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Abstract The combination of cuproptosis and immune checkpoint inhibition has shown promise in treating malignant tumors. However, it remains a challenge to deliver copper ions and immune checkpoint inhibitors efficiently and simultaneously to tumors. Herein, a mitochondria‐targeted nanoscale coordination polymer particle, Cu/TI, comprising Cu(II), and a triphenylphosphonium conjugate of 5‐carboxy‐8‐hydroxyquinoline (TI), for effective cuproptosis induction and programmed cell death‐1 (PD‐L1) downregulation is reported. Upon systemic administration, Cu/TI efficiently accumulates in tumor tissues to induce immunogenic cancer cell death and reduce PD‐L1 expression. Consequently, Cu/TI promotes the intratumoral infiltration and activation of cytotoxic T lymphocytes to greatly inhibit tumor progression of colorectal carcinoma and triple‐negative breast cancer in mouse models without causing obvious side effects.

Abstract Benign prostatic hyperplasia (BPH) is a multifactorial disease in which abnormal growth factor activation and embryonic reawakening are considered important factors. Here we demonstrated that the aberrant activation of transforming growth factor β (TGF-β)/Rho kinase 1 (ROCK1) increased the stemness of BPH tissue by recruiting mesenchymal stem cells (MSCs), indicating the important role of embryonic reawakening in BPH. When TGF-β/ROCK1 is abnormally activated, MSCs are recruited and differentiate into fibroblasts/myofibroblasts, leading to prostate stromal hyperplasia. Further research showed that inhibition of ROCK1 activation suppressed MSC migration and their potential for stromal differentiation. Collectively, our findings suggest that abnormal activation of TGF-β/ROCK1 regulates stem cell lineage specificity, and the small molecule inhibitor GSK269962A could target ROCK1 and may be a potential treatment for BPH. Graphical Abstract

Metal-organic framework (MOF) materials, characterized by their porosity and large specific surface areas, exhibit excellent adsorption properties. With the aim of removing Te(IV) from environmental aquatic systems, this study is the first to propose the use of MIL-100(Fe). The material reveals a strong adsorption capacity for Te(IV), with maximum adsorption of 531.9 mg/g, superior to other adsorbent materials. Adsorption isotherm and kinetic models indicate that the adsorption process primarily involves monolayer chemical adsorption. According to the thermodynamic parameters, the adsorption reaction is endothermic. The experiment individually examined factors affecting the material's adsorption performance, including adsorbent dose, initial concentration of Te(IV), pH, adsorption time, and coexisting ions. Even under high ion strength conditions and high concentrations of coexisting ions, the material's adsorption efficiency for Te(IV) still reached over 94%. The material has been successfully applied to remove Te(IV) from lake water, river water, and seawater, yielding satisfactory results. Due to the high salinity and ionic strength of the solution, the removal efficiency of Te(IV) in the seawater matrix was slightly lower than that in freshwater (river and lake water). Thus, this material shows promise for the removal of Te(IV) from complex aquatic systems. HIGHLIGHTS MIL-100(Fe) was prepared and characterized.; The Te(IV) can be adsorbed by MIL-100(Fe) effectively, and the adsorption process was primarily a monolayer chemical adsorption and an endothermic reaction.; The Te(IV) can be removed effectively in environmental water supplies by MIL-100(Fe).;

Abstract Hydrogen spillover widely occurs in a variety of hydrogen-involved chemical and physical processes. Recently, metal–organic frameworks have been extensively explored for their integration with noble metals toward various hydrogen-related applications, however, the hydrogen spillover in metal/MOF composite structures remains largely elusive given the challenges of collecting direct evidence due to system complexity. Here we show an elaborate strategy of modular signal amplification to decouple the behavior of hydrogen spillover in each functional regime, enabling spectroscopic visualization for interfacial dynamic processes. Remarkably, we successfully depict a full picture for dynamic replenishment of surface hydrogen atoms under interfacial hydrogen spillover by quick-scanning extended X-ray absorption fine structure, in situ surface-enhanced Raman spectroscopy and ab initio molecular dynamics calculation. With interfacial hydrogen spillover, Pd/ZIF-8 catalyst shows unique alkyne semihydrogenation activity and selectivity for alkynes molecules. The methodology demonstrated in this study also provides a basis for further exploration of interfacial species migration.

