The Mn3Cu3O8 shell not only prevents exposure of normal tissues to the Cu2O core to reduce systemic toxicity but also exhibits enhanced enzyme‐mimicking activity owing to the better band continuity near the Fermi surface. The glutathione oxidase (GSHOx)‐like activity of CMCO depletes glutathione (GSH), which diminishes the ability to chelate Cu ions, thereby exerting Cu toxicity and inducing cuproptosis in cancer cells. The catalase (CAT)‐like activity catalyzes the overexpressed H2O2 in the TME, thereby generating O2 in the tricarboxylic acid (TCA) cycle to enhance cuproptosis. More importantly, the Fenton‐like reaction based on the release of Mn ions and the inactivation of glutathione peroxidase 4 induced by the elimination of GSH results in ferroptosis, accompanied by the accumulation of lipid peroxidation and reactive oxygen species that can cleave stress‐induced heat shock proteins to compromise their protective capacity of cancer cells and further sensitize cuproptosis. CMCO nanozymes are partially sulfurized by hydrogen sulfide in the colorectal TME, exhibiting excellent photothermal properties and enzyme‐mimicking activity. The mild photothermal effect enhances the enzyme‐mimicking activity of the CMCO nanozymes, thus inducing high‐efficiency ferroptosis‐boosted‐cuproptosis.A core‐shell‐structured Cu 2O@Mn3Cu3O8 nanozyme exhibits excellent mimic enzyme activities due to better band continuity near the Fermi surface, which can be served as tumor microenvironment activated copper ionophore for achieving safe and efficient cuproptosis. More interestingly, cuproptosis can be sensitized with ferroptosis through cleaving protective heat shock proteins to enhance proteotoxicity, especially in inhibiting colorectal tumors with mild photothermal effect irradiation.The Cu Metal ions can efficiently suppress the growth of cancer cells without susceptibility to drug resistance by triggering biocatalysis, disrupting the osmotic balance, affecting metabolism, interfering with signal transduction, and damaging DNA. Among the numerous metal ions, cell death induced by copper ions is unique and distinct from other known cell death pathways . According to the inceptive research by Tsvetkov et al., the binding of copper to lipoylated components in the tricarboxylic acid (TCA) cycle can induce the aggregation of lipoylated proteins and subsequent loss of iron–sulfur (Fe–S) cluster proteins, which causes cell death via cuproptosis due to proteotoxic stress. The two key regulators of cuproptosis are lipoylation and the upstream regulator, FDX1. Specifically, FDX1 reduces Cu2+ to the more toxic Cu+ and promotes the clustering of lipoylated proteins and enzymes  involved in regulating the TCA cycle, whilst FDX1 results in the loss of Fe–S cluster proteins.Metal ions are essential for the normal activities of an organism and play important roles in various physiological processes.1 Due  which limits the binding of copper to the lipoylated components in the TCA, can inhibit the efficacy of cuproptosis. Tsvetkov et al. found that cuproptosis can upregulate stress‐induced heat shock proteins (HSPs), such as HSP70, thereby enhancing the stress capacity of cells, which in turn protects cellular proteins from stress‐induced denaturation, misfolding, and aggregation. Therefore, inhibiting cellular self‐protection by HSPs is the second issue to be addressed for applying cuproptosis in tumor treatment. Third, mitochondrial respiration involving cuproptosis requires the participation of oxygen (O2), whereas the TME is characterized by hypoxia, which can also limit the effect of cuproptosis. Finally, copper‐induced cell death is not specific to cancer cells as copper is equally lethal to normal cells. Thus, the rational design of TME‐activated nanoagents that serve as copper ionophores is significant for developing a responsive strategy for solving the above problems and achieving efficient and safe antitumor effects via cuproptosis.Considering the potential mechanism of cuproptosis and the characteristics of the tumor microenvironment (TME), there are still four questions regarding the construction of copper ionophores that need to be addressed for the application of cuproptosis in tumor treatment. First, chelation between copper and reduced glutathione ,5 whic Owing to the catalytic response of multivalent metal ions , inorganic nanozymes harboring metal ion redox couples that exhibit glutathione oxidase (GSHOx)‐like, peroxidase (POD)‐like, and catalase (CAT)‐like activities have shown remarkable efficacy in modulating the TME, thereby enhancing the therapeutic antitumor effects. GSHOx‐like activity decomposes overexpressed intercellular GSH in tumor cells, thus enhancing copper toxicity by effectively inhibiting the chelation of copper ions by GSH. Moreover, GSH depletion inactivates glutathione peroxidase 4 (GPX4), thereby upregulating lethal lipid peroxidation (LPO) and reactive oxygen species (ROS), which eventually induces ferroptosis. The generation of hydroxyl radicals (·OH) is augmented by catalyzing the decomposition of highly expressed hydrogen peroxide (H2O2) in the TME via POD‐like activity, which further consumes GSH, thereby enhancing copper toxicity and ferroptosis. A large amount of LPO and ROS can crosslink the primary amines of proteins, which destroys their structure and function, thus cleaving HSP70 and reducing the protective stress capacity of cancer cells. The CAT‐like activity of the nanozyme allows it to react with endogenous H2O2 to generate oxygen (O2), reversing the hypoxic tumor microenvironment, which enhances mitochondrial respiration and promotes cuproptosis. Some inorganic nanozymes with strong absorption in the near‐infrared (NIR) region exhibit NIR‐triggered photothermal effects for sensitizing enzyme‐mimicking activity, which further enhances the therapeutic efficacy as a catalytic antitumor agent. More importantly, artificial nanozymes with various structures  can undergo TME‐activated reactions and decomposition to achieve TME‐responsive anti‐tumor cuproptosis with low cytotoxicity to normal tissues.In recent years, nanozymes that mimic natural enzymatic activity have become a frontier in nanomedicine research.8 Owin2O, a semiconductor oxide containing monovalent copper ions (Cu+), can generate divalent copper ions (Cu2+) and elemental copper (Cu) by disproportionation reactions in an acidic environment, and thus can serve as a potential copper ionophore for TME‐activated cuproptosis. More importantly, Cu2O nanospheres can be used as matrix materials for constructing uniquely structured TME‐responsive nanozymes. However, the strong cytotoxicity of Cu2O in normal cells limits its biomedical applications. MnOx nanomaterials exhibit GSHOx‐like, POD‐like, and CAT‐like enzyme‐mimicking activity in the TME, while avoiding potential long‐term toxicity in vivo by TME‐responsive catabolism. Thus, based on the characteristics of these two semiconductor oxides, the construction and design of TME‐responsive manganese–copper oxide nanozymes, which possess multiple functions for Cu‐ion delivery and mimic enzyme activities, is an innovative strategy for achieving safe and efficient cuproptosis. Herein, we report multifunctional Cu2O@Mn3Cu3O8 core‐shell nanozymes for NIR‐triggered high‐efficiency ferroptosis‐boosted‐cuproptosis, for treating colorectal tumors  and bovine serum albumin (BSA) are respectively used as protective agents to avoid complete decomposition of Cu2O by the strongly oxidizing KMnO4. The Mn3Cu3O8 shell and Mn5O8 shell prevent the exposure of normal tissues to Cu2O prior to reaching the tumor lesion, thus reducing systemic toxicity. Moreover, the Mn3Cu3O8 shell exhibits enhanced enzyme‐mimicking activity owing to the better band continuity near the Fermi surface compared to that of the Mn5O8 shell. More interestingly, the diffusion of endogenous hydrogen sulfide (H2S) from the colorectal environment into the porous structure of Cu2O@Mn3Cu3O8 induces partial transformation of the metal‐semiconductor oxides to metal‐semiconductor sulfides having excellent photothermal effects, which further enhances the enzyme‐mimicking activity of Cu2O@Mn3Cu3O8 under NIR irradiation.Cuironment,19 and2+ ions are released from the Cu2O@Mn3Cu3O8 nanozymes, achieving enhanced cuproptosis through a multipronged strategy in a single system. The Cu+/Cu2+ and Mn2+/Mn3+/Mn4+ redox couples in the Cu2O@Mn3Cu3O8 nanozyme react with the overexpressed GSH and H2O2 in the TME to generate GSSG and O2 via GSHOx‐like‐ and CAT‐like activities, respectively. Relying on the dual strategy of avoiding chelation with GSH and enhancing mitochondrial respiration, the Cu toxicity is enhanced, leading to proteotoxic stress‐induced cancer cell death. Proteotoxic stress can upregulate the expression of HSP70 in cancer cells to enhance their stress capacity, thereby initiating a cellular self‐protection pathway to mitigate the damage caused by copper ion toxicity. The POD‐like activity of the nanozymes and Fenton‐like reaction of the released Mn ions catalyze the decomposition of overexpressed H2O2 in the TME to produce ·OH, which further depletes GSH and inactivates GPX4, thereby enabling ferroptosis. The large amount of LPO and ROS produced by ferroptosis in cancer cells depletes the stress protein HSP70 to relieve the limitation of ferroptosis. Partially sulfurized Cu2O@Mn3Cu3O8 undergoes moderate photothermal heating  and can thus significantly enhance the enzyme‐mimicking activity, thus realizing ferroptosis‐boosted high‐efficiency cuproptosis induced by a mild‐photothermal effect. After therapy, the Cu2O@Mn3Cu3O8 nanozymes effectively react with H2S in an acidic environment and are decomposed into Cu ions, Mn ions, and ultrasmall Cu7S4 nanoparticles, which can be effectively eliminated from the body in the urine via the renal filtration system, preventing long‐term retention of inorganic nanoparticles in the body. Therefore, this multi‐pronged strategy for enhancing cuproptosis is a safe and feasible treatment that can be applied in cancer therapy.After entering the colorectal TME, Cu22O@Mn3Cu3O8 (CMCO) core‐shell nanozymes were fabricated using cubic‐phase Cu2O nanospheres , was formed outside the Cu2O core . Thus, the core‐shell structure is recognized as Cu2O@Mn3Cu3O8 (CMCO). The dynamic light scattering (DLS) data  and Cu2+ (13.26%). The Cu2+ in Cu2O may be derived from the oxidation of Cu+ on the nanozyme surface during the preservation process or during detection. The Mn 2p and Cu 2p XPS profiles of CMCO /Mn3+ (26%)/Mn2+ (31.2%) valence states and Cu  and Cu2+ (46.58%). The higher ratio of Cu2+/Cu+ in CMCO confirmed that the outermost Cu in Cu2O was oxidized by KMnO4 in forming the Mn3Cu3O8 shell. Importantly, the Mn2+/Mn3+/Mn4+ and Cu+/Cu2+ redox couples provide immense potential for enzyme‐mimicking activity. Thus, we first studied the enzyme activity of the CMCO nanozymes in a mildly acidic TME (pH 6.5). Among the three nanozymes with core‐shell structures, CMCO obtained by the reaction of Cu2O with KMnO4 for 2 h showed the strongest POD‐like, GSHOx‐like, and CAT‐like activities  nanocomposite was synthesized by the reaction of KMnO4 with BSA‐modified Cu2O  was used as a probe to determine the kinetic constants for the decomposition of H2O2 based on the POD‐like activities of Cu2O, CMO, and CMCO. As shown in Figure 2O2. The Michaelis–Menten constant (Km) and maximal reaction velocity (Vmax) of the POD‐like structures were calculated from the Lineweaver–Bruker plot. As shown in Figure Km values for Cu2O, CMO, and CMCO were 0.301, 0.231, and 0.112 mM, and the Vmax values were 6.86 × 10−8, 3.09 × 10−7, and 1.013× 10−7 M·s−1, respectively. These values indicate that CMO induces the fastest decomposition of H2O2 via POD‐like catalysis, whereas CMCO has the highest affinity for H2O2. Thus, 5,5′‐dithiobis‐(2‐nitrobenzoic acid) (DTNB) was used as a probe to determine the kinetic constants for GSH depletion (GSHOx‐like activity) by the nanozymes. The GSH that was not converted by the GSHOx‐like of nanozymes reacted with DTNB to generate TNB. Figure 2O, CMO, and CMCO. The respective Vmax values were 16.16 × 10−6, 8.85 × 10−6, and 14.95 × 10−6 M·s−1, with corresponding Km values of 0.47, 0.287, and 0.436 mM, respectively. Cu2O and CMCO exhibited similar GSHOx‐like reaction velocities, which