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Systemic administration of an RNA binding and cell-penetrating antibody targets therapeutic RNA to multiple mouse models of cancer 一种RNA结合和细胞穿透抗体的系统管理针对多种癌症小鼠模型的治疗RNA
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-16 DOI: 10.1126/scitranslmed.adk1868
Elias Quijano, Diana Martinez-Saucedo, Zaira Ianniello, Natasha Pinto-Medici, Madison Rackear, Haoting Chen, Luiz Lola-Pereira, Yanfeng Liu, Denise Hegan, Xinning Shan, Robert Tseng, Deanne Yugawa, Sumedha Chowdhury, Minsoo Khang, Jay P. Singh, Rashed Abdullah, Perisa Azhir, Soki Kashima, Wendy S. Woods, Nicholas Gosstola, Bruce C. Turner, Stephen Squinto, Dale L. Ludwig, Ranjit S. Bindra, Marie E. Robert, David A. Braun, Pablo Perez Pinera, W. Mark Saltzman, Luisa F. Escobar-Hoyos, Peter M. Glazer
{"title":"Systemic administration of an RNA binding and cell-penetrating antibody targets therapeutic RNA to multiple mouse models of cancer","authors":"Elias Quijano,&nbsp;Diana Martinez-Saucedo,&nbsp;Zaira Ianniello,&nbsp;Natasha Pinto-Medici,&nbsp;Madison Rackear,&nbsp;Haoting Chen,&nbsp;Luiz Lola-Pereira,&nbsp;Yanfeng Liu,&nbsp;Denise Hegan,&nbsp;Xinning Shan,&nbsp;Robert Tseng,&nbsp;Deanne Yugawa,&nbsp;Sumedha Chowdhury,&nbsp;Minsoo Khang,&nbsp;Jay P. Singh,&nbsp;Rashed Abdullah,&nbsp;Perisa Azhir,&nbsp;Soki Kashima,&nbsp;Wendy S. Woods,&nbsp;Nicholas Gosstola,&nbsp;Bruce C. Turner,&nbsp;Stephen Squinto,&nbsp;Dale L. Ludwig,&nbsp;Ranjit S. Bindra,&nbsp;Marie E. Robert,&nbsp;David A. Braun,&nbsp;Pablo Perez Pinera,&nbsp;W. Mark Saltzman,&nbsp;Luisa F. Escobar-Hoyos,&nbsp;Peter M. Glazer","doi":"10.1126/scitranslmed.adk1868","DOIUrl":"10.1126/scitranslmed.adk1868","url":null,"abstract":"<div >There is intense interest in the advancement of RNAs as rationally designed therapeutic agents, especially in oncology, where a major focus is to use RNAs to stimulate pattern recognition receptors to leverage innate immune responses. However, the inability to selectively deliver therapeutic RNAs within target cells after intravenous administration now hinders the development of this type of treatment for cancer and other disorders. Here, we found that a tumor-targeting, cell-penetrating, and RNA binding monoclonal antibody, TMAB3, can form stable, noncovalent antibody/RNA complexes of a discrete size that mediate highly specific and functional delivery of RNAs into tumors. Using 3p-hpRNA, an agonist of the pattern recognition receptor retinoic acid–inducible gene-I (RIG-I), we observed robust antitumor efficacy of systemically administered TMAB3/3p-hpRNA complexes in mouse models of pancreatic cancer, medulloblastoma, and melanoma. In the KPC syngeneic, orthotopic pancreatic cancer model in immunocompetent mice, treatment with TMAB3/3p-hpRNA tripled animal survival, decreased tumor growth, and specifically targeted malignant cells, with a 1500-fold difference in RNA delivery into tumor cells versus nonmalignant cells within the tumor mass. Single-cell RNA sequencing (scRNA-seq) and flow cytometry demonstrated that TMAB3/3p-hpRNA treatment elicited a potent antitumoral immune response characterized by RIG-I activation and increased infiltration and activity of cytotoxic T cells. These studies established that TMAB3/RNA complexes can deliver RNA payloads specifically to hard-to-treat tumor cells to achieve antitumor efficacy, providing an antibody-based platform to advance the study of RNA therapies for the treatment of patients with cancer.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 807","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Oral delivery of liquid mRNA therapeutics by an engineered capsule for treatment of preclinical intestinal disease 通过工程胶囊口服液体mRNA治疗用于治疗临床前肠道疾病
