Porphyrinic Metal-organic Framework Research Articles

Hyaluronic acid-functionalized MOFs for combined sunitinib and siRNA therapy in renal cell carcinoma

Sunitinib is a first-line treatment for renal cell carcinoma (RCC), but suffers from drug resistance, causing therapy failure. Therefore, nano-scale delivery systems should be introduced for targeted delivery. Metal-organic frameworks (MOFs) are attractive drug carriers that not only enable multidrug combination therapies but also exert photodynamic effects by incorporating photosensitizers as components. Here, a Zr-based porphyrinic nanoscale MOF, PCN224, was prepared as the carrier for the co-delivery of sunitinib and the siRNA against vascular endothelial growth factor receptor-2 (VEGFR-2). Drug-loaded PCN-224 is coated with hyaluronic acid (HA) to prevent drug molecular leakage and to exert tumor-targeting effects (CD44 in tumor cells). Photodynamic therapy was conducted under 660 nm laser (50 mW·cm−2, 10 min) irradiation. Compared with St/siVEGFR-2@PCN-224@HA without the HA coating, St/siVEGFR-2@PCN-224@HA significantly suppressed cell viability and promoted cell apoptosis. Laser irradiation further increased the anti-cancer effect of St/siVEGFR-2@PCN-224@HA by generating cytotoxic ROS. H&E staining of major organs revealed no signs of damage, indicating the biosafety of St/siVEGFR-2@PCN-224@HA. The prepared St/siVEGFR-2@PCN-224@HA system enables triple inhibition of tumor growth via a combination of targeted therapy and genetic and photodynamic therapy to enhance the therapeutic effects on RCC.

Elevating Nonlinear Optical Response Through D-Electron Modulation in Metal-Organic Frameworks.

Electronic structure and excited state behavior is of pronounced influence on regulation of nonlinear optical (NLO) response. Herein, a serials of transition metal ions bearing different d-electron numbers were in situ coordinated within porphyrinic metal-organic frameworks (MOFs), creating NLO-responsive M-metal (metal=Fe, Co, Ni, Cu, and Zn) frameworks. It demonstrated that the NLO properties can be optimized with the increased occupancy of the d-shell, which enhances the degree of delocalization. Specifically, the full-filled (d10) electron configuration of Zn2+ stabilizes the electronic structure, combination with π-π* local excitation character of M-Zn, promoting charge transfer process and resulting in outstanding NLO properties. Moreover, parameters related to the nonlinear process (β, n2, Imχ(3), Reχ(3) and χ(3)) of M-Zn are calculated to be higher than those of other materials, consistent with theoretical calculations. This work paves the way for NLO modulation based on electronic analysis and provides a promising approach for constructing high-performance NLO materials.

Vat Photopolymerization 3D Printing of Hydrogels Embedding Metal-Organic Frameworks for Photodynamic Antimicrobial Therapy.

Given the variability in wounds based on the underlying causes, personalized medicine and tailored care for patients with wounds are required to ensure optimal therapeutic outcomes. With the emergence of high-precision and high-efficiency photocuring 3D printing technology, there is the potential for its use in customizing precise shapes that can match complex wound sites, thereby providing better treatment for patients with wound infections. In this work, porphyrinic metal-organic framework (MOF) crystals, serving as the functional filler, were incorporated into gelatin methacrylate (GelMA) as a photocurable composite resin to investigate the capabilities of producing customizable wound dressings through vat photopolymerization 3D printing. The embedded MOF crystals allow for better control of the photopolymerization process due to photon competition with the photoinitiator, enabling the precise printing of complex structures. In addition, these crystals impart photothermal and photodynamic capabilities to the printed object. The antibacterial assay confirms the potent photothermal and photodynamic bactericidal properties of the printed GelMA/MOF hydrogels. The hydrogel with the highest MOF content exhibited over 99.99% antibacterial efficiency against both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli after 30 min of light exposure (∼30 mW/cm2, λ ≥ 420 nm). Simultaneously, hemolysis and cytotoxicity evaluations validated their excellent biocompatibility. The findings presented here introduce a strategy for integrating photosensitive MOF and 3D printing to fabricate size-adjustable photothermal/photodynamic monoliths and patches, opening perspectives toward personalized treatment for wound management.