were both higher than those of CMO. Finally, a dissolved oxygen analyzer was used to determine the kinetic constants for H2O2 decomposition (CAT‐like activity) by the nanozymes. As shown in Figure 2O2 to generate significantly more O2 than that obtained with Cu2O and CMO. The values of Vmax and Km indicated that CMCO induced the fastest reaction and had the highest affinity (CAT‐like activity) for H2O2  of the CuO Figure  was presu Figure  was pres2O and CMCO nanozymes are shown in Figure 2O was oxidized to generate the Mn3Cu3O8 shell on the surface, the Fermi levels of Cu2O, Mn3Cu3O8, and CMCO were calculated , the band continuity of CMCO was even stronger, which indicates that the catalytic activity of the core‐shell‐structured CMCO is stronger than that of Cu2O or Mn3Cu3O8 alone. Figure 2O to O near Mn3Cu3O8, and an interaction (Cu─O bond) occurs between the heterojunctions. The atomic densities of the O‐Layer 5 and Cu‐Layer 4 states of the CMCO nanozymes were analyzed, as shown in Figure 2O to form the Mn3Cu3O8 shell. Because the catalytic reaction mainly occurs on the surface of the nanozymes, the d‐orbitals of the Mn5O8 shell and Mn3Cu3O8 shell were analyzed to compare the enzyme activities of CMO and CMCO, respectively. As shown in Figure 3Cu3O8 is ≈2.32 eV, whereas that of Mn5O8 is ≈−2.93 eV. A portion of the Mn density of states is distributed around Ef = −6 eV, whereas the density of states for Cu is concentrated and close to the Fermi level, which makes the center of the d‐band of Mn3Cu3O8 closer to the Fermi level, thus causing Mn3Cu3O8 to be more active than Mn5O8. Thus, CMCO is more likely to undergo redox reactions than CMO. As shown in Figure To determine the effectiveness of the CMCO nanozymes as enzyme mimics, theoretical calculations were performed. The structural models of the Cu2O was used to simulate the colorectal TME (weakly acidic with H2S overexpression). As shown in Figure 2S during the initial stages of entering the colorectal tumor site. Therefore, the reaction time of CMCO with NaHS was shortened to simulate the incomplete sulfuration of CMCO in the TME. As shown in Figures−1) and CMCO (from 0 to 200 µg·mL−1) or when the power density of the laser was increased (from 0.25 to 1.25 W·cm−2), the temperature generated by the reaction products under 1064 nm irradiation gradually increased. Excluding the absorption of water, pure CMCO had almost no photothermal effect except after the reaction with NaHS. The plot of the variation of the temperature when the NIR irradiation was turned on/off  spectra were acquired to detect the free radicals generated by the partially sulfurized CMCO and original CMCO nanozymes. 5,5‐Dimethyl‐1‐pyrroline‐N‐oxide (DMPO), as a capture agent, was used to detect the generation of hydroxyl radicals (·OH)    containing NaHS·xH As shown in Figures 2O nanoparticles were used as control materials. As shown in Figure 2O experienced a significant toxic effect. These results indicate that the formation of the Mn3Cu3O8 shell on the surface of Cu2O prevented direct exposure of the cells to the Cu2O core, thereby reducing the cytotoxicity to normal cells. To further test this hypothesis, normal mouse colonic smooth muscle cells (CSMC) were treated with different concentrations of CMCO or Cu2O. As shown in Figure 2O at various concentrations. However, the cytotoxicity of the CMCO nanozymes to CT26 cells was higher than the cytotoxicity to L929 cells. The CMCO nanozymes were more toxic to CT26 cells than Cu2O when the concentration of the nanoparticles was increased to 20 µg·mL−1. The CMCO nanozymes were effective against tumor cells in other cell lines, including murine and human cell lines , which is typically used to improve the biocompatibility of materials.26 As  Figures , where fTo investigate a possible mechanism  for the induction of cell death via the mild photothermal effect, Z‐VAD‐FMK , Ferrostain‐1 , and FDX‐1 siRNA were used in the cell viability assessment experiments. Notably, as an artificial synthetic antioxidant, Ferrostain‐1 achieves the goal of inhibiting ferroptosis via a reducing mechanism, thereby preventing damage to membrane lipids and thus suppressing apoptosis by depleting intracellular ROS. As shown in Figure 2 content in tumor cells results in more electron receptors in the ETC, which facilitates the regeneration of NADH+ and FAD to promote the TCA cycle. In a study by Tsvetkov, ECT was found to be essential for cuproptosis, and O2 was a factor that promoted cuproptosis. Overall, the TCA cycle indirectly requires O2 participation. Interestingly, in a recent study, Zhang et al. explained the role of O2 in cuproptosis from a different perspective. In their study, (BRD4) inhibitor JQ‐1 inhibited glycolysis in combination with oxygen, leading to a reduction in ATP, which blocked ATP7B (major export proteins that depend on ATP for energy and control copper efflux) and further increased intracellular copper accumulation, thereby enhancing cuproptosis. As shown in Figure 2) was significantly lower than that under hypoxic conditions (1% O2). In the present study, due to its CAT‐like activity, the CMCO nanozyme reacted with endogenous H2O2 to generate O2, reversing the hypoxic microenvironment, thereby increasing cuproptosis. Therefore, due to its CAT‐like activity, the CMCO nanozyme catalyzes the overexpression of H2O2 in the TME to generate O2 and promotes cuproptosis by enhancing mitochondrial respiration and inhibiting Cu+ efflux. As shown in Figure 2, which contributes to enhancing cuproptosis. Stress‐expressed HSPs were consumed by ROS produced by the OXD‐like and POD‐like enzyme‐mimicking activity of the nanozymes, and LPO was accumulated through ferroptosis, thus mitigating the inhibition of ferroptosis. More importantly, the mild photothermal effect enhanced the enzyme‐mimicking activity of the CMCO nanozymes, which further promoted the biochemical reaction processes described above. In summary, we achieved high‐efficiency ferroptosis‐boosted‐cuproptosis induced by a mild photothermal effect by using colorectal TME‐responsive CMCO nanozymes.To investigate the mechanism of cuproptosis, the expression of HSP70 protein was measured by WB. Both heat and coproptosis can induce the expression of HSP70 proteins, thereby inhibiting the killing effect on tumor cells. As shown in Figure CA cycle.27 In 2O, Cu2O + NIR, CMCO, and CMCO + NIR), and the anticancer efficacy was assessed. For the groups exposed to irradiation, a 1064 nm laser (1 W·cm−2) was used to irradiate the tumor site for 10 min  10 min after injection of the drug; the temperature of the tumors was controlled within 42 °C. As shown in Figure2O and CMCO compared to that in the groups treated with PBS and NIR. Moreover, tumor growth was inhibited by NIR irradiation. Photographs of the excised tumors of the different groups showed the same results  with NaHS to generate ultrasmall nanoparticles, where the reaction product was Cu7S4 (PDF#23‐0958). As shown in Figure 3Cu3O8 shell was easily decomposed into ultrasmall Cu7S4 nanoparticles after being injected into the body. These results correspond to the process used to form the Mn3Cu3O8 shell for transient protection of normal cells from direct exposure to the Cu2O core. As shown in Figure 2O. However, when the products of the reaction between CMCO and NaHS were injected into healthy mice, Cu ions were primarily excreted from the kidneys  nanozyme capable of inducing high efficiency ferroptosis‐boosted‐cuproptosis via mild‐photothermal effect for colorectal cancer therapy was synthesized. Due to the presence of Cu+/Cu2+ and Mn2+/Mn3+/Mn4+ redox couple, CMCO nanozyme exhibited a variety of enzyme‐mimicking  activity. CMCO exhibits stronger catalytic activity than Cu2O and analogue Cu2O@Mn5O8 (CMO) owing to the better band continuity as conductive material and closer to the Fermi level. CMCO nanozymes were partially sulfurized by specifically overexpressed H2S in the simulated colorectal TME, which not only released Cu and Mn ions, but also presented stable photothermal property, while maintaining the enzyme‐mimicking activity. The cellular level studies suggest that CMCO nanozymes showed good biocompatibility for normal cells due to the protective of Mn3Cu3O8 shell, but enormous toxic for colorectal cells, especially under the mild‐photothermal effect. The stress‐expressed HSPs were down‐regulated by enhanced ferroptosis induced by CMCO nanozymes, thus further sensitizing cuproptosis. Moreover, CMCO nanozymes exhibited prominent tumor growth inhibition performance and biosecurity in vivo. Collectively, this work first reports mild‐photothermal effect induce high efficiency ferroptosis‐boosted‐cuproptosis based on nanozyme, which provides a safe and feasible strategy for the treatment of colorectal cancer.In summary, a core‐shell‐structured Cu43)3·3H2O), hydrazine hydrate (N2H4·H2O), Polyvinylpyrrolidone , O‐Phenylenediamine (OPD), methylene blue (MB), 5,5′‐Dithiobis‐(2‐nitrobenzoic acid) (DTNB), 1, 3‐diphenylisobenzofuran (DPBF) and 3‐−2,5‐diphenyltetrazolium bromide (MTT) were purchased from Aladdin . Sodium hydrosulfide hydrate (NaSH·xH2O), Hydrogen Peroxide (H2O2), and Glutathione (reduced) were purchased from Macklin . Potassium permanganate (KMnO4) was purchased from Sinopharm . Bovine serum albumin (BSA) was purchased from BioFroxx . Bradford Protein Assay Kit, Hoechst, Reactive Oxygen Species (ROS) Assay Kit, and Calcein‐AM/PI Double Stain Kit were purchased from Beyotime . Reduced glutathione (GSH) assay kit was purchased from Solarbio . BCA protein assay kit, RPMI‐1640 medium, dulbecco's modified eagle medium (DMEM), fetal bovine serum (FBS), penicillin‐streptomycin and enhanced chemiluminescence (ECL) substrate kit were purchased from ThermoFisher Scientific . FDX‐1 siRNA and Transfection Reagent were purchased from RIBOBIO . Ferrostain‐1 was purchased from Sigma‐Aldrich . Z‐VAD‐FMK was purchased from TargetMol .All reagents were used directly without further purification. Copper (II) nitrate trihydrate (Cu(NO2−), and singlet oxygen (1O2) were verified by an A300 electron spin resonance (ESR) spectrometer . The UV–vis‐NIR adsorption spectrum was measured on a UV3600 spectrophotometer . The ions of Cu and Mn were detected on the iCAP RQ Inductively Coupled Plasma‐mass spectrometry (ICP‐MS) instrument . The thermal images were recorded using a T420 thermal camera .The Transmission electron microscopy (SEM) images were obtained using a Talos F200x SEM . The X‐ray diffraction (XRD) patterns were recorded on an Empyrean X‐ray powder diffractometer . The X‐ray photoelectron spectra (XPS) patterns were recorded on an Escalab Xi electron spectrometer . The dynamic light scattering (DLS) was measured on the NANO ZS Malvern instrument (UK). The hydroxyl radical (·OH), superoxide anion (O3)3·3H2O (0.02 M) under drastic magnetic stirring for 30 min. And then, 552 µL N2H4·H2O (35 wt.%) was added into the above mixtures. After 1 h, Cu2O was obtained by alternating centrifugation with deionized water and ethanol. At last, Cu2O was dispersed in 5 mL ethanol for storing.3.5 g PVP was scattered into 50 mL Cu(NO4 (20 mg) was dissolved in 20 mL deionized water, and then 1 mL Cu2O was added in it. After magnetic stirring for 2 h, Cu2O@Mn3Cu3O8 (CMCO) was obtained by centrifugation with water, and dispersed in 5 mL water for storing. 50 mg BSA was added into CMCO under magnetic stirring for 12 h to be applied in cell and animal experiment.KMnO2O was centrifugated and dispersed in 20 mL deionized water. 50 mg BSA was dissolved in Cu2O aqueous solution and magnetic stirred for 6 h. Cu2O@ BSA was obtained by centrifugation, and dispersed in 10 mL water. 10 mg KMnO4 was dissolved in 10 mL deionized water and dropwise added into Cu2O@BSA aqueous solution. After magnetic stirring for 1 h, Cu2O@Mn5O8 (CMO) was obtained by centrifugation with water, and dispersed in 5 mL water for storing.1 mL Cu2O for in vitro and in vivo experiments. Specifically, the mixed solution composed of CMCO or Cu2O and BSA at a concentration ratio of 1:2 was stirred for 4 h, and the BSA‐coated CMCO or Cu2O was obtained after centrifugation and washing.The surface electrostatic adsorption method was used to obtain BSA‐coated CMCO and BSA‐coated Cu2. The medium was replaced every other day.CT26 and L929 cells were cultured in RPMI 1640 medium supplemented with 1% (v/v) penicillin/streptomycin, and 10% (v/v) fetal bovine serum (FBS) at 37 °C under 5% CO6 cells, 100 µL) into the right dorsal region of mice. The tumor grew to 100 mm3 for the next experiment.Male Balb/c mice (six weeks) were bought from Vital River laboratories , and housed in specific‐pathogen‐free facilities in Laboratory Animal Center of Guangzhou Medical University. All the animal studies were performed in accordance with the regulations of Laboratory Animal Ethics Committee of Guangzhou Medical University . The CT26 tumor‐bearing mice were established as the animal model by subcutaneously injecting CT26 cells  with Bonferroni post‐hoc test was used for multi‐group comparisons in relevant animal experiment. In this paper, the differences were considered to be statistically significant when p < 0.05 (*).The number of samples (n) for each statistic is indicated in the relevant figure legends. Dates were expressed as mean ± standard deviation (SD). SPSS 18.0 software was used to process the measurement data. Student's More experimental methods are available in the Supporting Information.The authors declare no conflict of interest.Supporting InformationClick here for additional data file.