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-16 DOI: 10.1126/scitranslmed.adu1493
Xiangang Huang, Chuang Liu, Shonit Nair Sharma, Xinru You, Shuying Chen, Yongjiang Li, Hai-Jun Liu, Bin Liu, Qimanguli Saiding, Wei Chen, Yuhan Lee, Na Kong, Reza Abdi, Wei Tao
{"title":"Oral delivery of liquid mRNA therapeutics by an engineered capsule for treatment of preclinical intestinal disease","authors":"Xiangang Huang,&nbsp;Chuang Liu,&nbsp;Shonit Nair Sharma,&nbsp;Xinru You,&nbsp;Shuying Chen,&nbsp;Yongjiang Li,&nbsp;Hai-Jun Liu,&nbsp;Bin Liu,&nbsp;Qimanguli Saiding,&nbsp;Wei Chen,&nbsp;Yuhan Lee,&nbsp;Na Kong,&nbsp;Reza Abdi,&nbsp;Wei Tao","doi":"10.1126/scitranslmed.adu1493","DOIUrl":"10.1126/scitranslmed.adu1493","url":null,"abstract":"<div >Oral delivery of messenger RNA (mRNA) therapeutics could offer noninvasive and self-administered treatments and vaccinations. However, the development of oral mRNA therapeutics remains challenging because of the degradative conditions of the gastrointestinal (GI) tract. Here, we engineered a capsule-based device, named RNACap, designed for oral delivery of liquid mRNA nanoparticle (NP) therapeutics to the intestines. RNACap protects mRNA from the acidic stomach environment while allowing rapid release into the intestines in response to intestinal neutral pH, pressure release due to the dissolution of capsule cap, and natural intestinal contractions (peristalsis). This process enables NP-mediated delivery of mRNA into intestinal cells for in vivo transfection. We optimized an NP formulation for rapid intestinal mRNA delivery. In rat and porcine models, we confirmed that the RNACap remains intact in the stomach but releases its contents within the intestines. The release of mRNA NPs led to the expression of multiple mRNAs. The therapeutic effect of the RNACap was demonstrated by acute and delayed treatment in two rat colitis models. Orally administered RNACaps loaded with mRNA encoding interleukin-10 (<i>IL-10</i> mRNA NP) reduced proinflammatory cytokine concentrations in both blood and tissues, ultimately alleviating colitis. Furthermore, using a large-animal model of swine, we showed that RNACaps remained intact in the stomach, disassembled in the intestine, and resulted in robust mRNA expression just 8.5 hours after administration. RNACap represents a promising platform for the oral delivery of liquid mRNA therapeutics to the GI tract for treating challenging intestinal diseases and potentially other conditions.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 807","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Donor-recipient mismatch at the SIRPA locus adversely affects kidney allograft outcomes 在SIRPA位点供体-受体不匹配会对肾移植结果产生不利影响
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-16 DOI: 10.1126/scitranslmed.ady1135
Daqiang Zhao, Hehua Dai, Camila Macedo, Steven M. Sanders, Charbel Elias, Andrew J. Friday, Mohamad Zaidan, Amanda L. Williams, Beth D. Elinoff, Martin H. Oberbarnscheidt, Jayne Danska, Adriana Zeevi, Parmjeet Randhawa, Amit D. Tevar, Sundaram Hariharan, David M. Rothstein, Khodor I. Abou-Daya, Aleksandar Senev, Anat R. Tambur, Diana Metes, Olivier Thaunat, Fadi G. Lakkis, Aravind Cherukuri
{"title":"Donor-recipient mismatch at the SIRPA locus adversely affects kidney allograft outcomes","authors":"Daqiang Zhao,&nbsp;Hehua Dai,&nbsp;Camila Macedo,&nbsp;Steven M. Sanders,&nbsp;Charbel Elias,&nbsp;Andrew J. Friday,&nbsp;Mohamad Zaidan,&nbsp;Amanda L. Williams,&nbsp;Beth D. Elinoff,&nbsp;Martin H. Oberbarnscheidt,&nbsp;Jayne Danska,&nbsp;Adriana Zeevi,&nbsp;Parmjeet Randhawa,&nbsp;Amit D. Tevar,&nbsp;Sundaram Hariharan,&nbsp;David M. Rothstein,&nbsp;Khodor I. Abou-Daya,&nbsp;Aleksandar Senev,&nbsp;Anat R. Tambur,&nbsp;Diana Metes,&nbsp;Olivier Thaunat,&nbsp;Fadi