Molecular Architecture @ MOFs: Designing a Multifunctional Catalyst for the Cascade Reaction of Olefins via Epoxides to Cyclic Carbonates

Employing enzymatic reaction cascade principles to synthesize artificial materials with multiple autonomously operating active sites is one of the holy grails in modern catalysis research. In this regard, metal‐organic frameworks (MOFs) are promising host platforms. Yet, applying MOFs as enzyme‐mimicking catalysts is synthetically challenging. Herein, we present a design strategy for the synthesis of porphyrin‐based MOFs for the cascade catalysis of the conversion of olefins to epoxides and their cycloaddition with CO2 to cyclic carbonates. The MOFs feature tunable dual active sites with synthetically controllable metal variations. A clear dependence of the metal combination on the catalytic performance of the MOF catalysts is shown. This work advances the understanding essential for designing sophisticated, multifunctional porphyrin MOFs for efficient one‐pot cascade catalysis.

Tumor Microenvironment-Responsive Zn(II)-Porphyrin Nanotheranostics for Targeted Sonodynamic Therapy.

As a novel noninvasive tumor therapy, sonodynamic therapy (SDT) attracts booming concerns. However, the limited water solubility, inadequate biocompatibility, and low targeting ability of conventional sonosensitizers significantly hinder their potential for clinical application. Herein, novel zinc(II)-porphyrin nanotheranostics (HA@Zn-TCPP) were fabricated in which the zinc(II)-porphyrin (TCPP) metal-organic framework was first constructed by a simple thermal reaction, followed by the addition of hyaluronic acid (HA) for modification. The specific targeting ability of HA facilitated the internalization of HA@Zn-TCPP within tumor cells, resulting in its preferential accumulation in tumor tissues that exhibit CD44 receptor overexpression. The acidic tumor microenvironment induced the rapid decomposition of HA@Zn-TCPP, releasing free TCPP for activating SDT. This controllable generation of reactive oxygen species (ROS) could effectively decrease damage to normal tissues. The HA@Zn-TCPP exhibited remarkable antitumor effects in experiments, achieving a tumor inhibition rate of up to 82.1% when under ultrasound. This finding provides an imperative strategy to develop novel sonosensitizers for enhanced SDT.

Imparting functionality into porphyrin metal–organic framework aerogels with uniform distributions for diversified applications

The incorporation of various functional nanoentities into pure metal–organic framework (MOF) aerogels can not only introduce additional functionality but also expands the application scenarios of MOF aerogels. Herein, a general and simple strategy for uniform incorporation of various functional nanomaterials into a porphyrin MOF aerogel is presented. Specifically, this strategy primarily involves the introduction of a surfactant polyvinylpyrrolidone (PVP) to disperse the nanomaterials in lipophilic solvents, followed by a direct solvothermal reaction with the precursors of the porphyrin MOF aerogel. Additionally, uniform aerogel composites consisting of two MOF components have also been developed by careful optimizing the reaction conditions. The resulting nanoentity@MOF aerogel composites exhibit positive properties that stem from the synergistic effects between the nanoentities and MOF aerogel, offering advanced applications in areas such as photochemical electrochemistry, adsorption and photodegradation, electrochemical oxygen reduction reaction, and fluorescence.

Construction of ROS-balancing-engineered heterojunction photoswitch for achieving programmed inflammatory management and tissue regeneration

Early instigation and subsequent attenuation of inflammation are crucial for tissue regeneration, which poses a need for inflammatory regulation in the design of materials. In this work, a novel photocatalytic heterojunction consist of MXene, Zr-based porphyrinic metal–organic framework (named PCN-222), and Pt nanoparticles (termed MX/PCN@Pt HJs) is developed to achieve photo-controlled reactive oxygen species (ROS) generation and clearance. According to density function theory calculations and related experiments, the unique heterojunction formed by MXene and MOFs, abundant O2 adsorption sites of metal oxide clusters, and porous features of MOFs promoted the adsorption of active reactants and accelerated electron transfer, thereby exhibiting excellent photocatalytic performance. Meanwhile, the PCN-222 with superoxide dismutase (SOD) activity and Pt nanoparticles with catalase (CAT) activity endowed the MX/PCN@Pt HJs with SOD/CAT mimetic cascade performance. Through the photo-controlled regulation, the MX/PCN@Pt HJs acted as a photoswitch that flexibly achieved the switch between ROS generation and clearance. Effective production of ROS not only enabled antimicrobial activity but also contributed to a pro-inflammatory state; while the timely ROS scavenging activity effectively prevented the detrimental effects of sustained inflammation. Both in vitro and in vivo evaluations had confirmed the inflammatory modulation and tissue regeneration potency of the MX/PCN@Pt HJs based on the ROS-regulated strategy, which offer a vital understanding of the MOF-based photocatalytic heterojunction for programmed inflammatory regulation.