The nutritional properties of S2 and S3 samples compared with the control sample improved. Also, differences were observed in the beneficial effects of S2 and S3 compared with the control sample as total polyphenol content (TPC) increased 1.06 and 1.11 times, respectively (p < .05); antioxidant activities (AA) of S2 and S3 samples were 8.04 and 6.01 mg/ml and angiotensin‐converting enzyme (ACE) inhibitory activities were measured to be 8.2 and 7.86 mg/ml, respectively; also, α‐amylase and α‐glucosidase inhibitory activities of S2 and S3 samples were observed 4.48% and 5.70%, and 4.59% and 6.36%, respectively. From the organoleptic aspect, S3 had the highest acceptability. Generally, it is concluded that with the addition of DKP  to SPDS formulation, a functional soup could be produced considering the rich nutritional profile of DKP.Date kernel as a functional food component has a special importance due to its rich nutritional profile, low price, and ease of access. For this, in this research, the sub‐product was used for formulation of semi‐prepared dry soup (SPDS); the effect of adding 0 (S1 = control), 2 (S2), and 4 (S3) %w/w date kernel powder (DKP) on physicochemical, nutritional, and organoleptic properties and beneficial effects of SPDS samples were evaluated. The results revealed that S2 and S3 samples were different from the control sample in some physicochemical properties so that viscosity increased 1.27 and 1.52 times and  Date kernel powder (DKP) could be considered as the potential functional ingredient in healthy food products. DKP improved α‐amylase and α‐glucosidase and antioxidant activities of semi‐prepared and dry soup (SPDS). SPDS with improved nutritional properties was provided using DKP incorporation. SPDSs have received a lot of attention in recent years because of their favorable shelf life, easy transportation, and short time required for their preparation  of the total weight of the date and it is produced in large quantities as waste in date processing factories. Date kernel is odorless and has a light to dark brown color and a slightly mild bitter taste  kernel powder (variety Mazafati) from Pilar Company, onion powder from Rashak Company, whey protein powder from Shirpooyan Company, citric acid from Ensign Company, garlic powder from Rashak Company, Meat Flavor from Symrise Company, monosodium glutamate from Foodchem and spices from Behsab Company were prepared. All chemicals required for carrying out tests were supplied by Merck Company except sucrose, angiotensin‐converting enzyme (ACE), diphenyl 2‐picrylhydrazyl, hypuryl‐His‐Leu, α‐amylase and α‐glucosidase purchased from Sigma Company.Olein palm oil from Margarin Public Company, wheat and barley flakes from Abshar Sabz, Barbari wheat flour from Setareh Mortazavi Company, refined iodine‐free salt from Pars Namak Kaveh Company, orange lentil from Golestan Company, date  were prepared as soup samples enriched with higher than 4% DKPs had an astringent taste and a dark color; thus, they were unacceptable by panelists and removed, and samples were selected according to Table 2.3For preparation of soups, 75 g SPDS was mixed with 1 L cold water and boiled for 20 min at mild temperature. Then, the prepared and cooled soup was poured in a mixer, and the mixed sample (with ambient temperature) was tested.2.3.1Titratable acidity was calculated by titrating the samples with 0.1 N NaOH  and reported in terms of The viscosity of soup samples was measured by a rotational Brookfield viscometer (RVDV‐ II+ pro). After initial tests, DV64 was selected as the suitable spindle and viscosity was reported at room temperature in terms of Pa/s after 30 s  and rehydrated in a water bath at a given temperature (45°C) for 10 min; then, samples were filtered, weighed and the relevant factor was calculated Tot2.3.3The total polyphenol content (TPC) was calculated through the Folin–Ciocalteu method and reported in terms of mg gallic acid per 100 g of sample  required for the reduction of DPPH radicals to 50% of its original content and able to inhibit 50% of its activity. The lower IC50, the higher antioxidant capacity. The sample was mixed with 0.4 mmol/LDPPH radical in ethanol. The mixture was vigorously shaken and left for 10 min. The absorbance of the mixture was determined at 525 nm with a spectrophotometer (UV2100). The radical scavenging activity was calculated using Equation (Antioxidant activity (AA) was measured through the evaluation of free radical scavenging capacity of 2,2‐diphenyl−1‐picrylhydrazyl (DPPH) and reported in terms of IC50 was calculated according to Equation  in 0.1 M potassium phosphate buffer (pH 6.90) was then added to each tube and the mixtures were re‐incubated at 25°C for 5 min. Absorbance readings were recorded at 405 nm and the control (buffer in place of the filtered solution) was recorded as well.α‐amylase and α‐glucosidase inhibitory activities were measured through Laoufi et al.  method. C: absorbance of the control (100% enzyme activity). S: absorbance of the tested sample.The enzyme inhibition rate expressed as a percentage of inhibition was calculated using Equation .(4)Inh2.3.4Organoleptic properties of DKP were measured through evaluation of its color, flavor, taste, and odor.Organoleptic properties such as flavor, odor, oral and non‐oral texture , color, and overall acceptability of soup samples were measured by a 5‐point hedonic system. Evaluation levels included (from 1 to 5): 1 = inconsumable or very weak, 2 = unacceptable or weak, 3 = acceptable or average, 4 = satisfactory or good, 5 = very satisfactory or very good .2.4A completely randomized design was used to analyze and evaluate the data obtained from the different experiments. Analysis of variance and comparison of means (three replicates for each experiment) were carried out through SPSS software version 16.0 (Duncan's multiple range test and confidence level of 95%).33.13.1.1p < .05), and S1 and S3 had the highest pH value and acidity, respectively. Reduced pH and elevated pH could be attributed to the low pH and high acidity of DKP (Table Table KP Table . The reaKP Table .3.1.2p > .05) and promoted viscosity (p < .05); viscosity of S2 and S3 was 1.27 and 1.52 times higher than control sample, and, in fact, S3 had the highest viscosity.Table Reduced moisture content is ascribed to the availability of insoluble cellulose fibers, hemi‐cellulose, and lignin in DKP, which, owing to the lack of ability to absorb and hold water, caused the decrease in moisture content of DKP . Brightness index of S2 and S3 was 0.94 and 0.88 lower compared with the control sample, while their a* was 5.6 and 8.5 times higher and b* was 0.92 and 0.80 lower than those of the control sample.Table a* value too. The reduction of b* value reveals yellowness of soup samples. It should be noted that the color of DKP is very different from the color of wheat and barley flakes, and, as a result, impacts the darkness of the product.Natural colorants of date kernel such as flavonoids, anthocyanins, and carotenoids affect its color , partial decrease in protein content and no significant change in carbohydrate and ash contents.Table It is worth noting that date kernel oil has high antioxidant activity as well as considerable phenolic compounds . The comparison of different types of fibers of enriched soup samples (S2 and S3) with the control soup shows that their SDFs are 1.04 and 1.1 times, IDFs are 1.03 and 1.05 times, and TDFs are 1.03 and 1.09 times higher, respectively; S3 had the highest amount of different fiber types. The higher fiber content of DKP compared with wheat and barley is the reason for the observed results. The high fiber content of DKP provides the possibility of its application as a rich source of fibers in different food formulations . The comparison of these minerals in enriched soup samples (S2 and S3) with the control soup sample shows their calcium content was 1.01 and 1.03 times, the iron content was 1.05 and 1.11 times, the zinc content was 3.2 and 5.2 times and selenium content was 1.16 and 1.28 times higher than those of the control sample, respectively; S3 allocated the highest minerals contents to itself. The sodium content of soup samples dwindled as a consequence of the increase in percentage of DKP (p < .05), while no significant change was observed in potassium and magnesium content (p > .05).Table The reason for the increase in calcium, magnesium, iron, zinc, copper, and selenium content in enriched soup samples is the presence of DKP; as it is observed in the compounds of DKP Table , DKP is Martinez‐Ballesta et al.  reported3.2.4p > .05). Fiber‐rich cereals such as wheat and barley cause satiation. In this research, with the replacement of DKP, the amount of barley and wheat flakes was reduced compared with the control sample due to the uniformity of the raw material weight in the formulation of the samples. Despite this, the reduction in calorie was observed; thus, the reason for the slight reduction in calorie of enriched soup samples could be attributed to DKP. Al Juhaimi et al., Table 3.33.3.1p < .05). By comparing TPC of enriched soup samples (S2 and S3) with the control soup sample, it is observed that their TPC was 1.06 and 1.11 times higher, respectively, and S3 had the highest TPC. AA (IC50) of S2 and S3 was measured to be 8.04 and 6.01 mg/ml, respectively.The changes in AA and TPC of soup samples are inserted in Table p‐coumaric acid, syringic acid  in regulating blood pressure, inhibition of this enzyme is used to treat high blood pressure. ACE inhibitors, similar to synthetic drugs, are widely used to control blood pressure. Blood pressure medications, especially ACE inhibitors, are employed to regulate blood pressure in renin–angiotensin system. Owing to some of the side effects of drug inhibitors in case of long‐term use, natural sources such as plant extracts and bioactive peptides have been considered as alternatives to chemical drugs . ACE inhibitory activities (IC50) of S2 and S3 were measured to be 8.2 and 7.86 mg/ml. The addition of DKP to soup samples eventuates minimal ACE inhibition but this activity increases as the percentage of DKP addition intensifies, which could be attributed to the higher polyphenolic compounds and dietary fiber. In fact, phenols act as ACE inhibitors ; ACE inhibitory activity of the control muffin sample was significantly  higher than samples containing DKP. Patten et al. .Karakaya, El, Simsek, and Buyukkestelli  confirmen et al.  found thn et al.  confirmen et al.  reportedn et al.  confirme3.3.3p < .05). Samples S2 and S3 showed a significant increase in the inhibition of α‐amylase activity  as compared to control (2.49%). Also, the presence of 2% and 4% DKP improved the inhibition of α‐glucosidase activity in the soups to 4.59% and 6.36%, respectively, in comparison to control (1.06%). So, the highest inhibition appeared in S3, while control showed the weakest effect. The soup samples enriched with DKP exhibited a higher α‐glucosidase inhibitory activity than α‐amylase inhibitory activity. This observation suggests that bioactive compounds inhibiting α‐amylase and α‐glucosidase activity are present in DKP which could be attributed to the polyphenolic compounds and flavonoids. Phenolic compounds have been widely studied as α‐amylase and α‐glucosidase inhibitors  and α‐glucosidase  that decreases the post‐prandial hyperglycemia might represent a noteworthy method for treating type 2 diabetes . While the highest scores of organoleptic properties (except color) allocated to S3 sample, the highest score of color property belonged to S2 and the lowest score of color property to S3. Date kernel could be used as a food component to improve the sensory properties of food products, and the decrease in water activity affects product stability  raised. With the increase in the percentage of DKP, AA, TPC, and ACE inhibitory activity of soup samples improved. The soup samples exhibited a weak inhibitory activity of digestive enzymes, α‐amylase, and α‐glucosidase.Finally, the results of this study hint that DKP can be used as a cheap natural source for the production of functional foods such as SPDS based on cereals due to their valuable and functional compounds. For this purpose, the utmost amount of DKP for functional soup production is suggested to be 4% as the color change in products with higher than this threshold amount of DKP is unpleasant; besides, a high level of incorporation causes astringent taste and flavor. It is proposed that dark food products such as meat products, confectionery, chocolates, bakery products, cream‐filled of cakes and biscuits especially biscuits with cocoa and coffee flavors are the best choices for fortification with DKP.This research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors.The authors declare that there is no conflict of interest.The manuscript does not contain experiments using animals or human studies.


Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Genetic predisposition and immune dysfunction are involved in the pathogenesis of PD. Notably, peripheral inflammatory disorders and neuroinflammation are associated with PD neuropathology. Type 2 diabetes mellitus (T2DM) is associated with inflammatory disorders due to hyperglycaemia‐induced oxidative stress and the release of pro‐inflammatory cytokines. Particularly, insulin resistance (IR) in T2DM promotes the degeneration of dopaminergic neurons in the substantia nigra (SN). Thus, T2DM‐induced inflammatory disorders predispose to the development and progression of PD, and their targeting may reduce PD risk in T2DM. Therefore, this narrative review aims to find the potential link between T2DM and PD by investigating the role of inflammatory signalling pathways, mainly the nuclear factor kappa B (NF‐κB) and the nod‐like receptor pyrin 3 (NLRP3) inflammasome. NF‐κB is implicated in the pathogenesis of T2DM, and activation of NF‐κB with induction of neuronal apoptosis was also confirmed in PD patients. Systemic activation of NLRP3 inflammasome promotes the accumulation of α‐synuclein and degeneration of dopaminergic neurons in the SN. Increasing α‐synuclein in PD patients enhances NLRP3 inflammasome activation and the release of interleukin (IL)‐1β followed by the development of systemic inflammation and neuroinflammation. In conclusion, activation of the NF‐κB/NLRP3 inflammasome axis in T2DM patients could be the causal pathway in the development of PD. The inflammatory mechanisms triggered by activated NLRP3 inflammasome lead to pancreatic β‐cell dysfunction and the development of T2DM. Therefore, attenuation of inflammatory changes by inhibiting the NF‐κB/NLRP3 inflammasome axis in the early T2DM may reduce future PD risk. T2DM is regarded as a risk factor for PD. Notably, subjects with impaired glucose tolerance were shown to be at higher risk for the development of cognitive decline.Various studies revealed the association between T2DM and PD Table . EvidencOf note, IR in T2DM promotes the degeneration of dopaminergic neurons in the SN and other PD neuropathological processes since; insulin signalling regulates dopaminergic synaptic plasticity and neurotransmission in the SN.Indeed, preclinical and clinical evidence indicated that T2DM is associated with an increased risk for the development of PD.A prospective study on 25 PD patients with T2DM compared to 25 PD patients without T2DM followed for 36 months showed that T2DM patients with PD experience more motor dysfunctions.The probable link between PD and T2DM is the age factor, as both of these diseases are amplified by aging due to mitochondrial dysfunction and endoplasmic reticulum stress.Furthermore, pre‐diabetes also boosts the risk for the development of PD.It has been shown that T2DM accelerates the development of cognitive dysfunction and motor deficits in PD via the reduction of the accessibility and expression of dopamine transporters.An additional possible mechanism for the connection between PD and T2DM is the accumulation of amyloid proteins and misfolded proteins. Of interest, the accumulation of amyloid polypeptide in the pancreatic β cells and deposition of α‐synuclein with the formation of Lewy bodies are the hallmarks of T2DM and PD, respectively.These results proposed a shared mechanism between T2DM and PD outside the CNS. In T2DM patients, IR inhibits the insulin‐degrading enzyme (IDE) and increases the generation of α‐synuclein with an increased risk for the development of PD.Additionally, prolonged effects of T2DM promote the formation of advance glycation end‐product (AGE) in various tissues including CNS, mainly in the SN.Moreover, microglia cells play a critical role in synaptic regeneration by encouraging the release of neuroprotective factors.These results have anticipated the mutual relationship between T2DM and PD; in particular, T2DM could be a risk factor in the development of PD Figure .3Inflammatory signalling pathways mediated by the nuclear factor kappa B (NF‐κB), nod‐like receptor pyrin 3 (NLRP3) inflammasome and mitogen‐activated protein kinase (MAPK), as well as other signalling pathways, are involved in the pathogenesis of T2DM and PD.3.1NF‐κB is a DNA‐binding protein required for the transcription of many pro‐inflammatory cytokines and chemokines. NF‐κB plays a major role in coordinating the innate and adaptive immunity, cellular proliferation, apoptosis and development. NF‐κB is under the control of extracellular stimuli, it is inhibited by an inhibitor of κB (IκB) which sequesters NF‐κB in the cytosol and prevents its nuclear localisation.NF‐κB is involved in the early pathological events of T2DM.1–42 level in the CSF is reduced and not correlated with motor dysfunction in PD patients compared to the controls.1–42 level in the CSF is increased and correlated with the severity of PD. Nevertheless, Aβ1–42 inhibits BBB P‐glycoprotein through induction of NF‐κB with further reduction in the clearance of Aβ1–42.1–42 and α‐synuclein.On the other hand, NF‐κB is also involved in the pathogenesis of PD through the induction of inflammation‐mediated degeneration of dopaminergic neurons in the SN.Furthermore, dipeptidyl peptidase 4 (DPP4) inhibitors like vildagliptin reduce the expression of NF‐κB and the associated neuroinflammation, apoptosis, and oxidative stress in dopaminergic neurons of SN. DPP4 inhibitors also inhibit the expression of the RAGE, which act as a receptor for inflammatory S100/calgranulins and high mobility group box 1 (HMGB1), linking RAGE to both the consequences and causes of T2DM.Taken together, the NF‐κB signalling pathway which is activated in both PD and T2DM might be a possible link in the development of PD in T2DM patients Figure .3.2NLRP3 inflammasome is the nucleotide‐binding domain and the leucine‐rich repeat‐containing family and pyrin family which form a multiprotein complex. The main function of NLRP3 inflammasome is the activation of caspase‐1 and the consequent maturation of IL‐1β and IL‐18.Furthermore, the activated NLRP3 inflammasome promotes the development of IR and reduces glucose tolerance through modulation of gut microbiota and by increasing the expression of IL‐1β and IL‐18.Furthermore, an experimental study confirmed that the activation of the NLRP3 inflammasome leads to the propagation of vascular inflammation and pro‐inflammatory phenotype in diabetic mice.These findings indicated that the NLRP3 inflammasome is involved in the pathogenesis and complications of T2DM and targeting of NF‐κB and NLRP3 inflammasome signalling pathways by specific inhibitors could be effective in the management of T2DM Figure .On the other hand, the NLRP3 inflammasome is involved in the pathogenesis of PD.Furthermore, α‐synuclein plasma level which is a major constituent of Lewy bodies had been reported to be increased in PD patients compared to the healthy controls.Accordingly, the NLRP3 inflammasome could be a potential link between PD and T2DM. A previous study revealed that T2DM was associated with higher α‐synuclein plasma levels which induce systemic inflammation and can cross BBB with induction of neuroinflammation through activation of NLRP3 inflammasome.These findings indicate that T2DM‐induced hyperglycaemia promotes the activation of the NLRP3 inflammasome with the propagation of systemic inflammation and the development of neuroinflammation and subsequent degeneration of dopaminergic neurons in the SN Figure .Taken together, activation of the NF‐κB/NLRP3 inflammasome axis in T2DM patients could be the causal pathway for the development of PD. Targeting of this axis by anti‐inflammatory agents may prevent or attenuate the development of PD in T2DM patients.3.3The inflammation process in the human body plays a central role in the pathogenesis of many chronic diseases including T2DM and PD.4through AMP‐activated protein kinase (AMPK) activation, as well as prevent neurodegeneration and neuroinflammation.Targeting peripheral inflammation and neuroinflammation is integral in the attenuation of neurological complications including the development and progression of PD in T2DM. A cohort study on 64,166 T2DM and non‐T2DM patients on sulfonylureas alone or in combination with metformin followed for the development of PD showed that PD was increased by 2.2‐fold in T2DM, and sulfonylureas increased this risk by 57% which eliminated by combination with metformin.Furthermore, DPP4 inhibitors like sitagliptin are commonly used in the management of T2DM and can reduce the propagation of neuroinflammation in different neurodegenerative disorders like AD and PD.These observations proposed that antidiabetic agents can mitigate inflammatory disorders which are implicated in the pathogenesis of PD.5PD is one of the most common neurodegenerative disease due to the degeneration of dopaminergic neurons in the SN. Genetic predisposition and immune dysfunction are involved in the pathogenesis of PD. Besides, T2DM is linked with inflammatory disorders due to hyperglycaemia‐induced oxidative stress and the release of pro‐inflammatory cytokines. Therefore, T2DM may increase PD risk through the activation of inflammatory signaling pathways including NF‐κB and the NLRP3 inflammasome which impair insulin signaling and increase the risk for the development of brain IR a hallmark of PD neuropathology. Taken together, NF‐κB/NLRP3 inflammasome axis could be the causal pathway in the development of PD in T2DM patients. Targeting of this axis by anti‐inflammatory agents may prevent the development of PD in T2DM patients.6Targeting the inflammatory signaling pathways including NF‐κB and the NLRP3 inflammasome in T2DM patients may reduce future PD risk. A recent study observed that insulin‐sensitising drug metformin improves glucose homeostasis by inhibiting the central and peripheral NF‐κB and the NLRP3 inflammasome signaling pathways.Mohammed Alrouji: Validation ; visualization . Hayder M. Al‐kuraishy: Conceptualization ; writing – original draft . Ali I. Al‐Gareeb: Conceptualization ; writing – original draft . Athanasios Alexiou: Writing – review and editing . Marios Papadakis: Supervision ; writing – review and editing . Majid S. Jabir: Writing – review and editing . Hebatallah M. Saad: Project administration ; writing – review and editing . Gaber El‐Saber Batiha: Writing – review and editing .7This work was supported by the University of Witten‐Herdecke Germany.The authors declare no conflict of interest.