G. Lakkis,&nbsp;Aravind Cherukuri","doi":"10.1126/scitranslmed.ady1135","DOIUrl":"10.1126/scitranslmed.ady1135","url":null,"abstract":"<div >Donor-recipient mismatches in histocompatibility antigens recognized by lymphoid cells have been demonstrated to adversely affect allograft outcomes. In contrast, it remains unclear whether mismatches sensed by innate myeloid cells have a similar effect. We investigated the consequences of mismatch in the polymorphic gene encoding signal regulatory protein α (SIRPα) on kidney allograft pathology and survival in mice and humans. We found that SIRPα variants elicit monocyte activation by binding to CD47 and that eliminating SIRPα mismatch or recipient CD47 expression prevented chronic allograft pathology in mice receiving major histocompatibility complex (MHC)–mismatched renal allografts. Human genomic analysis identified two haplotype categories, A and B, encoding SIRPα variants with distinct CD47 binding interfaces. In kidney transplant recipients (<i>N</i> = 455), SIRPα mismatch was associated with increased acute rejection and graft fibrosis in the first posttransplant year, and A recipients of B kidneys had reduced long-term graft survival (hazard ratio, 3.2; 95% confidence interval, 1.5 to 6.9; <i>P</i> = 0.002), a finding that was confirmed in an independent validation cohort (<i>N</i> = 258). Moreover, monocytes in these graft recipients had an activated phenotype. The effects of SIRPα mismatch were independent of ancestry, human leukocyte antigen mismatch, donor-specific antibodies, and delayed graft function. Therefore, these data demonstrate that a donor-recipient mismatch that causes innate immune activation is a determinant of kidney transplantation outcomes.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 807","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
S100A8/A9 perturbation in bone marrow blunts antitumor immunity by promoting protumorigenic myelopoiesis in mouse models 在小鼠模型中,骨髓中S100A8/A9的扰动通过促进致瘤性骨髓生成而减弱抗肿瘤免疫
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-16 DOI: 10.1126/scitranslmed.adr3963
Wen Luo, Xingxing Su, Qiao Zhang, Zhongyu Wang, Zheng Jin, Yanan Li, Yang Fei, Dong Zeng, Xianghua Zeng, Guitong Lv, Mengyi Li, Jiani Huang, Haoran Zha, Ji Liu, Zhong Luo, Haixia Long, Bo Zhu
{"title":"S100A8/A9 perturbation in bone marrow blunts antitumor immunity by promoting protumorigenic myelopoiesis in mouse models","authors":"Wen Luo,&nbsp;Xingxing Su,&nbsp;Qiao Zhang,&nbsp;Zhongyu Wang,&nbsp;Zheng Jin,&nbsp;Yanan Li,&nbsp;Yang Fei,&nbsp;Dong Zeng,&nbsp;Xianghua Zeng,&nbsp;Guitong Lv,&nbsp;Mengyi Li,&nbsp;Jiani Huang,&nbsp;Haoran Zha,&nbsp;Ji Liu,&nbsp;Zhong Luo,&nbsp;Haixia Long,&nbsp;Bo Zhu","doi":"10.1126/scitranslmed.adr3963","DOIUrl":"10.1126/scitranslmed.adr3963","url":null,"abstract":"<div >S100A8/A9 plays a critical role in the formation of an immunosuppressive tumor microenvironment. Therefore, it is important to identify inhibitors targeting S100A8/A9 to enhance antitumor immunity. However, systemic targeting of S100A8/A9 in clinical trials has shown minimal effects. Understanding the reasons underlying this underperformance is important for developing drugs targeting S100A8/A9 that could effectively reverse the immunosuppressive tumor microenvironment. In this study, using hematopoietic system–specific conditional knockout mice in heterotopic models of lung and colon cancer and systemic pharmacological interference, we demonstrated that S100A8/A9 perturbation in the hematopoietic system accelerates tumor progression by attenuating T cell–mediated antitumor immunity. Mechanistically, S100A8/A9 perturbation triggered myeloid-biased differentiation in the bone marrow by promoting the production of abnormal granulocyte-monocyte progenitors. The local release of S100A8/A9 inhibitors using a tumor-targeted drug delivery system exhibited antitumor potential by avoiding myelopoiesis-promoting effects. These findings reveal a mechanism underlying the limited efficacy of systemic S100A8/A9 inhibition and propose a targeted strategy to enhance antitumor effects.