ABSTRACTBenign prostatic hyperplasia (BPH) is a prevalent disease among middle-aged and elderly males, but its pathogenesis remains unclear. Dysbiosis of the microbiome is increasingly recognized as a significant factor in various human diseases. Prostate tissue also contains a unique microbiome, and its dysbiosis has been proposed to contribute to prostate diseases. Here, we obtained prostate tissues and preoperative catheterized urine from 24 BPH individuals, and 8 normal prostate samples as controls, which followed strict aseptic measures. Using metagenomic next-generation sequencing (mNGS), we found the disparities in the microbiome composition between normal and BPH tissues, with Pseudomonas significantly enriched in BPH tissues, as confirmed by fluorescence in situ hybridization (FISH). Additionally, we showed that the prostate microbiome differed from the urine microbiome. In vitro experiments revealed that lipopolysaccharide (LPS) of Pseudomonas activated NF-κB signalling, leading to inflammation, proliferation, and EMT processes, while inhibiting apoptosis in prostatic cells. Overall, our research determines the presence of microbiome dysbiosis in BPH, and suggests that Pseudomonas, as the dominant microflora, may promote the progression of BPH through LPS activation of NF-κB signalling.

Abstract The recent discovery of copper‐mediated and mitochondrion‐dependent cuproptosis has aroused strong interest in harnessing this novel mechanism of cell death for cancer therapy. Here the design of a core‐shell nanoparticle, CuP/Er, for the co‐delivery of copper (Cu) and erastin (Er) to cancer cells for synergistic cuproptosis and ferroptosis is reported. The anti‐Warburg effect of Er sensitizes tumor cells to Cu‐mediated cuproptosis, leading to irreparable mitochondrial damage by depleting glutathione and enhancing lipid peroxidation. CuP/Er induces strong immunogenic cell death, enhances antigen presentation, and upregulates programmed death‐ligand 1 expression. Consequently, CuP/Er promotes proliferation and infiltration of T cells, and when combined with immune checkpoint blockade, effectively reinvigorates T cells to mediate the regression of murine colon adenocarcinoma and triple‐negative breast cancer and prevent tumor metastasis. This study suggests a unique opportunity to synergize cuproptosis and ferroptosis with combination therapy nanoparticles to elicit strong antitumor effects and potentiate current cancer immunotherapies.

Introduction2-Amino-1-methyl-6-phenylimidazole [4,5-b] pyridine (PhIP), a heterocyclic amine (HAA), is found in meat products heated at high temperatures. However, PhIP is a mutagenic and potential carcinogenic compound. Cassiae semen, a type of medicine and food homology plant, is abundant in China and has been less applied for inhibiting heterocyclic amines.MethodsTo investigate the inhibitory effect of cassiae semen extract on PhIP formation within a model system and elucidate the inhibitory mechanism, an ultrasonic-assisted method with 70% ethanol was used to obtain cassiae semen extract, which was added to a model system (0.6 mmol of phenylalanine: creatinine, 1:1). PhIP was analyzed by LC–MS to determine inhibitory effect. The byproducts of the system and the mechanism of PhIP inhibition were verified by adding the extract to a model mixture of phenylacetaldehyde, phenylacetaldehyde and creatinine.ResultsThe results indicated that PhIP production decreased as the concentration of cassiae semen extract increased, and the highest inhibition rate was 91.9%. Byproduct (E), with a mass–charge ratio of m/z 199.9, was detected in the phenylalanine and creatinine model system but was not detected in the other systems. The cassiae semen extract may have reacted with phenylalanine to produce byproduct (E), which prevented the degradation of phenylalanine by the Strecker reaction to produce phenylacetaldehyde.DiscussionCassiae semen extract consumed phenylalanine, which is the precursor for PhIP, thus inhibiting the formation of phenylacetaldehyde and ultimately inhibiting PhIP formation. The main objective of this study was to elucidate the mechanism by which cassiae semen inhibit PhIP formation and establish a theoretical and scientific foundation for practical control measures.

Prostate adenocarcinoma (PRAD), driven by both genetic and epigenetic factors, is a common malignancy that affects men worldwide. We aimed to identify and characterize differentially expressed epigenetic-related genes (ERGs) in PRAD and investigate their potential roles in disease progression and prognosis. We used PRAD samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to identify prognosis-associated ERGs. Thirteen ERGs with two distinct expression profiles were identified through consensus clustering. Gene set variation analysis highlighted differences in pathway activities, particularly in the Hedgehog and Notch pathways. Higher epigenetic scores correlated with favorable prognosis and improved immunotherapeutic response. Experimental validation underscored the importance of CBX3 and KAT2A, suggesting their pivotal roles in PRAD. This study provides crucial insights into the epigenetic scoring approach and presents a promising prognostic tool, with CBX3 and KAT2A as key players. These findings pave the way for targeted and personalized interventions for the treatment of PRAD.

