Pub Date : 2024-05-31DOI: 10.1038/s41551-024-01215-5
The majority of the human non-coding genome remains poorly studied. A user-friendly genome-wide screening system composed of thousands of paired single-guide RNAs for the deletion of non-coding regions revealed key functions of many non-coding elements in cell growth and cell differentiation and in cellular response to drugs.
{"title":"Paired CRISPR screening libraries for studying the function of the non-coding genome at scale","authors":"","doi":"10.1038/s41551-024-01215-5","DOIUrl":"10.1038/s41551-024-01215-5","url":null,"abstract":"The majority of the human non-coding genome remains poorly studied. A user-friendly genome-wide screening system composed of thousands of paired single-guide RNAs for the deletion of non-coding regions revealed key functions of many non-coding elements in cell growth and cell differentiation and in cellular response to drugs.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 7","pages":"806-807"},"PeriodicalIF":26.8,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141182351","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}
Pub Date : 2024-05-22DOI: 10.1038/s41551-024-01204-8
Yufeng Li, Minkang Tan, Almira Akkari-Henić, Limin Zhang, Maarten Kip, Shengnan Sun, Jorian J. Sepers, Ningning Xu, Yavuz Ariyurek, Susan L. Kloet, Richard P. Davis, Harald Mikkers, Joshua J. Gruber, Michael P. Snyder, Xiao Li, Baoxu Pang
The functions of non-coding regulatory elements (NCREs), which constitute a major fraction of the human genome, have not been systematically studied. Here we report a method involving libraries of paired single-guide RNAs targeting both ends of an NCRE as a screening system for the Cas9-mediated deletion of thousands of NCREs genome-wide to study their functions in distinct biological contexts. By using K562 and 293T cell lines and human embryonic stem cells, we show that NCREs can have redundant functions, and that many ultra-conserved elements have silencer activity and play essential roles in cell growth and in cellular responses to drugs (notably, the ultra-conserved element PAX6_Tarzan may be critical for heart development, as removing it from human embryonic stem cells led to defects in cardiomyocyte differentiation). The high-throughput screen, which is compatible with single-cell sequencing, may allow for the identification of druggable NCREs. The functions of non-coding regulatory elements can be systematically studied genome-wide at high throughput in human cells via their Cas9-mediated deletion through libraries of paired single-guide RNAs targeting both ends of each element.
{"title":"Genome-wide Cas9-mediated screening of essential non-coding regulatory elements via libraries of paired single-guide RNAs","authors":"Yufeng Li, Minkang Tan, Almira Akkari-Henić, Limin Zhang, Maarten Kip, Shengnan Sun, Jorian J. Sepers, Ningning Xu, Yavuz Ariyurek, Susan L. Kloet, Richard P. Davis, Harald Mikkers, Joshua J. Gruber, Michael P. Snyder, Xiao Li, Baoxu Pang","doi":"10.1038/s41551-024-01204-8","DOIUrl":"10.1038/s41551-024-01204-8","url":null,"abstract":"The functions of non-coding regulatory elements (NCREs), which constitute a major fraction of the human genome, have not been systematically studied. Here we report a method involving libraries of paired single-guide RNAs targeting both ends of an NCRE as a screening system for the Cas9-mediated deletion of thousands of NCREs genome-wide to study their functions in distinct biological contexts. By using K562 and 293T cell lines and human embryonic stem cells, we show that NCREs can have redundant functions, and that many ultra-conserved elements have silencer activity and play essential roles in cell growth and in cellular responses to drugs (notably, the ultra-conserved element PAX6_Tarzan may be critical for heart development, as removing it from human embryonic stem cells led to defects in cardiomyocyte differentiation). The high-throughput screen, which is compatible with single-cell sequencing, may allow for the identification of druggable NCREs. The functions of non-coding regulatory elements can be systematically studied genome-wide at high throughput in human cells via their Cas9-mediated deletion through libraries of paired single-guide RNAs targeting both ends of each element.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 7","pages":"890-908"},"PeriodicalIF":26.8,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01204-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079087","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}
Pub Date : 2024-05-22DOI: 10.1038/s41551-024-01212-8
Michelle Z. Dion, Natalie Artzi
The physicochemical properties of cationic helical polypeptides can be optimized to induce endoplasmic reticulum stress in antigen-presenting cells so as to elicit antitumour innate immune responses.