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 807","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adr3963","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting SIRT2 induces MLH1 deficiency and boosts antitumor immunity in preclinical colorectal cancer models 靶向SIRT2诱导MLH1缺失,增强临床前结直肠癌模型的抗肿瘤免疫
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-16 DOI: 10.1126/scitranslmed.adv0766
Qianling Gao, Lanlan Yang, Shubiao Ye, Mingru Mai, Yiting Liu, Xuefei Jiang, Xingzhi Feng, Zihuan Yang
{"title":"Targeting SIRT2 induces MLH1 deficiency and boosts antitumor immunity in preclinical colorectal cancer models","authors":"Qianling Gao,&nbsp;Lanlan Yang,&nbsp;Shubiao Ye,&nbsp;Mingru Mai,&nbsp;Yiting Liu,&nbsp;Xuefei Jiang,&nbsp;Xingzhi Feng,&nbsp;Zihuan Yang","doi":"10.1126/scitranslmed.adv0766","DOIUrl":"10.1126/scitranslmed.adv0766","url":null,"abstract":"<div >Low tumor mutation burden and an immunosuppressive tumor microenvironment (TME) of colorectal cancers (CRCs) contribute to resistance to immune-checkpoint inhibitors in patients. Understanding the mechanisms of cancer immune evasion will be helpful to develop new therapeutic strategies. Here, leveraging mass spectrometry–based proteomic profiling data and clinical validation, we identified that low sirtuin 2 (SIRT2) expression was associated with improved prognosis and an immune-active TME in CRC. Specifically, genetic knockdown or pharmacological inhibition of SIRT2 resulted in enhanced infiltration and cytotoxicity of CD8<sup>+</sup> T cells, leading to tumor regression across multiple CRC mouse models and patient-derived organoids. Further in vitro experimental analysis demonstrated that SIRT2 interacted with and deacetylated MutL protein homolog 1 (MLH1) at Lys<sup>402/443/461</sup>, thereby preventing MLH1 ubiquitination and degradation. SIRT2 knockdown or inhibition down-regulated MLH1, increasing DNA damage and activating the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway. In addition, both in vivo and in vitro experiments indicated that SIRT2 inhibition stimulated the production of tumor neoantigens and enhanced major histocompatibility complex class I (MHC-I) expression, reprogramming the TME toward an immune-active status and inducing long-lasting immune memory. Last, a combination strategy using SIRT2 inhibitor 2-cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide (AGK2) and anti–programmed cell death protein–1 (PD-1) therapy enhanced immune response, making tumors susceptible to immunotherapy and driving substantial tumor regression in vivo. Our study uncovers a role of SIRT2 in reprogramming TME and underscores the potential of targeting SIRT2 to sensitize CRC to immunotherapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 807","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Complement is activated in patients with acute chest syndrome caused by sickle cell disease and represents a therapeutic target 补体在镰状细胞病引起的急性胸综合征患者中被激活,是一个治疗靶点
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-16 DOI: 10.1126/scitranslmed.adl4922
Satheesh Chonat, Jayre A. Jones, Seema R. Patel, William M. Briones, Michelle L. Schoettler, Maya Maarouf, Lauren A. Jeffers, Olufolake Adisa, Fang Tan, Earl Fields, Morgan S. Sterling, Ryan P. Jajosky, Hans Verkerke, Sara H. Graciaa, Elisabetta M. Foppiani, Ross M. Fasano, Patricia E. Zerra, Yongzhi Qiu, Connie M. Arthur, Wilbur A. Lam, Solomon F. Ofori-Acquah, Michael Koval, Clinton H. Joiner, David R. Archer, Sean R. Stowell