Herpesviruses, prevalent DNA viruses with a double-stranded structure, establish enduring infections and play a part in various diseases. Despite their deployment of multiple tactics to evade the immune system, both localized and systemic inflammatory responses are triggered by the innate immune system’s recognition of them. Recent progress has offered more profound understandings of the mechanisms behind the activation of the innate immune system by herpesviruses, specifically through inflammatory signaling. This process encompasses the initiation of an intracellular nucleoprotein complex, the inflammasome associated with inflammation.Following activation, proinflammatory cytokines such as IL-1β and IL-18 are released by the inflammasome, concurrently instigating a programmed pathway for cell death. Despite the structural resemblances between herpesviruses, the distinctive methods of inflammatory activation and the ensuing outcomes in diseases linked to the virus exhibit variations.The objective of this review is to emphasize both the similarities and differences in the mechanisms of inflammatory activation among herpesviruses, elucidating their significance in diseases resulting from these viral infections.Additionally, it identifies areas requiring further research to comprehensively grasp the impact of this crucial innate immune signaling pathway on the pathogenesis of these prevalent viruses.

Abstract Bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation and osteoblast function play critical roles in bone formation, which is a highly regulated process. Long noncoding RNAs (lncRNAs) perform diverse functions in a variety of biological processes, including BMSC osteogenic differentiation. Although several studies have reported that HOX transcript antisense RNA (HOTAIR) is involved in BMSC osteogenic differentiation, its effect on bone formation in vivo remains unclear. Here, by constructing transgenic mice with BMSC (Prx1-HOTAIR)- and osteoblast (Bglap-HOTAIR)-specific overexpression of HOTAIR, we found that Prx1-HOTAIR and Bglap-HOTAIR transgenic mice show different bone phenotypes in vivo. Specifically, Prx1-HOTAIR mice showed delayed bone formation, while Bglap-HOTAIR mice showed increased bone formation. HOTAIR inhibits BMSC osteogenic differentiation but promotes osteoblast function in vitro. Furthermore, we identified that HOTAIR is mainly located in the nucleus of BMSCs and in the cytoplasm of osteoblasts. HOTAIR displays a nucleocytoplasmic translocation pattern during BMSC osteogenic differentiation. We first identified that the RNA-binding protein human antigen R (HuR) is responsible for HOTAIR nucleocytoplasmic translocation. HOTAIR is essential for osteoblast function, and cytoplasmic HOTAIR binds to miR-214 and acts as a ceRNA to increase Atf4 protein levels and osteoblast function. Bglap-HOTAIR mice, but not Prx1-HOTAIR mice, showed alleviation of bone loss induced by unloading. This study reveals the importance of temporal and spatial regulation of HOTAIR in BMSC osteogenic differentiation and bone formation, which provides new insights into precise regulation as a target for bone loss.

Abstract Mechanical force loading is essential for maintaining bone homeostasis, and unloading exposure can lead to bone loss. Osteoclasts are the only bone resorbing cells and play a crucial role in bone remodeling. The molecular mechanisms underlying mechanical stimulation-induced changes in osteoclast function remain to be fully elucidated. Our previous research found Ca2+-activated Cl− channel Anoctamin 1 (Ano1) was an essential regulator for osteoclast function. Here, we report that Ano1 mediates osteoclast responses to mechanical stimulation. In vitro, osteoclast activities are obviously affected by mechanical stress, which is accompanied by the changes of Ano1 levels, intracellular Cl− concentration and Ca2+ downstream signaling. Ano1 knockout or calcium binding mutants blunts the response of osteoclast to mechanical stimulation. In vivo, Ano1 knockout in osteoclast blunts loading induced osteoclast inhibition and unloading induced bone loss and. These results demonstrate that Ano1 plays an important role in mechanical stimulation induced osteoclast activity changes.