Electrolyte Composition‐Dependent Product Selectivity in CO2 Reduction with a Porphyrinic Metal–Organic Framework Catalyst

AbstractA copper porphyrin‐derived metal–organic framework electrocatalyst, FICN‐8, was synthesized and its catalytic activity for CO2 reduction reaction (CO2RR) was investigated. FICN‐8 selectively catalyzed electrochemical reduction of CO2 to CO in anhydrous acetonitrile electrolyte. However, formic acid became the dominant CO2RR product with the addition of a proton source to the system. Mechanistic studies revealed the change of major reduction pathway upon proton source addition, while catalyst‐bound hydride (*H) species was proposed as the key intermediate for formic acid production. This work highlights the importance of electrolyte composition on CO2RR product selectivity.

An Oxidative Stress Nano-Amplifier for Improved Tumor Elimination and Combined Immunotherapy.

Amplifying oxidative stress to disrupt intracellular redox homeostasis can accelerate tumor cell death. In this work, an oxidative stress amplifier (PP@T) is prepared for enhanced tumor oxidation therapy to reduce tumor growth and metastases. The nano-amplifier has been successfully constructed by embedding MTH1 inhibitor (TH588) in the PDA-coated porphyrin metal-organic framework PCN-224. The controllable-released TH588 is demonstrated from pores can hinder MTH1-mediated damage-repairing process by preventing the hydrolysis of 8-oxo-dG, thereby amplifying oxidative stress and exacerbating the oxidative DNA damage induced by the sonodynamic therapy of PP@T under ultrasound irradiation. Furthermore, PP@T can effectively induce immunogenic cell death to trigger systemic anti-tumor immune response. When administered in combination with immune checkpoint blockade, PP@T not only impedes the progression of the primary tumor but also achieves obvious antimetastasis in breast cancer murine models, including orthotopic and artificial whole-body metastasis models. Furthermore, the nanoplatform also provides photoacoustic imaging for in vivo treatment guidance. In conclusion, by amplifying oxidative stress and reactive oxygen species sensitized immunotherapy, this image-guided nanosystem shows potential for highly specific, effective combined therapy against tumor cells with negligible side-effects to normal cells which will provide a new insight for precise tumor treatment.

Nanozyme Decorated Metal-Organic Framework Nanosheet for Enhanced Photodynamic Therapy Against Hypoxic Tumor.

Photodynamic therapy (PDT) has attracted increasing attention in the clinical treatment of epidermal and luminal tumors. However, the PDT efficacy in practice is severely impeded by tumor hypoxia and the adverse factors associated with hydrophobic photosensitizers (PSs), including low delivery capacity, poor photoactivity and limited ROS diffusion. In this study, Pt nanozymes decorated two-dimensional (2D) porphyrin metal-organic framework (MOF) nanosheets (PMOF@HA) were fabricated and investigated to conquer the obstacles of PDT against hypoxic tumors. PMOF@HA was synthesized by the coordination of transition metal iron (Zr4+) and PS (TCPP), in situ generation of Pt nanozyme and surface modification with hyaluronic acid (HA). The abilities of hypoxic relief and ROS generation were evaluated by detecting the changes of O2 and 1O2 concentration. The cellular uptake was investigated using flow cytometry and confocal laser scanning microscopy. The SMMC-7721 cells and the subcutaneous tumor-bearing mice were used to demonstrate the PDT efficacy of PMOF@HA in vitro and in vivo, respectively. Benefiting from the 2D structure and inherent properties of MOF materials, the prepared PMOF@HA could not only serve as nano-PS with high PS loading but also ensure the rational distance between PS molecules to avoid aggregation-induced quenching, enhance the photosensitive activity and promote the rapid diffusion of generated radical oxide species (ROS). Meanwhile, Pt nanozymes with catalase-like activity effectively catalyzed intratumoral overproduced H2O2 into O2 to alleviate tumor hypoxia. Additionally, PMOF@HA, with the help of externally coated HA, significantly improved the stability and increased the cell uptake by CD44 overexpressed tumor cells to strengthen O2 self-supply and PDT efficacy. This study provided a new strategy of integrating 2D porphyrin MOF nanosheets with nanozymes to conquer the obstacles of PDT against hypoxic tumors.