In Table 2 and eTable 3 in Supplement 1, the units for penicillin should have been micrograms per milliliter. This article has been corrected.1In the Consensus Statement titled “Guidelines for Diagnosis and Management of Infective Endocarditis in Adults: A WikiGuidelines Group Consensus Statement,”


Experimental and numerical approaches revealed the self-assembly pathway where the cyclization step to form the triangular complex is blocked by dcb–. It was also found that one of the molecular squares assembled into a dimeric structure owing to the solvophobic effect, which was characterized by nuclear magnetic resonance spectroscopy and single-crystal X-ray analysis.Pathway selection principles in reversible reaction networks such as molecular self-assembly have not been established yet, because achieving kinetic control in reversible reaction networks is more complicated than in irreversible ones. In this study, we discovered that coordination squares consisting of  4L4 coordination squares consisting of cis-protected Rh(II) corner sites and linear ditopic ligands under kinetic control, preventing the formation of triangles by modulating the energy landscape with use of a leaving ligand.Achieving kinetic control over reversible self-assembly processes remains challenging. Here, the authors assemble Rh One of the reasons why such a sequential assembly process is adopted is because the formation of undesired assemblies whose structures are far from the desired one is efficiently prevented in the assembly process. If there exist some other assemblies with similar thermodynamic stabilities, selective assembly of the desired one under thermodynamic control is impossible. In such cases, pathway selection under kinetic control is inevitable, but the general principles of pathway selection in complicated reversible reaction networks have yet to be fully understood3.Pathway-dependent molecular self-assembly has often been seen in the realm of nature, especially in the multicomponent self-assembly of viruses24. Thanks to the L–M–L bond angle of 90° around transition metal ions with octahedral and square planer coordination spheres, upon complexation with linear ditopic ligands, square complexes are expected to be thermodynamically most stable over other polygonal structures. However, in many cases triangular complexes were coproduced in solution even using rigid linear ditopic ligands as the side of the polygons, although triangles are geometrically largely different from squares45. Therefore, the selective formation of molecular squares and the understanding of their origin remain challenging in supramolecular chemistry46.Molecular square is one of the most representative molecular architectures in coordination self-assembly55. Our understanding of the energy landscapes of molecular self-assembly is not as thorough as we can rationally design them, and to the best of our knowledge, there is no report on the selective formation of a triangular or square complex under kinetic control.Under the condition where the energy barriers between square and triangular compounds are relatively high, there is a chance to produce the square in a higher yield than that obtained at equilibrium, kinetically preventing the triangle. Such a kinetic approach is quite limited in artificial molecular self-assembly, except for unexpected observations of kinetic trapsRh4L4 squares in solution under kinetic control, perfectly preventing the formation of the Rh3L3 triangle using a designed monotopic carboxylate as the leaving ligand  complexes.Here, we report the self-assembly of the cis-protected dinuclear Rh(II) complexes (Rh2+: [Rh2(DAniF)2]2+56 and [Rh2(O2C-R-CO2)]2+57) and linear dicarboxylates (L2–) were selectively obtained in crystalline states57. As Rh(II)–carboxylate coordination bonds in dinuclear Rh(II) complexes are relatively strong, the reversibility of the coordination bond is low58, which would allow the self-assembly of the Rh4L4 squares to proceed under kinetic control. Thus, we were interested in why the Rh4L4 squares were selectively produced in the solid state in the previous research.Cotton and his co-workers and others reported that molecular squares composed of Rh(CH3CN)4](BF4)2 and 12– in CH3CN ([12–] = 10 mM) according to the literature56. Dark red solid precipitated in 1 day. Its 1H NMR spectrum in CDCl3 showed two prominent singlet signals of Hd 3 at 298 K ([12–] = 1.0 mM), where precipitation did not occur during the self-assembly, resulting in a mixture of Rh313 and Rh414 in a 1:2 ratio 4](BF4)2 and another ditopic ligand (22–) in CDCl3 gave the triangular and square complexes in a 1:2 ratio 4]2+ and the linear ditopic ligands (L2–) at room temperature gave a mixture of a molecular square (major) and a triangle (minor) in solution, and the Rh414 square was selectively crystallized from the mixture.To investigate the solution process, self-assembly was performed in CDCltio Fig. . SimilarRh-based self-assembly. 2,6-Dichlorobenzoate (dcb–) was chosen as the leaving ligand 60 is lower than that of benzoic acid (4.21), the coordination ability of dcb– is lower than those of the ditopic ligands (L2–), suggesting that dcb– can act as a leaving ligand. To test the potential of dcb– as a leaving ligand, the ligand exchange of dcb– in Rh(dcb)2 with p-toluate (tol–) in CDCl3 was monitored by 1H NMR spectroscopy 2 in 82% yield 2 and L2– (12– and 22–) in CDCl3 at 298 K was monitored by 1H NMR spectroscopy 63. Basically, it is difficult to obtain information about intermediates in molecular self-assembly, because most of intermediates are unobservable. Indeed, only small minor signals for intermediates were observed by 1H NMR spectroscopy during the self-assembly of the Rh4L4 squares  and Pt(II) ions.We were interested in why the res Fig. . In suchRh(dcb)2 and L2–) and the products (Rh4L4 and dcb–) were quantified by 1H NMR spectroscopy  c (a–c are 0 or positive integer), which is indicated as  for simplicity. The  values of RhaLb(dcb)c are defined as n = (2a – c)/b and k = a/b63. The n value indicates the average number of Rh2+ bound to a single ditopic ligand, L2– . The k value indicates the ratio of Rh2+ against L2–. The experimentally obtained  values, which is indicated as , are calculated for the average composition of all intermediates (Rha〉〈Lb〉〈(dcb)c〉〈), whose time-development was used for the discussion on the self-assembly process  Fig. . The speess Fig. .Fig. 3Se65. The  values of the three types of oligomers are distinctly plotted on different straight lines in the n-k map  values become close to , which is the  value of the cyclic structures (triangle and square). Thus, the  plot enables us to discuss which type of oligomers was mainly produced and how large the chain-like oligomers grew during self-assembly.There are three types of chain intermediates classified according to the difference in the terminals (Types I–III) Fig. 64,65. Thmap Fig. . With anRh414 square, the 〈n〉 value was smaller than 1 at an early stage , so further analysis could not be performed  were set to almost zero, which is consistent with the experimental result that the 1H NMR signals of Rh323 did not appear during the self-assembly Rh424 was numerically simulated in the reaction network, which enabled us to determine the major self-assembly pathway. The top 10 elementary reactions with high net frequencies are listed in Supplementary Table 67. Connecting the elementary reactions with the highest net reaction frequency from Rh424 to the substrates resulted in the dominant self-assembly pathways 1, which is indicated as   Fig. .68.The change in the existence ratios of the intermediates in the major self-assembly pathway shows that the existence of  is much smaller than that of the other intermediates  the cyclization of  to form  by breaking the coordination bond between Rh(II) and the leaving ligand (CH3CN or dcb–)  (x ≥ 0), by breaking a Rh–L coordination bond  (x ≥ 0) should be prevented either using Rh(dcb)2 or [Rh(CH3CN)4]2+. In addition, when dcb– is the leaving ligand, the cyclization of  to form  should be prevented. In other words, the cyclization of Rh3L3(CH3CN)2 occurs, while that of Rh3L3(dcb) is kinetically blocked.Next, we discuss why the pathways to the b–) Fig. , left anond Fig. , right. 70, triangular formation should take place by the attack of the terminal non-coordinated carboxylate group of L to the axial site of a Rh(II) center in Type II intermediates .Considering the associative ligand exchange mechanism of Rh(II)–carboxylate bondstes Fig. . The insRh313 and Rh414 in CDCl3 at 60 °C did not show any change of their ratio  at 100 °C for 2 days 2 and the ditopic ligand). The idea that the selective self-assembly of the Rh4L4 squares took place by the conversion of the Rh3L3 triangles into the Rh4L4 squares by the catalytic effect of dcb– during the self-assembly is ruled out by the fact that the signals of the Rh3L3 triangles were not observed during the self-assembly -carboxylate bonds, the ligand exchange is expected to be facilitated by monotopic carboxylate with weak coordination ability such as dcbopy Fig. . The sigRh414 was dissolved in CD3NO2/CDCl3 (9:1 (v/v))  suggests the aggregation of the square 4]2 dimer -based assemblies are neutral molecules, which is largely different from other positively or negatively charged coordination assemblies with counter ions. One of the advantages of neutral coordination assemblies is that they can be assembled into higher order structure without electrostatic repulsion between themselves, leading to a closely packed structure in the crystalline state and in solution. A new set of signals appeared when v)) Fig. . A similare Fig. . All sigmer Fig.  obtainedRh414)2 dimer in CD3NO2/CDCl3 (9:1 (v/v)) was characterized by 1H DOSY, -COSY, and -NOESY spectroscopy  and Hd(in) protons in the NOESY spectrum  and the dimer ((Rh414)2) shifted toward the dimer with an increase in the composition ratio of CD3NO2/CDCl3 2 is estimated to be higher than 107 M–1 under the assumption that 10% monomer exists , which prevents the cyclization of the Rh3L3(dcb) chain intermediate. This is the first example of the selective formation of coordination squares under kinetic control in solution. The metastable yet kinetically highly stabilized Rh3L3 triangles can be transformed into the Rh4L4 squares with dcb– under very mild conditions. These results indicate that the energy landscape of the dinuclear Rh(II)-based coordination self-assembly can be tuned by the leaving ligand. This basic knowledge can be applied to a wide range of Rh(II)-based metal-organic polyhedra (MOPs)73, whose self-assembly is limited compared with MOPs composed of other transition metal ions owing to the relatively inert equatorial Rh(II)–carboxylate bonds. Because Rh(II)-based MOPs possess high thermal and chemical stabilities and catalytic activity, they are expected as a platform for new materials, so exploring the novel structures of Rh(II)-based MOPs and their efficient self-assembly by modulating the energy landscapes will make a great progress in this field.In conclusion, the self-assembly of the 1H NMR spectra were recorded using a Bruker AV-500 (500 MHz) spectrometer. All 1H