reach a turnover number of 38 500, an order of magnitude higher than that of its homogeneous counterpart. This work highlights the opportunity in merging photoredox and organometallic catalysts in MOFs to effect challenging organic transformations.