Pufferfish is prone to deterioration due to abundant nutrients and high moisture content. Drying technology can extend the shelf life and enhance the flavor quality of aquatic products. The study investigated the effect of hot air drying (HAD), microwave vacuum drying (MVD) and hot air assisted radio frequency drying (HARFD) on the taste and volatile profiles of Takifugu obscurus. Different drying methods had significant influence on the color, rehydration, 5'-nucleotides, free amino acids and volatile components (P < 0.05). The results showed that HAD and HARFD could promote the flavor of T. obscurus by producing higher equivalent umami concentration (EUC) values, which were about two times of MVD group, and more pronounced pleasant odor according to sensory analysis. HAD is more appropriate for industrial application than HARFD and MVD considering the economic benefits. This study could provide a reference for the industrial application of drying T. obscurus.

IntroductionPapillomaviruses (PVs) can cause hyperplasia in the skin and mucous membranes of humans, mammals, and non-mammalian animals, and are a significant risk factor for cervical and genital cancers.MethodsUsing next-generation sequencing (NGS), we identified two novel strains of papillomavirus, PV-HMU-1 and PV-HMU-2, in swabs taken from belugas (Delphinapterus leucas) at Polar Ocean Parks in Qingdao and Dalian.ResultsWe amplified the complete genomes of both strains and screened ten belugas and one false killer whale (Pseudorca crassidens) for the late gene (L1) to determine the infection rate. In Qingdao, 50% of the two sampled belugas were infected with PV-HMU-1, while the false killer whale was negative. In Dalian, 71% of the eight sampled belugas were infected with PV-HMU-2. In their L1 genes, PV-HMU-1 and PV-HMU-2 showed 64.99 and 68.12% amino acid identity, respectively, with other members of Papillomaviridae. Phylogenetic analysis of combinatorial amino acid sequences revealed that PV-HMU-1 and PV-HMU-2 clustered with other known dolphin PVs but formed distinct branches. PVs carried by belugas were proposed as novel species under Firstpapillomavirinae.ConclusionThe discovery of these two novel PVs enhances our understanding of the genetic diversity of papillomaviruses and their impact on the beluga population.

Abstract Background Hepatitis E virus (HEV) is an important zoonotic pathogen, Genotypes 3 and 4 are the main zoonotic genotype. Due to the lack of mature and effective culture cell lines, researches on genotype IV swine HEV (SHEV‐4) infection and pathogenic mechanism have been carried out in pigs, gerbils and non‐human primate models. Objectives The aim of this study was to establish a rat infection model by intra‐peritoneal infection with SHEV‐4, which provided a new research idea and scientific basis for further revealing the mechanism of HEV infection and preventing HEV infection. Methods SHEV‐4 virus was administered intra‐peritoneally to 6‐ to 8‐week‐old mice to observe the serological changes and virus release. Results According to the results of the rat serum HEV IgG, ALT and AST levels, swine HEV, minus‐strand HEV RNA can infect Sprague–Dawley rats across species, and there are no obvious clinical symptoms after infection. HEV RNA was detected in most tissues and organs after infection, but the viral load was low. The liver had pathological changes of chronic hepatitis. Conclusions We found that the rat model of porcine HEV infection is a small animal model suitable for the study of HEV infection.

Abstract Mechanical stimulation plays an important role in bone remodeling. Exercise-induced mechanical loading enhances bone strength, whereas mechanical unloading leads to bone loss. Increasing evidence has demonstrated that long noncoding RNAs (lncRNAs) play key roles in diverse biological, physiological and pathological contexts. However, the roles of lncRNAs in mechanotransduction and their relationships with bone formation remain unknown. In this study, we screened mechanosensing lncRNAs in osteoblasts and identified Neat1, the most clearly decreased lncRNA under simulated microgravity. Of note, not only Neat1 expression but also the specific paraspeckle structure formed by Neat1 was sensitive to different mechanical stimulations, which were closely associated with osteoblast function. Paraspeckles exhibited small punctate aggregates under simulated microgravity and elongated prolate or larger irregular structures under mechanical loading. Neat1 knockout mice displayed disrupted bone formation, impaired bone structure and strength, and reduced bone mass. Neat1 deficiency in osteoblasts reduced the response of osteoblasts to mechanical stimulation. In vivo, Neat1 knockout in mice weakened the bone phenotypes in response to mechanical loading and hindlimb unloading stimulation. Mechanistically, paraspeckles promoted nuclear retention of E3 ubiquitin ligase Smurf1 mRNA and downregulation of their translation, thus inhibiting ubiquitination-mediated degradation of the osteoblast master transcription factor Runx2, a Smurf1 target. Our study revealed that Neat1 plays an essential role in osteoblast function under mechanical stimulation, which provides a paradigm for the function of the lncRNA-assembled structure in response to mechanical stimulation and offers a therapeutic strategy for long-term spaceflight- or bedrest-induced bone loss and age-related osteoporosis.