{"title":"Complement is activated in patients with acute chest syndrome caused by sickle cell disease and represents a therapeutic target","authors":"Satheesh Chonat,&nbsp;Jayre A. Jones,&nbsp;Seema R. Patel,&nbsp;William M. Briones,&nbsp;Michelle L. Schoettler,&nbsp;Maya Maarouf,&nbsp;Lauren A. Jeffers,&nbsp;Olufolake Adisa,&nbsp;Fang Tan,&nbsp;Earl Fields,&nbsp;Morgan S. Sterling,&nbsp;Ryan P. Jajosky,&nbsp;Hans Verkerke,&nbsp;Sara H. Graciaa,&nbsp;Elisabetta M. Foppiani,&nbsp;Ross M. Fasano,&nbsp;Patricia E. Zerra,&nbsp;Yongzhi Qiu,&nbsp;Connie M. Arthur,&nbsp;Wilbur A. Lam,&nbsp;Solomon F. Ofori-Acquah,&nbsp;Michael Koval,&nbsp;Clinton H. Joiner,&nbsp;David R. Archer,&nbsp;Sean R. Stowell","doi":"10.1126/scitranslmed.adl4922","DOIUrl":"10.1126/scitranslmed.adl4922","url":null,"abstract":"<div >Despite being the first genetic disease described, sickle cell disease (SCD) continues to result in severe complications. Of these complications, acute chest syndrome (ACS), a form of acute lung injury, leads all-cause mortality. However, the pathophysiology of ACS remains incompletely understood, resulting in patients with ACS receiving only supportive measures. Here, we found that ACS is accompanied by activation of the complement pathway, an evolutionarily ancient innate immune system responsible for eliminating microbes. Using a well-defined preclinical model of SCD, hemolysis, a precursor of ACS, not only induced ACS but also drove robust complement activation. Artificial activation of complement alone similarly induced ACS, whereas genetic removal or pharmacological inhibition of complement rendered SCD mice resistant to ACS even after induction of hemolysis. These results demonstrate that complement drives ACS, establishing a link between SCD and this ancient form of immunity that provides an opportunity for targeted treatment of this complication.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 807","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Erratum for the Research Article “Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer” by J. Li et al. J. Li等人的研究文章“肿瘤特异性GPX4降解增强胰腺癌小鼠模型中铁中毒引发的抗肿瘤免疫反应”的更正。
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-16 DOI: 10.1126/scitranslmed.aea0591
{"title":"Erratum for the Research Article “Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer” by J. Li et al.","authors":"","doi":"10.1126/scitranslmed.aea0591","DOIUrl":"10.1126/scitranslmed.aea0591","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 807","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Myeloid MAS–driven macrophage efferocytosis promotes resolution in ischemia-stressed mouse and human livers 髓系mas驱动的巨噬细胞efferocytosis促进缺血应激小鼠和人类肝脏的解决
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-09 DOI: 10.1126/scitranslmed.adr2725
Shuai Chen, Bingyuan Huang, Shanshan Li, Zhijing Wang, Yizhong Chang, Huaming Huang, Chun Liu, Shuo Zhang, Manchang Jin, Haoyu Jia, Bo Yang, Ziwen Tao, Li Chen, Kai Guo, Zhi Lu, Jing Li, Fei Wang, Changqing Yang
{"title":"Myeloid MAS–driven macrophage efferocytosis promotes resolution in ischemia-stressed mouse and human livers","authors":"Shuai Chen,&nbsp;Bingyuan Huang,&nbsp;Shanshan Li,&nbsp;Zhijing Wang,&nbsp;Yizhong Chang,&nbsp;Huaming Huang,&nbsp;Chun Liu,&nbsp;Shuo Zhang,&nbsp;Manchang Jin,&nbsp;Haoyu Jia,&nbsp;Bo Yang,&nbsp;Ziwen Tao,&nbsp;Li Chen,&nbsp;Kai Guo,&nbsp;Zhi Lu,&nbsp;Jing Li,&nbsp;Fei Wang,&nbsp;Changqing Yang","doi":"10.1126/scitranslmed.adr2725","DOIUrl":"10.1126/scitranslmed.adr2725","url":null,"abstract":"<div >Liver ischemia-reperfusion injury (LIRI) is an inevitable detrimental event after liver transplantation. The MAS receptor plays a protective role in various