Journal of Nanobiotechnology最新文献

{"title":"Dual-pathway tumor radiosensitization strategy based on engineered bacteria capable of targeted delivery of AuNPs and specific hypoxia alleviation.","authors":"Lingling Lei, Haonan Xu, Mingjie Li, Meng Du, Zhiyi Chen","doi":"10.1186/s12951-025-03329-7","DOIUrl":"https://doi.org/10.1186/s12951-025-03329-7","url":null,"abstract":"<p><strong>Background: </strong>Radiotherapy efficacy remains constrained by two key challenges: dose-dependent toxicity to healthy tissues at high radiation doses and hypoxia-mediated tumor radioresistance. While radiosensitizers like gold nanoparticles can enhance tumor-specific radiation deposition, their targeted delivery to tumors presents a significant hurdle. Bacteria have emerged as promising bio-carriers that not only actively target tumors and penetrate complex microenvironments, but can also be genetically engineered as multifunctional platforms for radiosensitizer delivery and hypoxia alleviation.</p><p><strong>Results: </strong>An integrated nanosystem (PCM@AuNPs), composed of engineered bacteria (PCM) and gold nanoparticles (AuNPs), is used to increase the effectiveness of radiotherapy. PCM can target and colonize tumor sites more effectively, thus improving the delivery efficiency of radiosensitizers. Furthermore, PCM overexpresses catalase (CAT), which decomposes excess H₂O₂ into O₂, helping to mitigate hypoxia in the TME. Under X-ray irradiation, PCM@AuNPs significantly enhance radiosensitization, leading to improved tumor growth inhibition while maintaining good biocompatibility.</p><p><strong>Conclusions: </strong>An effective strategy based on an integrated nanosystem (PCM@AuNPs) for radiosensitization through multiple pathways is developed. This novel engineered bacterial strategy holds great promise for enhancing radiosensitization in cancer therapy.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":"23 1","pages":"254"},"PeriodicalIF":10.6,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"5-FU@HFn combined with decitabine induces pyroptosis and enhances antitumor immunotherapy for chronic myeloid leukemia.","authors":"Zuowei Yuan, Guoyun Jiang, Ying Yuan, Qian Liang, Yaxin Hou, Wenyao Zhang, Lujia Tang, Kelong Fan, Wenli Feng","doi":"10.1186/s12951-025-03335-9","DOIUrl":"10.1186/s12951-025-03335-9","url":null,"abstract":"<p><strong>Background: </strong>Tyrosine kinase inhibitors (TKIs) constitute the primary treatment for chronic myeloid leukemia (CML). However, resistance to TKIs often leads to treatment failure. Pyroptosis, a form of programmed cell death, has emerged as a promising strategy in cancer therapy due to its ability to eliminate tumor cells while stimulating antitumor immunity. Low-dose decitabine (DAC) has been shown to reverse methylation-induced silencing of the pyroptosis-related gene gasdermin E (GSDME) in some tumor cells, offering a potential new therapeutic option for CML. Herein, we propose a combination therapy using 5-fluorouracil (5-FU), a broad-spectrum chemotherapeutic agent, and low-dose DAC to induce pyroptosis in CML cells via the caspase-3/GSDME pathway. However, the nonspecific targeting of 5-FU diminishes its pyroptosis efficacy and causes off-target toxicity, highlighting the need for a targeted drug delivery system.</p><p><strong>Results: </strong>In this study, we developed 5-FU@HFn nanoparticles (NPs) by loading 5-FU into the recombinant human heavy chain ferritin (HFn) nanocage through a high-temperature via the drug channels on the protein cage. The loading efficiency was approximately 50.62 ± 1.17 µg of 5-FU per mg of HFn. 5-FU@HFn NPs selectively targeted CML cells through CD71-mediated uptake, significantly enhancing the therapeutic effects of 5-FU. When combined with DAC, 5-FU@HFn NPs effectively activated pyroptosis via the caspase-3/GSDME pathway in both TKI-sensitive and TKI-resistant CML cells. In a CML mouse model, this combination therapy significantly suppressed tumorigenesis and triggered a robust antitumor immune response, facilitating the clearance of leukemic cells. Furthermore, the 5-FU@HFn NPs exhibited excellent in vivo safety.</p><p><strong>Conclusions: </strong>The innovative therapeutic strategy, combining 5-FU@HFn nanoparticles with low-dose DAC, effectively induces caspase-3/GSDME-mediated pyroptosis and activates antitumor immunity for CML. This approach offers a potential alternative for patients resistant or intolerant to TKIs.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":"23 1","pages":"252"},"PeriodicalIF":10.