Abstract The binding of plasma proteins to nanomedicines is widely considered detrimental to their delivery to tumors. Here, the design of OxPt/SN38 nanoparticle containing a hydrophilic oxaliplatin (OxPt) prodrug in a coordination polymer core and a hydrophobic cholesterol‐conjugated SN38 prodrug on the lipid shell for active tumor targeting is reported. OxPt/SN38 hitchhikes on low‐density lipoprotein (LDL) particles, concentrates in tumors via LDL receptor‐mediated endocytosis, and selectively releases SN38 and OxPt in acidic, esterase‐rich, and reducing tumor microenvironments, leading to 6.0‐ and 4.9‐times higher accumulations in tumors over free drugs. By simultaneously crosslinking DNA and inhibiting topoisomerase I, OxPt/SN38 achieved 92–98% tumor growth inhibition in five colorectal cancer tumor models and prolonged mouse survival by 58–80 days compared to free drug controls in three human colorectal cancer tumor models without causing serious side effects. The study has uncovered a novel nanomedicine strategy to co‐deliver combination chemotherapies to tumors via active targeting of the LDL receptor.

Object detection is challenging in high spatial resolution (HSR) remote sensing images that have a complex background and irregular object locations. To minimize manual annotation cost in supervised learning methods and achieve advanced detection performance, we proposed a point-based weakly supervised learning method to address the object detection challenge in HSR remote sensing images. In the study, point labels are introduced to guide candidate bounding box mining and generate pseudobounding boxes for objects. Then, pseudobounding boxes are applied to train the detection model. A progressive candidate bounding box mining strategy is proposed to refine object detection. Experiments are conducted on a comprehensive HSR dataset which contains four categories. Results indicate the proposed method achieves competitive performance compared to YOLOv5 which is trained on manual bounding box annotations. In comparison to the state-of-the-art weakly supervised learning method, our method outperforms WSDDN method with 0.62 mean average precision score.

Astroviruses infect human and animals and cause diarrhea, fever, and vomiting. In severe cases, these infections may be fatal in infants and juvenile animals. Previous evidence showed that humans in contact with infected animals can develop serological responses to astroviruses. Mamastrovirus 11 is a species of Mamastrovirus and was first reported in 2018. It was detected in the fecal samples of a California sea lion. The genome sequence of its capsid protein (CP) was submitted to GenBank. However, the genome sequence of its non-structural protein region was not elucidated. In the present study, we characterized the genome sequences of the novel astroviruses AstroV-HMU-1 and AstroV-like-HMU-2. These were obtained from California sea lions (Zalophus californianus) and walruses (Odobenus rosmarus) presenting with loose stools. A phylogenetic analysis revealed that the CP of AstroV-HMU-1 closely clustered with Mamastrovirus 11 while its RNA-dependent RNA polymerase (RdRp) and serine protease (SP) were closely related to the mink astrovirus in the genus Mamastrovirus. The genome of AstroV-HMU-1 provided basic information regarding the NS protein regions of Mamastrovirus 11. Recombination analyses showed that the genomes of Z. californianus AstroV-HMU-1, VA2/human and the mink astrovirus may have recombined long ago. The NS of AstroV-like-HMU-2 segregated from the Astroviridae in the deep root of the phylogenetic tree and exhibited 36% amino acid identity with other mamastroviruses. Thus, AstroV-like-HMU-2 was proposed as a member of a new genus in the unclassified Astroviridae. The present study suggested that that the loose stools of pinnipeds may be the result of occasional infection by this novel astrovirus. This discovery provides a scientific basis for future investigations into other animal-borne infectious diseases.

As hematopoietic stem cells can differentiate into all hematopoietic lineages, mitigating the damage to hematopoietic stem cells is important for recovery from overdose radiation injury. Cells in bone marrow microenvironment are essential for hematopoietic stem cells maintenance and protection, and many of the paracrine mediators have been discovered in shaping hematopoietic function. Several recent reports support exosomes as effective regulators of hematopoietic stem cells, but the role of osteoblast derived exosomes in hematopoietic stem cells protection is less understood. Here, we investigated that osteoblast derived exosomes could alleviate radiation damage to hematopoietic stem cells. We show that intravenous injection of osteoblast derived exosomes promoted WBC, lymphocyte, monocyte and hematopoietic stem cells recovery after irradiation significantly. By sequencing osteoblast derived exosomes derived miRNAs and verified in vitro, we identified miR-21 is involved in hematopoietic stem cells protection via targeting PDCD4. Collectively, our data demonstrate that osteoblast derived exosomes derived miR-21 is a resultful regulator to radio-protection of hematopoietic stem cells and provide a new strategy for reducing radiation induced hematopoietic injury.