Revolutionizing Tetracycline Hydrochloride Remediation: 3D Motile Light-Driven MOFs Based Micromotors in Harsh Saline Environments.

Traditional light-driven metal-organic-frameworks (MOFs)-based micromotors (MOFtors) are typically constrained to two-dimensional (2D) motion under ultraviolet or near-infrared light and often demonstrate instability and susceptibility to ions in high-saline environments. This limitation is particularly relevant to employing micromotors in water purification, as real wastewater is frequently coupled with high salinity. In response to these challenges, ultrastable MOFtors capable of three-dimensional (3D) motion under a broad spectrum of light through thermophoresis and electrophoresis are successfully synthesized. The MOFtors integrated photocatalytic porphyrin MOFs (PCN-224) with a photothermal component made of polypyrrole (PPy) by three distinct methodologies, resulting in micromotors with different motion behavior and catalytic performance. Impressively, the optimized MOFtors display exceptional maximum velocity of 1305±327µms-1 under blue light and 2357±453µms-1 under UV light. In harsh saline environments, these MOFtors are not only maintain high motility but also exhibit superior tetracycline hydrochloride (TCH) removal efficiency of 3578±510mgg-1, coupling with sulfate radical-based advanced oxidation processes and peroxymonosulfate. This research underscores the significant potential of highly efficient MOFtors with robust photocatalytic activity in effectively removing TCH in challenging saline conditions, representing a substantial advancement in applying MOFtors within real-world water treatment technologies.

Pt/Pd dual-modified porphyrin metal-organic frameworks for NIR-II photothermal-enhanced photodynamic/catalytic therapy

Photodynamic therapy (PDT) and catalytic therapy were promising treatment modes, but tumor hypoxia and poor catalytic activity severely limited their efficacies. Herein, using a porphyrin metal–organic framework (PCN-224) as nanocarrier, a platinum/palladium (Pt/Pd) dual-modified PCN-224 nanoprobe (PCN-224-Pt@Pd) with strong peroxidase (POD)/catalase (CAT)-like activities was developed, achieving photothermal-promoted PDT/catalytic therapy. Compared with single ultrasmall Pt modifying, CAT-like activity of Pt/Pd dual-modifying increased oxygen concentration from 6.24 to 9.35 mg/L, which improved singlet oxygen (1O2) yield from 63.8 % to 82.9 %. Moreover, POD-like activity of Pt/Pd dual-modifying significantly accelerated hydroxyl radicals (·OH) generation. Importantly, PCN-224-Pt@Pd possessed near-infrared II (NIR-II) photothermal effect with a high efficiency (55.6 %), which further promoted ·OH production. Under combined therapy of PCN-224-Pt@Pd, the cell survival rate greatly reduced to 5.8 %, and the tumors were cured, suggesting NIR-II photothermal-enhanced PDT/catalytic therapy.

Ultrasmall iridium-encapsulated porphyrin metal-organic frameworks for enhanced photodynamic/catalytic therapy by producing reactive oxygen species storm

Transition metal-coordinated porphyrin metal-organic frameworks (MOFs) were perspective in photodynamic therapy (PDT) and catalytic therapy. However, the tumor hypoxia and the insufficient endogenous hydrogen peroxide (H2O2) seriously limited their efficacies. Herein, by encapsulating ultrasmall iridium (Ir) and modifying glucose oxidase (GOx), an iron-coordinated porphyrin MOF (Fe-MOF) nanoplatform (Fe-MOF@Ir/GOx) was designed to strengthen PDT/catalytic therapy by producing reactive oxygen species (ROS) storm. In this nanoplatform, Fe-MOF showed glutathione (GSH)-responsive degradation, by which porphyrin, GOx and ultrasmall Ir were released. Moreover, ultrasmall Ir possessed dual-activities of catalase (CAT)-like and peroxidase (POD)-like, which provided sufficient oxygen (O2) to enhance PDT efficacy, and hydroxyl radical (·OH) production was also improved by combining Fenton reaction of Fe2+. Further, GOx catalyzed endogenous glucose produced H2O2, also reduced pH value, which accelerated Fenton reaction and resulted in generation of ROS storm. Therefore, the developed Fe-MOF@Ir/GOx nanoplatform demonstrated enhanced PDT/catalytic therapy by producing ROS storm, and also provided a promising strategy to promote degradation/metabolism of inorganic nanoplatforms.