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IgM has a better relative distribution in inflammation sites and tumor tissues than IgG.","authors":"Abdulaziz M Aldayel, Mohammad Bosaeed, Sarah Almansour, Naif Khalaf Alharbi, Mohammed Alenazi, Haya A Aljami, Omar Aldibasi, Abdulrhman Aljouie, Haiyue Xu, Zhengrong Cui","doi":"10.1186/s12951-025-03213-4","DOIUrl":"https://doi.org/10.1186/s12951-025-03213-4","url":null,"abstract":"<p><p>Immunoglobulins (Igs) play a crucial role in host's defense and in developing therapies against inflammatory diseases and cancer. Herein, we first studied the relative distribution of IgM and IgG in mouse models with acute or chronic inflammation. We found that IgM showed a more selective distribution towards inflammation sites than IgG. Similarly, in a tumor-bearing mouse model, IgM showed a higher tumor-to-blood or -to healthy organs ratio than IgG. We hypothesized that the difference in the sizes between IgM and IgG may have contributed to the differences in their relative distribution, which was supported by using an IgG nanoparticle system that was similar to IgM in size. To confirm the findings in clinics, we investigated IgM and IgG levels in the blood and bronchoalveolar lavage fluid (BALF) of patients diagnosed with fungal pneumonia and showed that the relative distribution of IgM was significantly higher than IgG in the BALF samples as compared to that in serum. Such an understanding of our immune system at the nano-level may help us develop more effective biotechnological interventions against inflammatory diseases and cancers.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":"23 1","pages":"253"},"PeriodicalIF":10.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles: a new frontier in diagnosing and treating graft-versus-host disease after allogeneic hematopoietic cell transplantation.","authors":"Peipei Wu, Zhangfei Wang, Yongping Sun, Zhixiang Cheng, Min Wang, Baolong Wang","doi":"10.1186/s12951-025-03297-y","DOIUrl":"10.1186/s12951-025-03297-y","url":null,"abstract":"<p><p>Graft-versus-host disease (GvHD) is a prevalent complication following allogeneic hematopoietic stem cell transplantation (HSCT) and is characterized by relatively high morbidity and mortality rates. GvHD can result in extensive systemic damage in patients following allogeneic HSCT (allo-HSCT), with the skin, gastrointestinal tract, and liver frequently being the primary target organs affected. The severe manifestations of acute intestinal GvHD often indicate a poor prognosis for patients after allo-HSCT. Endoscopy and histopathological evaluation remain employed to diagnose GvHD, and auxiliary examinations exclude differential diagnoses. Currently, reliable serum biomarkers for the diagnosis and differential diagnosis of GvHD are scarce. As an essential part of standard transplant protocols, early application of immunosuppressive drugs effectively prevents GvHD. Among them, steroids represent first-line therapeutic agents, and the JAK2 inhibitor ruxolitinib represents the second-line therapeutic agent. Currently, no efficacious treatment modality exists for steroid-resistant aGvHD. Therefore, the diagnosis and treatment of GvHD still face significant medical demands. Extracellular vesicles (EVs) are nanometer to micrometer-scale biomembrane vesicles containing various bioactive components, such as proteins, nucleotides, and metabolites. Distinctive changes in serum-derived EV components occur in patients after allo-HSCT; Hence, EVs are expected to be potential biomarkers for diagnosing and treating GvHD. Furthermore, cell-free therapeutics characterized by EVs derived from mesenchymal stem cells (MSCs) have manifested remarkable therapeutic efficacy in preclinical models and preclinical trials of GvHD. Customized engineered EVs with fewer toxic and side effects for the combined treatment of GvHD hold broad prospects for clinical translation. This review article examines the potential value of translating EVs into clinical applications for the diagnosis and treatment of GvHD. It summarizes the latest advancements and prospects of engineered EVs applying GvHD.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":"23 1","pages":"251"},"PeriodicalIF":10.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: MSC microvesicles loaded G-quadruplex-enhanced circular single-stranded DNA-9 inhibits tumor growth by targeting MDSCs.","authors":"Jingxia Han, Rong Qin, Shaoting Zheng, Xiaohui Hou, Xiaorui Wang, Huihui An, Zhongwei Li, Yinan Li, Heng Zhang, Denghui Zhai, Huijuan Liu, Jing Meng, Tao Sun","doi":"10.1186/s12951-025-03313-1","DOIUrl":"10.1186/s12951-025-03313-1","url":null,"abstract":"","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":"23 1","pages":"250"},"PeriodicalIF":10.