This study provides a comprehensive analysis of global, continental, and national trends in the prevalence and mortality of prostate cancer (PC), breast cancer (BC), and thyroid cancer (TC). Utilizing 2021 Global Burden of Diseases (GBD2021) data, prevalence and death rates for 2021 were examined, with temporal trends from 1990 to 2021 analyzed via Joinpoint regression. Annual percentage change (APC) and average APC (AAPC) were calculated with 95% CI. Distributive inequalities were quantified using the slope index of inequality and concentration index. In 2021, PC, BC, and TC showed higher global age-standardized prevalence rates (ASPR) in Europe and America compared to Africa and Asia, while higher age-standardized death rates (ASDR) for PC and BC were noted in Africa. Over the study period, significant global increases in ASPR were observed for PC (AAPC = 0.78, 95% CI: 0.67 to 0.89), BC (AAPC = 0.31, 95% CI: 0.24 to 0.37), and TC (AAPC = 1.42, 95% CI: 1.31 to 1.52). Conversely, ASDR significantly decreased for PC (AAPC = -0.83, 95% CI: -0.92 to -0.74), BC (AAPC = -0.48, 95% CI: -0.56 to -0.39), and TC (AAPC = -0.23, 95% CI: -0.29 to -0.17). Variations were observed across continents and time periods, affecting 204 countries and territories. Higher Social Development Index (SDI) levels were associated with a more pronounced burden of these cancers. The findings highlight significant global heterogeneity in prevalence, death rates, and temporal trends of endocrine cancers, with important implications for epidemiology and public health policies. [ABSTRACT FROM AUTHOR]

Abstract: Triptolide, a purified diterpenoid from the herb Tripterygium wilfordii Hook.f., was widely used to treat many diseases. However, the hepatotoxicity of triptolide limited its clinical use. Research showed oxidative stress played an important role in triptolide-induced liver injury. To investigate the effect of vitamin C, which was one of the most effective antioxidants, on triptolide-induced hepatotoxicity and its potential mechanism in mice. In the present study, acute liver injury was induced by intraperitoneal injection of triptolide and vitamin C was orally administered. The results showed treatment with vitamin C prevented the triptolide-induced liver injury by reducing the levels of aspartate transaminase from 286.86 to 192.48 U/mL and alanine aminotransferase from 746.75 to 203.36 U/mL. Histopathological changes of liver corresponded to the same trend. Furthermore, vitamin C also protected the liver against triptolide-induced oxidative stress by inhibiting the generation of malondialdehyde (2.22 to 1.49 nmol/mgprot) and hydrogen peroxide (14.74 to 7.19 mmol/gprot) and restoring the level of total superoxide dismutase (24.32 to 42.55 U/mgprot) and glutathione (7.69 to 13.03 μg/mgprot). These results indicated that vitamin C could protect against triptolide-induced liver injury via reducing oxidative stress, and vitamin C may pose a significant health protection in the clinical use of triptolide.

Abstract SARS-CoV-2 infection is initiated by Spike glycoprotein binding to the human angiotensin-converting enzyme 2 (ACE2) receptor via its receptor binding domain. Blocking this interaction has been proven to be an effective approach to inhibit virus infection. Here we report the discovery of a neutralizing nanobody named VHH60, which was directly produced from an engineering nanobody library based on a commercialized nanobody within a very short period. VHH60 competes with human ACE2 to bind the receptor binding domain of the Spike protein at S351, S470-471and S493-494 as determined by structural analysis, with an affinity of 2.56 nM. It inhibits infections of both ancestral SARS-CoV-2 strain and pseudotyped viruses harboring SARS-CoV-2 wildtype, key mutations or variants at the nanomolar level. Furthermore, VHH60 suppressed SARS-CoV-2 infection and propagation 50-fold better and protected mice from death for twice as long as the control group after SARS-CoV-2 nasal infections in vivo. Therefore, VHH60 is not only a powerful nanobody with a promising profile for disease control but also provides evidence for a highly effective and rapid approach to generating therapeutic nanobodies.