Cascade Nanozyme Comprising Pt-Coated Porphyrin Metal–Organic Frameworks Boosting Reactive Oxygen Species Generation for Sonodynamic Theranostics of a Tumor

Cascade Nanozyme Comprising Pt-Coated Porphyrin Metal–Organic Frameworks Boosting Reactive Oxygen Species Generation for Sonodynamic Theranostics of a Tumor

Nanosized Porphyrinic Metal–Organic Frameworks for the Construction of Transparent Membranes as a Multiresponsive Optical Gas Sensor

The well‐known and excellent colorimetric sensing capacity of porphyrins, along with the exceptional structural properties of metal–organic frameworks (MOFs), make porphyrin‐based MOFs, such as PCN‐222, ideal candidates for the construction of a chemical sensor based on absorbance. However, to the best of authors’ knowledge, no high‐quality porphyrin‐based MOF gas sensors have been developed to date, most likely due to the difficulties in: 1) preparing nanosized porphyrin‐MOFs to minimize scattering in absorbance measurements; and 2) incorporating MOFs into transparent membranes for practical use. Herein, a simple and fast microwave‐assisted method for preparing high‐quality nanosized PCN‐222 crystals and their metalated derivatives PCN‐222(M) is reported to finely tune the sensing response. Next, the successful dispersion of these PCN‐222(M) nanoparticles into poly(dimethylsiloxane) to create flexible and transparent membranes is demonstrated. This integration yields a multiresponsive optical gas sensor exhibiting excellent sensitivity and the ability to discriminate between various volatile organic compounds via pattern recognition identification.

Traffic lights inspired colorimetric sensing platform for cadmium/lead ions: PO43- induced structural change of porphyrin metal-organic framework

Developing rapid and user-friendly visual techniques for distinguishing and identifying heavy metal ions is a critical pursuit in food and environmental analysis. In this work, a zirconium-based metal organic framework (MOF) known as PCN-222 has been synthesized, serving as a colorimetric nanoplatform for the differentiation and detection of Cd2+ and Pb2+ in the presence of PO43-. The remarkable characteristic of PCN-222 stems from its reaction with PO43-, where the robust bonding between PO43- and Zr nodes triggers the collapses of PCN-222, leading to the release of ligands (TCPP) with visible alteration in solution color to light red. When exposure to Cd2+ and Pb2+, shifts to green and yellow, respectively, are discernible. These changes can be ascribed to differences in the size, atomic configuration, and electronegativity of the two metal ions, which impact their interaction with TCPP. The innovative concept of a nanomaterial traffic light is introduced based on these color transitions. Accurate quantification of Cd2+ and Pb2+ can be efficiently accomplished both individually and concurrently using UV spectroscopy and a mobile phone APP, providing adaptability in method selection depending on on-site conditions. Moreover, the platform effectively tackles selectivity challenges associated with ligand-based detection methods, showcasing high sensitivity, distinct visual indications, and simplicity in instrumentation requirements.

Incorporating Zinc Metal Sites in Aluminum-Coordinated Porphyrin Metal-Organic Frameworks for Enhanced Photocatalytic Nitrogen Reduction to Ammonia.

Rationally designing photocatalysts is crucial for the solar-driven nitrogen reduction reaction (NRR) due to the stable N≡N triple bond. Metal-organic frameworks (MOFs) are considered promising candidates but suffer from insufficient active sites and inferior charge transport. Herein, it is demonstrated that incorporating 3d metal ions, such as zinc (Zn) or iron (Fe) ions, into Al-coordinated porphyrin MOFs (Al-PMOFs) enables the enhanced ammonia yield of 88.7 and 65.0µggcat -1h-1, 2.5- and 1.8-fold increase compared to the pristine Al-PMOF (35.4µggcat -1h-1), respectively. The origin of ammonia (NH3) is verified via isotopic labeling experiments. Incorporating Zn or Fe into Al-PMOF generates active sites in Al-PMOF, that is, Zn-N4 or Fe-N4 sites, which not only facilitates the adsorption and activation of N2 molecules but suppresses the charge recombination. Photophysical and theoretical studies further reveal the upshift of the lowest unoccupied molecular orbital (LUMO) level to a more energetic position upon inserting 3d metal ions (with a more significant shift in Zn than Fe). The promoted nitrogen activation, suppressed charge recombination, and more negative LUMO levels in Al-PMOF(3d metal) contribute to a higher photocatalytic activity than pristine Al-PMOF. This work provides a promising strategy for designing photocatalysts for efficient solar-to-chemical conversion.