NMR spectra were referenced using a residual solvent peak, CDCl3 (δ 7.26), acetone-d6 (δ 2.05), CD3NO2 (δ 4.33). Electrospray ionization time-of-flight (ESI-TOF) mass spectra were obtained using a Waters Xevo G2-S Tof mass spectrometer.Rh(CH3CN)4](BF4)2 (Rh: Rh2(DAniF)2, DAniF: N,N′-bis(4-methoxyphenyl)formamidinate)74 was prepared according to the literature. The 1H and 13C{1H} NMR spectra of all substrates are available in Supplementary Data Rh(dcb)2 was prepared by mixing [Rh(CH3CN)4](BF4)2 and n-Bu4N·dcb in a 1:2 ration in NMR tube at 298 K and were used for the self-assembly after the quantification based on the internal standard ([2.2]paracyclophane). See more detail in section “Monitoring of the self-assembly of the Rh4L4 squares”.Unless otherwise noted, all solvents and reagents were obtained from commercial suppliers  and were used as received. Deuterated solvents were used after dehydration with Molecular Sieves 4 Å. paracyclophane by 1H NMR. A solution of ditopic ligand (n-Bu4N)2·L  in CDCl3 (200 μL) and CDCl3 (250 μL) were added to tube II and the exact amount of L2– in tube II was determined through the comparison of the signal intensity with [2.2]paracyclophane by 1H NMR. Then, 1.0 eq. (against the amount of ligand L2– in tube II) of solution A  was added to tube II. The self-assembly of the Rh4L4 square was monitored at 298 K by 1H NMR spectroscopy. The selected 1H NMR spectra measure during the self-assembly are shown in Fig. 12–]0 = 1.0 mM and [22–]0 = 0.86 mM). The amounts and the existence ratios of L2–, Rh(dcb)2, the Rh4L4 square, and dcb– were quantified by the integral value of each 1H NMR signal against the signal of the internal standard ([2.2]paracyclophane) according to the determination methodology described in the section “Determination of the existence ratios of each species”. The data, the average values of the existence ratios, and the  values with standard errors are listed in Supplementary Tables Rh414 and Rh424 squares, respectively.A 2.4 mM solution of [2.2]paracyclophane in CHCl3 25 μL, wh1H NMR signal against the internal standard [2.2]paracyclophane is used as the integral value in this description. We define the integral values of the signal for the substrates and the products at each time t as follows:The relative integral value of each IL(t): 1/4 of the integral value of the d proton in free ligand 12–IM(t): 1/2 of the integral value of the e proton of dcb– in Rh(dcb)2I440(t): 1/4 of the integral value of the d proton in the Rh414 squareIdcb(t): the integral value of the f proton of free dcb– (before 1 h) or 1/2 of the integral value of the e proton of free dcb– (after 1 h)IL(t): 1/4 of the integral value of the e proton in free ligand 22–IM(t): 1/2 of the integral value of the f proton of dcb– in Rh(dcb)2I440(t): 1/4 of the integral value of the d proton in the Rh424 squareIdcb(t): the integral value of the g proton of free dcb–IM(0) was determined based on the exact concentration of solution A determined by 1H NMR and the exact volume of solution A added into tube II.IL(0) was determined by 1H NMR measurement before the addition of solution A into tube II.Rh(dcb)2 corresponds to IM(0), the existence ratio of Rh(dcb)2 at t is expressed by IM(t)/IM(0).As the total  amount of 2– corresponds to IL(0), the existence ratio of L2– at t is expressed by IL(t)/IL(0).As the total amount of free ligand LRh4L4 square is quantified based on L2–, the existence ratio of the Rh4L4 square at t is expressed by I440(t)/IL(0).As the total amount of the – corresponds to IM(0), the existence ratio of dcb– at t is expressed by Idcb(t)/IM(0).As the total amount of dcb1H NMR (Int) is determined based on the amount of L2– in Int. Thus, the existence ratio of Int is calculated by subtracting the other species containing L2–  from the total amount of L2– (IL(0)). The existence ratio of Int at t is expressed by (IL(0) – IL(t) – I440(t))/IL(0).The existence ratio of the total intermediates not observed by 〈a〉Rh centers corresponds to IM(0)/2.The initial amount of Rh centers in Rh(dcb)2 at t corresponds to IM(t)/2.The amount of Rh centers in the Rh4L4 square at t corresponds to I440(t).The amount of Rh centers in Int at t is thus expressed by IM(0)/2 – IM(t)/2 – I440(t).The amount of 〈b〉2– corresponds to IL(0).The initial amount of L2– at t corresponds to IL(t).The amount of free L2– in the Rh4L4 square at t corresponds to I440(t).The amount of L2– in Int at t is thus expressed by IL(0) – IL(t) – I440(t).The amount of L〈c〉– corresponds to IM(0).The total amount of dcb– at t corresponds to Idcb(t).The amount of free dcb– in Rh(dcb)2 at t corresponds to IM(t).The amount of dcb– in Int at t is thus expressed by IM(0) – Idcb(t) – IM(t).The amount of dcbn〉 and 〈k〉 values are determined with these 〈a〉, 〈b〉, and 〈c〉 values by Eqs. (The 〈 by Eqs.  and 2)..n〉 and 〈Rh4L4 square from RhX2 (X: the leaving ligand) and L2– (22–) is constructed as follows. Starting from the substrates, that is, RhX2 and L2–, the reaction path is traced to form the possible intermediate chemical species with up to ten ditopic ligands (L2–). In this network, the Rh3L3 triangle is also considered as intermediate species. With these procedures taken, it is found that the total of 34 molecular species (including both the substrates and the product themselves) construct a reaction network composed of 1,698 elementary reactions. It should be noted that some of those reactions have the forward and backward processes (see the classification of the reaction type given below). All the intermediates considered in this network model and a simplified reaction network are shown in Supplementary Fig. For the numerical analysis of self-assembly process (NASAP), a reaction network for the self-assembly of the This reaction network turns out to be so large that it is impossible to assign an individual rate constant to each reaction and to search for the parameter in such a vast parameter space to fit the experimental results best. Therefore, we divided the whole elementary reactions into ten classes possessing similar characteristics and defined rate constants as follows:2– by RhX2 with releasing a leaving ligand X.i. Incorporation of free Lk1 [min–1 M–1] and k–1 [min–1 M–1] for forward and backward reactions, respectively.RhX2 and the second site of L2–, whose opposite site is already bonded with another Rh.ii. Reaction of k2 [min–1 M–1] and k–2 [min–1 M–1].2– and the second site of Rh, which is already coordinated by another L2–.iii. Reaction of free Lk3 [min–1 M–1] and k–3 [min–1 M–1].2– and Rh, both of whose other sites are already bonded with Rh and L2–, respectively.iv. Reaction at the second sites of Lk4 [min–1 M–1] and k–4 [min–1 M–1].v. L-L exchange reaction. This reaction can lead to both the growth and the decomposition of oligomers, or produce no net change in the reaction system.k5 [min–1 M–1].vi. Cyclization to make a square via L-X exchange.k6 [min–1] and k–6 [min–1 M–1].vii. Cyclization to make a square via L-L exchange.k7 [min–1] and k–7 [min–1 M–1].viii. Cyclization to make a triangle via L-X exchange.k8 [min–1] and k–8 [min–1 M–1].ix. Cyclization to make a triangle via L-L exchange.k9 [min–1] and k–9 [min–1 M–1].x. X-X exchange, which practically produces no change in the reaction system.k10 [min–1 M–1].RhX2 and L2– to produce [RhLX]– and X, the rate constant is given as k1 times 2 (the number of Rh–X bonds in RhX2) times 2 (the number of coordination sites in L2–), i.e.,Typical examples of each type of elementary reaction are shown in Supplementary Fig. It was adopted this setting to explicitly distinguish the structural difference among the species with the same composition.n〉, 〈k〉) values, we have adopted a stochastic approach based on the chemical master equation, the so-called Gillespie algorithm. In this algorithm, for all the possible N chemical reactions including molecular species Sai, Sbi, Sci, …,Rtot is calculated asIn order to numerically track the time evolution of the existence ratios for both reactants and products and the  asStarting from the initial time if if if s2 ∈  is independently given to fix the time incremental dt asAnother uniform random number t = t + dt, together with the update of the numbers of corresponding molecular species, i.e., 〈Sai〉 → 〈Sai〉 – 1, 〈Sbi〉 → 〈Sbi〉 – 1, 〈Sci〉 → 〈Sci〉 + 1, …. The reason why this approach traces the chemical reactions and actually works well is given in the literature in detail, along with the practical way to implement it78.Time is updated as The program for fixing the rate constant values is handmade for only this purpose. In order to obtain one of the best parameter sets, the following practical procedures are taken:ki = 10 mi. Starting from the initial guess value for each mi, time evolutions of the global self-assembly event are traced with giving each mi a stepwise increment or decrement, searching for smaller values of the residual sum of squares (RSS) for the experimental data at hand.First, the rate constant sets are defined in the form of m1, m2, m3, …) = . In another guess, rate constants for the oligomerization are given 10 to 100 times larger values than others by intention, for the reason that those reactions  generally occur very fast at the initial stage of the global self-assembly.Initial guess sets are given in several different ways for exploring as broad parameter space as possible. An example is the uniform one like . The Avogadro number and the volume of the simulation box were set to be NA = 6.0 × 1023 and V = 2.5 × 10–17 L, respectively, which give the same concentration as the experiments were carried out under [22–]0 = [Rh]0 = 0.86 mM.With the initial conditions (numbers of species), 〈1H NMR signals of the Rh3L3 triangle were not observed during the self-assembly  should be zero. Indeed, any good parameter set of the rate constants with large k8 and k9 was not found.Because n〉, 〈k〉) plot in good agreement with the experimental counterparts. The adequacy of the fitting to the experimental data was evaluated from the residual sum of squares (RSS) with the average of the experimental data, obtained from three runs. For all the time steps ti at which the experimental data of existence ratios RexS and parameters nave and kave are available, RSS’s are calculated with the numerically obtained values RnuS as ,After the rate constant search was finished, refined simulations were performed for some rate parameter sets that give existence ratios and the  of each elementary reaction in the course of the self-assembly process. Therefore, the dominant reaction pathway as shown in Fig. The advantage of using the reaction frequency is that the main intermediates participating in the dominant self-assembly pathway are not missed with the reason of the existence ratio being small due to high reaction rate values associated with that species. For example, the existence ratio of 4,4,1) is very low compared with other Type II intermediates . Diffraction data of the single crystal were collected on a VariMax Dual single crystal X-ray diffractometer with PILATUS 200 K detector (Rigaku Corporation) at 93(2) K, using Mo Kα (λ = 0.71073 Å) radiation monochromated by multilayer mirror optics. Bragg spots were integrated using the CrysAlisPro program package (Rigaku Corporation). An empirical absorption correction based on the multi-scan method using spherical harmonics was implemented in the SCALE3 ABSPACK scaling algorithm. The structure was solved by an intrinsic phasing method on the SHELXT program79 and refined by a full-matrix least-squares minimization on F2 executed by the SHELXL program80, using Olex2 software package (OlexSys Ltd)81. Thermal displacement parameters were refined anisotropically for all non-hydrogen atoms. All the hydrogen atoms except for those on C70, C100, C137, C145 of terminal methoxy groups were located at calculated positions and the parameters were refined with a riding model. The data were corrected for disordered electron density of crystal solvents in void spaces by using the PLATON SQUEEZE method82. The crystal structure is shown in Fig. Rh414(dmso-S)4]2 are summarized in Supplementary Table A single crystal was immersed in and coated with perfluoropolyalkylether , and then mounted on a MicroMountKα λ = 0.1073 Å raPeer Review FileSupplementary InformationDescription of additional supplementary filesSupplementary data 1Supplementary data 2