diseases. However, the specific roles of MAS in myeloid cell innate immunity and the maintenance of hepatic tissue homeostasis remain unclear. Here, we showed that mice with systemic, Kupffer cell–specific, or myeloid cell–specific <i>Mas1</i> deficiency were vulnerable to LIRI. Single-cell RNA sequencing, spatial transcriptomics, and intravital imaging revealed that myeloid deficiency of <i>Mas1</i> resulted in impaired macrophage efferocytosis by down-regulating MER tyrosine kinase (MERTK), leading to the accumulation of aged neutrophils and exacerbation of inflammation and pathology. Mechanistic studies indicated that the MAS receptor regulated the Krüppel-like factor 4 (KLF4)/MERTK axis in macrophages via the protein kinase A (PKA)/cAMP response element–binding protein (CREB) signaling pathway. KLF4 directly bound to the promoter region of MERTK and transcriptionally promoted its expression in macrophages, leading to attenuation of the liver inflammatory response. Macrophage-specific knockout of KLF4 and MERTK in the mice also resulted in impaired macrophage efferocytosis with the accumulation of aged neutrophils. Macrophage-specific overexpression of KLF4 in vivo effectively reversed the phenotype exacerbated by myeloid <i>Mas1</i> deficiency. In addition, we demonstrated that MAS<sup>+</sup>MERTK<sup>+</sup> macrophages actively migrated toward aged neutrophils in ischemia-stressed human livers, thereby promptly clearing aged neutrophils. In summary, this study documented the regulatory function of the MAS/KLF4/MERTK axis in macrophage efferocytosis via PKA/CREB signaling. This axis may thus serve as a therapeutic target and checkpoint regulator of homeostasis in response to LIRI.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 806","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Adenovirus and mRNA vaccines as well as mucosal boosting improve protective efficacy against influenza virus challenge in macaques 腺病毒和mRNA疫苗以及粘膜增强可提高猕猴对流感病毒攻击的保护效果
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-09 DOI: 10.1126/scitranslmed.adu7646
Catherine Jacob-Dolan, David Hope, Jinyan Liu, Alejandra Waller-Pulido, Brookelynne Verrette, Dalia N. Cabrera-Barragan, Samuel J. Nangle, Qixin Wang, Ross Blanc, Jana Fisher, Ninaad Lasrado, Liping Wang, Anthony Cook, Laurent Pessiant, Mark Lewis, Hanne Andersen, Markay Hopps, Ingrid L. Scully, Pirada Suphaphiphat Allen, Ryan P. McNamara, Annaliesa S. Anderson, Dan H. Barouch
{"title":"Adenovirus and mRNA vaccines as well as mucosal boosting improve protective efficacy against influenza virus challenge in macaques","authors":"Catherine Jacob-Dolan,&nbsp;David Hope,&nbsp;Jinyan Liu,&nbsp;Alejandra Waller-Pulido,&nbsp;Brookelynne Verrette,&nbsp;Dalia N. Cabrera-Barragan,&nbsp;Samuel J. Nangle,&nbsp;Qixin Wang,&nbsp;Ross Blanc,&nbsp;Jana Fisher,&nbsp;Ninaad Lasrado,&nbsp;Liping Wang,&nbsp;Anthony Cook,&nbsp;Laurent Pessiant,&nbsp;Mark Lewis,&nbsp;Hanne Andersen,&nbsp;Markay Hopps,&nbsp;Ingrid L. Scully,&nbsp;Pirada Suphaphiphat Allen,&nbsp;Ryan P. McNamara,&nbsp;Annaliesa S. Anderson,&nbsp;Dan H. Barouch","doi":"10.1126/scitranslmed.adu7646","DOIUrl":"10.1126/scitranslmed.adu7646","url":null,"abstract":"<div >The clinically approved seasonal influenza vaccines provide only 10 to 60% efficacy, necessitating strategies to improve vaccine performance. Here, we explored strategies for improving influenza vaccine efficacy using gene-based vaccines and mucosal boosting strategies in nonhuman primates. All vaccinated cynomolgus macaques were primed with the clinical quadrivalent inactivated virus (QIV) vaccine. We evaluated a rhesus adenovirus (RhAd52) vector delivered by intramuscular or mucosal routes and an mRNA vaccine encoding the hemagglutinin of A/H1N1/Wisconsin/67/2022 