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Radiation-induced ferroptosis via liposomal delivery of 7-Dehydrocholesterol.","authors":"Jianwen Li, Shuyue Zhan, Wei Yang, He Zhang, Xinrui Ma, Fanghui Chen, Amy Li, Pakteema Tong, Fangchao Jiang, Zhengwei Cao, Ian Delahunty, Jiayi Wang, Yufei Wu, Zhi Liu, Zibo Li, Yong Teng, Libin Xu, Jin Xie","doi":"10.1186/s12951-025-03303-3","DOIUrl":"10.1186/s12951-025-03303-3","url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis is an emerging cell death mechanism characterized by uncontrolled lipid peroxidation. However, selectively inducing ferroptosis in cancer cells remains a challenge.</p><p><strong>Methods: </strong>We explore an approach that enables ferroptosis induction through external radiation. The key component of this technology is 7-dehydrocholesterol (7DHC), a natural biosynthetic precursor of cholesterol. To facilitate delivery, we demonstrate that 7DHC, like cholesterol, can be incorporated into the lipid layer of liposomes. To enhance targeting, we also introduced NTS_mut, a ligand for the neurotensin receptor 1 (NTSR1), which is overexpressed in multiple malignancies, into liposomes.</p><p><strong>Results: </strong>Under radiation, 7DHC reacts with radiation-induced reactive oxygen species (ROS), initiating a radical chain reaction with polyunsaturated fatty acids (PUFAs) in cell membranes. This process results in direct lipid peroxidation and subsequent ferroptotic cell death. In vivo studies demonstrate that NTS_mut-conjugated, 7DHC-loaded liposomes (N-7DHC-lipos) effectively accumulate in tumors and significantly enhance the efficacy of radiation therapy.</p><p><strong>Conclusion: </strong>While conventional radiosensitizers primarily target DNA and its repair mechanisms, our study introduces a strategy to enhance radiotherapy by specifically activating ferroptosis within the irradiated area, thereby minimizing systemic toxicity. Such a strategy of controlled activation of ferroptosis offers a favorable therapeutic index and potentially opens avenues for clinical application.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":"23 1","pages":"249"},"PeriodicalIF":10.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduction of colitis in mice by chemically programmed supramolecular nanoassemblies of vitamin-lipid conjugates.","authors":"Shiyun Xian, Fanchao Meng, Xiaona Chen, Liqing Zhu, Hangxiang Wang","doi":"10.1186/s12951-025-03322-0","DOIUrl":"10.1186/s12951-025-03322-0","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is a relapsing disorder characterized by uncontrolled chronic inflammation of the gastrointestinal tract, posing a significant therapeutic challenge owing to the limited efficacy and undesirable side effects of current therapeutic options. A key pathological hallmark of IBD is the excessive production of reactive oxygen species (ROS). Hence, therapeutic strategies aimed at reducing ROS levels are promising for relieving these inflammatory conditions. Vitamin C-a natural nutrient for the human body-is well known for its potent antioxidant effects. However, the clinical development of vitamin C as a therapeutic drug has been hindered by its poor stability, rapid metabolism, and inadequate tissue accumulation. Herein, we report that the bioavailability of vitamin C can be enhanced by chemically reprogramming it with a small panel of long-chain fatty acids that aid in the aqueous self-assembly of the resulting drug conjugates to create self-deliverable nanoassemblies, enhancing their inflammation disease-oriented delivery and cellular uptake. In mice with dextran sulfate sodium-induced colitis, the optimal vitamin C-lipid nanoassemblies preferentially accumulated in inflamed colonic tissues following systemic administration and substantially ameliorated disease severity. We extended this strategy to incorporate the clinically approved glucocorticoid budesonide into the vitamin C nanosystem, facilitating a synergistic combination. In the chronic colitis model, the combination treatment reduced inflammation without compromising global immunity. Mechanistically, the treatment modulated the intestinal inflammatory microenvironment and altered the immune cell landscape, partly through regulation of the gut microbiome. Given its anticipated negligible side effects, this novel nanoassembly platform leveraging small-molecule lipidation may become a promising therapeutic for treating various inflammatory diseases.