The experimental and theoretical analysis demonstrate that the highly stable polyhedral framework, composed of Fe—O octahedrons and M—O tetrahedrons, provides a highly effective air catalytic activity and long‐term stability, and meanwhile keeps good structural stability. The FeMoO electrode delivers a cycle life of over 1800 h by applying a simple half‐sealed condition in ambient air. It is found that surface‐rich Fe vacancy can act as an O2 pump to accelerate the catalytic reaction. Furthermore, the FeMoO catalyst exhibits a superior catalytic capability for the decomposition of Li2CO3. H2O in the air can be regarded as the main contribution to the anode corrosion and the deterioration of LAB cells could be attributed to the formation of LiOH·H2O at the end of cycling. The present work provides in‐depth insights to understand the catalytic mechanism in air and constitutes a conceptual breakthrough in catalyst design for efficient cell structure in practical LABs.Lithium–air batteries (LABs), owing to their ultrahigh theoretical energy density, are recognized as one of the next‐generation energy storage techniques. However, it remains a tricky problem to find highly active cathode catalyst operating within ambient air. In this contribution, a highly active Fe 2Mo3O12 cathode catalyst with a highly stable polyhedral framework and efficient capability for the formation and decomposition of Li2O2 and Li2CO3 boosts the performance of Li–air batteries.Garnet type Fe All the studies reported so far, however, can deliver a satisfactory performance only in a pure O2 or simulated air atmosphere. Under the assistance of electrolytes such as ionic liquid‐based electrolytes, and liquid‐based cathode catalysts like InX3/MoS2, TEMPO/MoP, and LiI/CNT, a well‐constructed LABs cell can show compelling cycle performances. It is suggested that the 2D MoS2, as a solid cathode catalyst, could deliver a good electrochemical performance in an air‐like atmosphere using an ionic liquid‐based electrolyte and Li2CO3‐protected Li anode. Nevertheless, the presence of H2O, CO2, and a pretty low content of O2 in open air would lead to the formation of various discharge products including low‐ or un‐conductive Li2O2, Li2CO3, LiOH, etc. Therefore, the cathode catalyst applied in practical LABs in air atmosphere must possess multiple catalytic capabilities for the formation/decomposition of complex discharge products but not only Li2O2. However, a high‐performance cathode catalyst in the open air without systemic assistance still remains a pivotal challenge for LABs, predominantly owing to limitations in the low catalytic reaction kinetics and chemical selectivity toward multiple discharge products.Based on the formation/decomposition of lithium peroxide (Ligasoline.1 All 2(MoO4)3 (FeMoO) was used as a cathode catalyst for LAB. Its high LABs performance only depends on the high catalytic capability in air without the treatments of electrolyte, liquid‐based cathode catalyst, gas selective film, and protective lithium anode. Here, we report a highly active garnet Fe2(MoO4)3 (FeMoO) as a cathode catalyst for LABs operating in the ambient air. Density functional theory (DFT) calculations combined with experimental measurements demonstrated that the highly stable polyhedral framework can boost the catalytic capability in air and maintain the vacancy‐concentrated surface structure during cycling thus leading to impressive electrochemical stability. In addition, a simple half‐sealed testing condition was applied to delay the volatilization of electrolytes and diffusion of H2O in the open air, and we found that the death of LABs cells can be mainly attributed to the corrosion of the Li anode, in which no modification has been made. The FeMoO electrode with a cationic vacancy concentrated surface can last for over 1800 h at a low current density of 200 mA g−1 without any degradation, and deliver a cycle stability for over 290 cycles at a high current density of 500 mA g−1 with a limited capacity of 600 mAh g−1 in ambient air. It was revealed that the surface of the Li anode gradually transformed to LiOH during cycling and the formation of LiOH·H2O at the end of cycling caused a sudden soar in the charge potential, which results in the death of the LABs. The dominant discharge product is amorphous Li2−xO2, which is preferentially generated on the Mo‐concentrated surface with a high Fe vacancy concentration. The instability of Li2O2 on Fe vacancy led to the decomposition of the discharge product and can act as an O2 pump to accelerate the catalytic reaction in the air. In addition, even though the side product Li2CO3 is confirmed to be formed through a second reaction between Li2O2 and CO2, the high catalytic capability for the decomposition of Li2CO3 in the FeMoO electrode is observed and demonstrated.In this work, we reported a conceptual breakthrough for highly active cathode catalysts of LABs. Garnet Fe22(MoO4)3 with A3B2(CO4)3 garnet‐type structure as the cathode catalyst for LABs, in which Fe ions occupy the octahedral B sites and Mo ions occupy the tetrahedral C sites as shown in Figure  All the tetrahedra and octahedra are isolated from each other but form into a stable polyhedral frame by corner‐sharing with an oxygen anion. The electron density of state (DOS) of bulk FeMoO garnet in Figure 6 octahedra at the Fermi level enhances the electron transport between MoO4 tetrahedral nodes. Figure 2O2 on the different planes of FeMoO garnet. The up‐spin polarized d‐band center of Fe—Mo on (202) facets  is the most positive with a strong bonding with Li2O2. The up‐spin polarized d‐band center is still the highest after the initial bonding with Li2O2, demonstrating the potential catalytic capability in LABs.In this work, we selected Fen Figure 6 All 2(MoO4)3 (PDF No. 83‐1701), and the selected area electron diffraction (SAED) in Figure 2 g−1, respectively, measured by the Brunauer–Emmett–Teller (BET) method as shown in Figure The FeMoO garnet catalyst was fabricated using an electrospinning strategy coupled with annealing 3 garnet without any impurity phases for all the samples. The Raman spectra  was applied to identify the surface condition of the FeMoO catalysts. From the survey XPS spectra  and few oxygen vacancy (531.3 eV) existed on the surface of the FeMoO particles as observed from the high‐resolution XPS spectra of Mo, Fe, and O  was detected for the Mo occupying tetrahedral sites . It has been demonstrated that oxygen vacancies formed when annealed at reducing atmosphere, and cationic vacancy usually formed at oxidizing atmosphere for oxide particles. The oxidizing atmosphere will lead to the re‐orientation of oxide particles at high temperature and create cationic vacancy on the surface. In this work, the FeMoO catalyst was calcined in air, and Mo site maintained the stable Mo6+ valance state and the existence of Fe2+ was identified by the XPS spectra, furthermore, the Mo/Fe ratio changed to about 4:1 to form a Mo concentrated surface for the FeMoO‐600 sample. As a result, Fe vacancy was created on the surface of FeMoO catalyst. These results indicated that the FeMoO catalyst calcined at a high temperature exhibited high crystallinity as well as a Fe vacancy concentrated surface, which in turn delivered the best performance of LABs.From the powder X‐ray diffraction .7 It h−2. The humidity of the test environment ranged from 10% to 25% as shown in Figure The electrochemical performance of the FeMoO garnet as potential LABs cathode catalysts are explored using the CR2032‐type coin cells with a lithium plate as the counter electrode. The air electrode consists of FeMoO catalyst, Ketjen Black (KB), and polytetrafluoroethylene (PTFE) binder with a mass ratio of 4:4:2. The average loading mass of the active materials on an air electrode is 1.0 mg cmFigure −1 and 157 cycles at 500 mA g−1  in air atmosphere. By using the half‐sealed air test condition, the FeMoO‐600 electrode exhibited excellent cycle stability of 298 cycles  at 2.8 V and the oxygen evolution reaction (OER) at 3.12 and 3.75 V, and the integral areas of the CV curves indicated that the half‐sealed air condition did not influence the catalytic capability and reaction kinetics of the FeMoO electrode compared to those in open air. As shown in Figure −1 with a cutoff voltage window of 2.35–4.7 V at 200, 500, 800, and 1000 mA g−1 in half‐sealed air with the Coulombic efficiencies of 99.57%, 97.02%, 93.49%, and 97.45%, respectively, and the discharge potential of 2.5 V is similar to those in O2  of the FeMoO‐600 electrode changed slightly from the pristine 39 to 52 Ω after CV cycles in half‐sealed air, which is similar to that in O2 (from the pristine 44.8 to 66 Ω) and open air (from the pristine 37.7 to 45.2 Ω). These results indicated that there is no influence on the catalytic capacity of the FeMoO catalysts in different air test conditions. The different Rct values of the FeMoO electrode tested in air and O2 should be attributed to the different composition and morphology of the discharge products.Figure Figure 2O2 and other possible side products (Li2CO3 and LiOH) were identified at the initial stage (600 mAh g−1). On the contrary, the diffraction peaks of Li2O2 were identified after full discharge. Furthermore, similar XRD results were obtained for the discharge products in open air and pure O2 , while the additional peak located at 55.07 eV is attributed to the formation of Li2O2. At the initial discharge stage (600 mAh g−1), the discharge products were mainly amorphous Li2−xO2 with few Li2O2, but no Li2CO3 and other side products were identified , the peak belonging to the Li2O2 became stronger indicating the conversion from Li2−xO2 to Li2O2, and the peak of Li2CO3 (55.5 eV) was identified when discharging to 2000 mAh g−1. From the high‐resolution XPS spectrum of C 1s  can be also observed at the same stage. It is suggested that the formation of Li2CO3 might be attributed to the second reaction between Li2O2 and CO2 (2Li2O2 + 2CO2 = 2Li2CO3 + O2). After recharging, the discharge products