delivered intramuscularly as boosts compared with the QIV vaccine delivered intramuscularly and the quadrivalent live-attenuated influenza virus (LAIV) vaccine delivered intranasally. Boosting with RhAd52 and mRNA vaccines induced more robust humoral and cellular immune responses than the clinically approved vaccines and provided improved protective efficacy against a high-dose homologous challenge with A/H1N1/Wisconsin/67/2022. The RhAd52 vaccine delivered by the intratracheal route elicited robust mucosal antibody and T cell responses and provided optimal protection in the upper and lower respiratory tracts. Both peripheral and mucosal antibody responses, as well as mucosal T cell responses, correlated with protection against viral loads. Altogether, this study defines strategies for improving H1N1 seasonal influenza vaccine efficacy by using gene-based vaccines and by optimizing mucosal immunity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 806","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adu7646","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease 靶向赖氨酸- trna合成酶的抗锥虫喹唑啉类药物在急性恰加斯病小鼠模型中显示出部分疗效
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-09 DOI: 10.1126/scitranslmed.adu4564
Lindsay B. Tulloch, Hugh Tawell, Annie E. Taylor, Marta Lopes Lima, Alice Dawson, Sandra Carvalho, Richard J. Wall, Victoriano Corpas-Lopez, Gourav Dey, Jack Duggan, Luma Godoy Magalhaes, Leah S. Torrie, Laura Frame, David Robinson, Stephen Patterson, Michele Tinti, George W. Weaver, William J. Robinson, Monica Cal, Marcel Kaiser, Pascal Mäser, Peter Sjö, Benjamin Perry, John M. Kelly, Amanda Fortes Francisco, Avninder S. Bhambra, Susan Wyllie
{"title":"Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease","authors":"Lindsay B. Tulloch,&nbsp;Hugh Tawell,&nbsp;Annie E. Taylor,&nbsp;Marta Lopes Lima,&nbsp;Alice Dawson,&nbsp;Sandra Carvalho,&nbsp;Richard J. Wall,&nbsp;Victoriano Corpas-Lopez,&nbsp;Gourav Dey,&nbsp;Jack Duggan,&nbsp;Luma Godoy Magalhaes,&nbsp;Leah S. Torrie,&nbsp;Laura Frame,&nbsp;David Robinson,&nbsp;Stephen Patterson,&nbsp;Michele Tinti,&nbsp;George W. Weaver,&nbsp;William J. Robinson,&nbsp;Monica Cal,&nbsp;Marcel Kaiser,&nbsp;Pascal Mäser,&nbsp;Peter Sjö,&nbsp;Benjamin Perry,&nbsp;John M. Kelly,&nbsp;Amanda Fortes Francisco,&nbsp;Avninder S. Bhambra,&nbsp;Susan Wyllie","doi":"10.1126/scitranslmed.adu4564","DOIUrl":"10.1126/scitranslmed.adu4564","url":null,"abstract":"<div >The protozoan parasite <i>Trypanosoma cruzi</i> causes Chagas disease, which is among the deadliest parasitic infections in Latin America. Current therapies are toxic and lack efficacy against the chronic stage of infection; thus, new drugs are urgently needed. Here, we describe a previously unidentified series of quinazoline compounds with potential against <i>Trypanosoma cruzi</i> and the related trypanosomatid parasites <i>Trypanosoma brucei</i> and <i>Leishmania donovani</i>. We demonstrated partial efficacy of a lead quinazoline compound in a mouse model of acute Chagas disease. Mechanism of action studies using several orthogonal approaches showed that this quinazoline compound series targeted the ATP-binding pocket of <i>T. cruzi</i> lysyl-tRNA synthetase 1 (KRS1). A high-resolution crystal structure of KRS1 bound to the drug indicated binding interactions that led to KRS1 inhibition. Our study identified KRS1 as a druggable target for treating <i>T. cruzi</i> infection in a mouse model. This quinazoline series shows potential for treating Chagas disease but will require further development to become a future treatment for this neglected disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 806","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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