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":"23 1","pages":"247"},"PeriodicalIF":10.6,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Near-infrared light triggered in situ release of CO for enhanced therapy of glioblastoma.","authors":"Juan Ge, Miaomiao Zuo, Qirong Wang, Zhen Li","doi":"10.1186/s12951-025-03162-y","DOIUrl":"10.1186/s12951-025-03162-y","url":null,"abstract":"","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":"23 1","pages":"245"},"PeriodicalIF":10.6,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-modality immune nano-activator harnessing Mn²⁺ and quercetin to potentiate the cGAS-STING pathway for advanced cancer metalloimmunotherapy.","authors":"Shanshan Ma, Xuequan Zhang, Xiaoqi Zhu, Kangning Yan, Qin Wang, Lei Lei, Jiasheng Li, Jing Guo, Weizhong Tang, Junjie Liu, Jun Cao, Duo Wang, Tao Luo","doi":"10.1186/s12951-025-03336-8","DOIUrl":"10.1186/s12951-025-03336-8","url":null,"abstract":"<p><p>Manganese ions (Mn²⁺) have emerged as promising activators of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. However, their clinical application was hindered by low bioavailability and limited immune activation pathways, which impaired their ability to trigger robust immune responses and achieve significant antitumor effects. To address these challenges, we developed a dual-modality immune nano-activator by coordinating manganese ions with quercetin. This strategy was designed to enhance the cGAS-STING pathway activation and elicit the immunogenic cell death, thereby strengthening the antitumor immune response. The engineered nano-activator demonstrated superior tumor-targeting ability and efficient cellular internalization. Upon exposure to near-infrared irradiation, the system harnessed photothermal effects to induce apoptosis in tumor cells while simultaneously accelerating the release of manganese ions and quercetin. The released manganese ions facilitated the generation of reactive oxygen species, which in conjunction with quercetin-induced apoptosis, amplified photothermal-induced DNA damage. This DNA damage further promoted the release of cytosolic DNA, which in turn activated the cGAS-STING pathway, thereby intensifying immune activation. Notably, the nano-activator also triggered immunogenic cell death, which synergized with the cGAS-STING activation to promote dendritic cell maturation and activate antigen-specific T-cell, significantly enhancing the immune response against the tumor. Both in vitro and in vivo studies confirmed that this nano-activator effectively inhibited tumor growth, with particularly pronounced effects when combined with anti-CTLA-4 antibodies.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":"23 1","pages":"248"},"PeriodicalIF":10.6,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In situ construction of heterojunctions to regulate the biodegradation behavior of copper carriers for tumor-specific cuproptosis-enhanced sono-immunotherapy.","authors":"Xiqian Cao, Lingwei Mao, Yijun Tian, Lang Yan, Bijiang Geng, Yingtang Zhou, Jiangbo Zhu","doi":"10.1186/s12951-025-03334-w","DOIUrl":"10.1186/s12951-025-03334-w","url":null,"abstract":"<p><p>Cuproptosis, a novel approach utilizing copper carriers to trigger programmed cell death, exhibits promise for enhancing traditional therapies and activating robust adaptive immune responses. However, the uncontrolled release of Cu ions risks triggering cuproptosis in healthy tissues, potentially causing irreversible damage. To address this, we report on the use of a Cu-MOF (copper metal-organic framework) protective layer to regulate the biodegradation of copper-based nanomaterials. In situ formation of Cu-MOF on Cu₂O nanocubes not only stabilizes the material under physiological conditions but also enhances its sonodynamic therapy (SDT) capabilities by establishing a Z-Scheme heterojunction. Upon SDT activation, the targeted Cu ion release at the tumor site triggers a cascade of reactions, generating reactive oxygen species (ROS) via Fenton-like processes and depleting glutathione (GSH). This ROS surge, combined with effective cuproptosis, modulates the immunosuppressive tumor microenvironment, inducing immunogenic cell death to eliminate primary tumors and inhibit metastasis. This study offers a new paradigm for the controlled integration of SDT, chemodynamic therapy (CDT), cuproptosis, and immunotherapy, achieving precise tumor-targeted treatment via controlled copper nanomaterial degradation.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":"23 1","pages":"246"},"PeriodicalIF":10.6,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}