can be decomposed completely, meanwhile, the final discharge product before being fully charged was founded to be Li2−xO2 as shown in Figure 2CO3 formed during the discharging process, and the peak of Li2CO3 (1450 and 1497 cm−1) became stronger when discharge to 2000 mAh g−1, corresponding with the XPS analysis. Furthermore, when working for 230 cycles at 500 and 600 mAh g−1, the discharge products were mainly Li2−xO2 and Li2CO3  was assembled into a Li—CO2 cell and worked for 190 cycles at a current density of 500 mA g−1 with a limited capacity of 600 mAh g−1 showing excellent catalytic capability for the decomposition of Li2CO3. Li2CO3 is an unexpected main discharge product for the LABs. The formation of Li2CO3 mainly comes from the decomposition of electrolyte, side reactions between electrolyte and carbon additive, CO2 and discharge products. The formation of Li2CO3 will influence the catalytic reaction kinetics, the morphology of discharge products, and the overpotentials of LABs. Through the formation of Li2CO3, the decomposition of discharge products becomes complicated. Despite the decomposition of Li2O2, the decomposition of Li2CO3 can be proceeded through the direct decomposition, C2O62− Mediated, O2 evolution, CO32− electrooxidation, and carbon involved pathways. As a result, the formation of Li2CO3 is a mainly problem to develop high performance LABs. In this work, the FeMoO catalyst exhibited superior catalytic capability for the formation/decomposition of Li2CO3, as the Li—CO2 cell can stably worked over 190 cycles. The working mechanism for the formation/decomposition of Li2CO3 on FeMoO catalyst needs more investigation.The evolution of the discharge product on the FeMoO electrode was identified through XRD, XPS, and Fourier transform infrared (FT‐IR) measurements. From the XRD pattern in s Figure  of the dd Figure . After ts Figure , the pea3 Figure , indicat2O2  as the main lattice plane shows the lowest surface energy as indicated in Figure 2 formed prior at the high potential for all planes compared to Li2O2 (see the Supporting Information for a detailed description), indicating a single‐electron transfer process during the formation of Li2O2 on the surface of FeMoO catalyst. As a result, the fundamental three‐step reactions are constructed to evaluate the catalytic capability of the FeMoO garnet for the formation/decomposition of Li2O2DFT calculations are applied to gain insights into the catalytic activity of the FeMoO garnet structure. From the PDOS for the Fe and Mo nodes in the bulk FeMoO Figure , the FeMtrahedra.18 The2O2 on the Fe active sites between the MoO4 tetrahedra, in which the total overpotentials are 1.13 and 1.52 V, respectively. When the discharge products are extended to Li4O4, the overpotential of the (202) plane decreases to 1.16 V with a low reaction energy barrier for Li4O4* formation as shown in Figure 2O2. Meanwhile, the catalytic capability of the (022) plane decreases significantly with a total overpotential over 4 V, due to the potential control step shift from the generation of LiO2* to that of Li4O4* , (20−2), (40−2), and (202) are repulsive for O2. These results indicated that a refined catalytic reaction can be obtained on the surface of the FeMoO, in which the formation of discharge products will start from the adsorption of Li+. Notably, the FeMoO structure exhibits extremely high adsorption energies  and low adsorption strength for H2O (0 eV), indicating the poor reactivity for the formation of LiOH on the FeMoO surface in air. With high adsorption energies for CO2, the (202) facet can obtain strong CO2 redox activity for Li—CO2 batteries. From the charge density difference plots shown in Figure 2 part in LiO2 is almost dissociated from Li+ with little charge transfer when adsorbed on the (202) plane, indicating the unstable adsorption of superoxide species which can avoid the surface oxidation from strong oxidizing intermediate and limit the conversion from LiO2 to Li2O2 on the (202) surface. On the contrary, the Fe nodes of the (202) plane show enhanced chemical binding and charge transfer efficiency with Li2O2. These results might be associated with the formation of the amorphous Li2−xO2 discharge products identified in experiments, and the high stability of FeMoO garnet catalyst during cycling.Figure n of Li+.18 Nots Figure  for CO2 4 tetrahedra and an increase in unbonded electrons  obtained the best LABs performance. The catalytic capability of the (202) plane with a Fe vacancy is studied in response. After the generation of Fe vacancies, the adsorption energies of the reaction adsorbates exhibit an obvious increase due to a lack of coordination of bridge oxygen between the Fe and Mo node in the MoOm Figure , resulti2O2 on the (202) plane is shown in Figure 4 tetrahedron near the Fe site plays a critical role in the stable adsorption of the discharge products. Near the Fermi level, the Mo 4d and Fe 3d orbitals become more localized and stronger, especially for the Fe 3d orbitals exhibiting strong polarization, which is beneficial for the charge transfer between discharge products and active sites. Furthermore, as the presence of the Fe vacancy, Mo and the bridge oxygen connecting with the Fe site generate an electron‐rich state and the high‐level electronic states above the Fermi level increase leading to efficiency in adsorption and electron transfer for the reaction species.The PDOS after adsorption of Li32. The discharge products were mainly amorphous Li2−xO2 and Li2CO3 in an air atmosphere and the corrosion of Li anode influenced the cycle stability of the air electrode significantly. The instability nature of LiO2 and Li2O2 on Fe vacancy contributed to the formation of amorphous discharge products and accelerated the catalytic reaction kinetics. These findings revealed the underlying catalytic mechanism of LABs in an air atmosphere to close the knowledge gap between different discharge products derived from complex interface reactions and a facile way to find applicable catalysts in air electrodes. Furthermore, promising as the FeMoO garnet showed a very sound performance in air, this kind of low‐cost metal oxide cathode catalyst could be a potential stock for the commercial engineering design of LABs.In summary, the FeMoO garnet exhibited highly active catalytic capability as the cathode catalyst in LABs and delivered excellent cycle stability in air. Experimental and theoretical calculations demonstrated that the stable polyhedral framework composed by Fe—O octahedrons and M—O tetrahedrons in the garnet structure provides highly efficient air catalytic activity and stable surface conditions during cycling. We compared the reaction kinetics and electrocatalytic mechanism of the FeMoO garnet in air and pure O42(MoO4)3 was prepared via electrospinning as well as the proper calcination method. In brief, 1.5 g polyvinylpyrrolidone (PVP) was dissolved in 10 mL dimethylformamide at room temperature and stirred for 3 h. Meanwhile, 2 mL of acetic acid was added to the solution to adjust the pH. 0.47696 g FeCl2⋅4H2O and 0.63526 g (NH4)6Mo7O24⋅4H2O were weighed according to the ratio of Mo/Fe 3:2. The (NH4)6Mo7O24⋅4H2O was dissolved in 3 mL deionized water. Then the dissolved ammonium molybdate and ferrous chloride were added into the PVP solution, respectively and stir for 10–30 min to get a uniform and transparent red precursor sol. The voltage was set at 13 kV by the electrostatic spinning method and the pushing speed was 0.5 mm min−1. The obtained products were collected and dried at 60 °C for 24 h. Finally, they were calcined in the air atmosphere at 2 °C min−1 and different temperatures .All reagents used in the experiment were analytical grade and without further purification. Fe−2.The synthesized ferromolybdate material was used as a catalyst to prepare an oxygen electrode and test the electrochemical properties of the catalyst. The preparation process was as follows. A certain amount of iron molybdate catalyst, KB carbon, and polytetrafluoroethylene (PTFE) binder (4:4:2 by mass) was added to 3 mL of isopropanol to obtain the mixture under ultrasonication. The mixture was uniformly coated on carbon paper and dried under vacuum at 120 °C for 12 h. The loading mass of active materials was 1 mg cmm LiTIFSi/TEGDME as electrolyte. All cells were loaded into an argon‐filled  glove box at room temperature.The LAB point cell consists of an anode shell , prepared oxygen electrode , glass fiber diaphragm , lithium metal foil as the anode , spring plate , steel sheet , negative shell , and 1 α (λ = 1.540 Å) radiation. The morphologies were examined by FESEM (Regulus 8220) and further investigated with HR‐TEM . Raman spectroscopy was carried out with a Via Reflex instrument with an excitation laser of 532 nm. The specific surface area and pore size distribution were calculated through the N2 adsorption–desorption method by BET and Barrett–Joyner–Halenda with Micrometritics (ASAP 2420) apparatus. Simultaneously, high resolution XPS was carried out on an ESCALAB 250Xi spectrometer with an excitation source of Al Kα = 280.00 eV to detect the surface electronic states and element binding nature. The discharge products accumulated at the anode were characterized by FT‐IR (Nicolet iS 5 FT‐IR). To evaluate the changes in morphology and structure of electrode materials after the electrochemical tests, various characterizations were conducted. All tested cells were disassembled in the glove box after electrochemical measurement and sealed within a polyimide film to minimize the exposure time to the air.XRD (Rigaku D/Max‐r B) was conducted to investigate the phase structure with Cu‐K+/Li). The specific capacity and current density were calculated definitely according to the weight of loaded catalysts on carbon paper. The cyclic voltammetry (CV) was measured at a scan rate of 0.1 mV s−1 in the potential range of 2.35 to 4.7 V. The EIS was performed within the frequency range from 105 to 0.1 Hz. EIS was performed on a CHI660 electrochemical workstation.Li–air batteries were tested on a LAND CT2001A multi‐channel battery testing system with a cutoff voltage between 2.35 and 4.7 V (vs Li The projector augmented wave method was used to describe the electron–ion interaction. The electron exchange and correlation energy were treated by the Perdew–Burke–Ernzerhof function of the generalized gradient approximation. The cut‐off energy was set to 400 eV and a k‐point grid was generated by the gamma‐centered Monkhorst–Pack approach. The criterion of force relaxation and energy for structural relaxation were 0.02 eV Å−1 and 10−4 eV, respectively. Evaluation of van der Waals forces with DFT‐D3 dispersion correction for long‐range interactions. The vacuum layer was considered to be ≈15 Å on each side. Similar models and parameters were used in catalytic reaction calculations. Gibbs free energy and Bader charge analysis were also successfully applied. Due to large unit cells and low symmetry, all crystal planes calculated were not expanded.All data of calculation were obtained by Vienna ab initio simulation package based on DFT.20 TheThe authors declare no conflict of interest.Supporting InformationClick here for additional data file.