Improving the Photoactivity of Porphyrin-Based Metal-Organic Frameworks via Constructing [Ce-O] Active Site and Vacancy.

Defect engineering of metal-organic frameworks (MOFs) is a versatile approach to tailoring their electronic structures and photocatalytic performance. Herein, Ce-based porphyrin MOFs (CMFs) featuring controlled structural defects were successfully prepared using a simple acid modulation strategy to drive the photocatalytic H2 generation. The [Ce-O] unit serves as the active site via a ligand-to-metal charge transfer process, which has been confirmed by in situ XPS analysis. Abundant exposed coordinatively unsaturated Ce-O centers are beneficial for the adsorption and activation of water molecules, which is an important factor for improving the photocatalytic performance of the synthesized defective MOFs. In addition, optical and electrochemical experiments indicate that CMFs with more oxygen vacancies possess higher charge separation efficiency. As a result, the optimized CMF(Zn)-200 sample afforded high stability and activity in the H2 generation (up to 1603.3 μmol·g-1·h-1 under cocatalyst-free conditions) and tetracycline hydrochloride removal efficiency (97%), which was 8.45 and 97 times higher than that of pure meso-tetra(4-carboxyphenyl)porphine. This study demonstrates that effective structural modulation and defect introduction can improve the activity and stability of PMOF-based photocatalysts.

Investigation of the free-base Zr-porphyrin MOFs as relative humidity sensors for an indoor setting

Maintaining optimal relative humidity is paramount for human comfort. Therefore, the utilization of quartz crystal microbalance (QCM) as a relative humidity sensor platform holds significant promise due to its cost-effectiveness and high sensitivity. This study explores the efficacy of three free-base Zr porphyrin metal-organic frameworks (MOFs) - namely MOF-525, MOF-545, and NU-902 - as sensitive materials for QCM-based relative humidity sensors. Our extended experimental findings reveal that these materials exhibit notable sensitivity, particularly within relative humidity ranges of 40–100 %. However, we observe potential irreversible adsorption sites within the MOF-545 framework, hindering its ability to revert to its initial state after prolonged exposure. In light of this observation, we conduct periodic cycling experiments at relative humidity levels of 40–70 % to evaluate the measurement repeatability and feasibility of these sensors for indoor applications. Interestingly, the periodic cycling study demonstrates that MOF-545 shows promising repeatability, positioning it as a strong contender for indoor relative humidity sensing. In contrast, MOF-525 may necessitate extended desorption time, and NU-902 displays diminished sensitivity at low relative humidity levels. Nevertheless, a preliminary treatment of the MOF-545 QCM sensor may be necessary to address irreversible adsorption sites and uphold measurement repeatability, as only reversible adsorption sites are currently accessible. This study underscores the potential of MOF-based QCM sensors for effective relative humidity monitoring in indoor environments, thus facilitating improved comfort and environmental control.

Design of Atomically Dispersed CoN4 Sites and Co Clusters for Synergistically Enhanced Oxygen Reduction Electrocatalysis.

Constructing dual-site catalysts consisting of atomically dispersed metal single atoms and metal atomic clusters (MACs) is a promising approach to further boost the catalytic activity for oxygen reduction reaction (ORR). Herein, a porous CoSA-AC@SNC featuring the coexistence of Co single-atom sites (CoN4) and S-coordinated Co atomic clusters (SCo6) in S, N co-doped carbon substrate is successfully synthesized by using porphyrinic metal-organic framework (Co-TPyP MOF) as the precursor. The introduction of the sulfur source creates abundant microstructural defects to anchor Co metal clusters, thus modulating the electronic structure of its surrounding carbon substrate. The synergistic effect between the two types of active sites and structural advantages, in turn, results in high ORR performance of CoSA-AC@SNC with half-wave potential (E1/2) of 0.86V and Tafel slope of 50.17mVdec-1. Density functional theory (DFT) calculations also support the synergistic effect between CoN4 and SCo6 by detailing the catalytic mechanism for the improved ORR performance. The as-fabricated Zn-air battery (ZAB) using CoSA-AC@SNC demonstrates impressive peak power density of 174.1mWcm-2 and charge/discharge durability for 148h. This work provides a facile synthesis route for dual-site catalysts and can be extended to the development of other efficient atomically dispersed metal-based electrocatalysts.