可以优化阳离子螺旋多肽的理化特性，以诱导抗原递呈细胞产生内质网应激，从而激发抗肿瘤先天性免疫反应。
{"title":"Polypeptide agonists of innate immune sensors","authors":"Michelle Z. Dion, Natalie Artzi","doi":"10.1038/s41551-024-01212-8","DOIUrl":"10.1038/s41551-024-01212-8","url":null,"abstract":"The physicochemical properties of cationic helical polypeptides can be optimized to induce endoplasmic reticulum stress in antigen-presenting cells so as to elicit antitumour innate immune responses.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 5","pages":"495-496"},"PeriodicalIF":28.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079095","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}
Pub Date : 2024-05-20DOI: 10.1038/s41551-024-01214-6
Oscar P. B. Wiklander, Doste R. Mamand, Dara K. Mohammad, Wenyi Zheng, Rim Jawad Wiklander, Taras Sych, Antje M. Zickler, Xiuming Liang, Heena Sharma, Andrea Lavado, Jeremy Bost, Samantha Roudi, Giulia Corso, Angus J. Lennaárd, Manuchehr Abedi-Valugerdi, Imre Mäger, Evren Alici, Erdinc Sezgin, Joel Z. Nordin, Dhanu Gupta, André Görgens, Samir EL Andaloussi
Extracellular vesicles (EVs) function as natural delivery vectors and mediators of biological signals across tissues. Here, by leveraging these functionalities, we show that EVs decorated with an antibody-binding moiety specific for the fragment crystallizable (Fc) domain can be used as a modular delivery system for targeted cancer therapy. The Fc-EVs can be decorated with different types of immunoglobulin G antibody and thus be targeted to virtually any tissue of interest. Following optimization of the engineered EVs by screening Fc-binding and EV-sorting moieties, we show the targeting of EVs to cancer cells displaying the human epidermal receptor 2 or the programmed-death ligand 1, as well as lower tumour burden and extended survival of mice with subcutaneous melanoma tumours when systemically injected with EVs displaying an antibody for the programmed-death ligand 1 and loaded with the chemotherapeutic doxorubicin. EVs with Fc-binding domains may be adapted to display other Fc-fused proteins, bispecific antibodies and antibody–drug conjugates. Extracellular vesicles decorated with an antibody-binding moiety specific for the fragment crystallizable domain can be used as a modular delivery system for targeted cancer therapy.
细胞外囊泡（EVs）具有天然递送载体和跨组织生物信号媒介的功能。在这里，通过利用这些功能，我们展示了用可结晶片段（Fc）结构域特异性抗体结合分子装饰的细胞外囊泡可用作癌症靶向治疗的模块化递送系统。Fc-EV可以用不同类型的免疫球蛋白G抗体装饰，因此几乎可以靶向治疗任何感兴趣的组织。通过筛选 Fc 结合和 EV 分类分子对工程化 EV 进行优化后，我们展示了 EV 对显示人类表皮受体 2 或程序性死亡配体 1 的癌细胞的靶向性，以及全身注射显示程序性死亡配体 1 抗体并装载化疗药物多柔比星的 EV 后，黑色素瘤皮下肿瘤小鼠的肿瘤负荷降低和存活期延长。具有 Fc 结合域的 EVs 可用于显示其他 Fc 融合蛋白、双特异性抗体和抗体-药物共轭物。
{"title":"Antibody-displaying extracellular vesicles for targeted cancer therapy","authors":"Oscar P. B. Wiklander, Doste R. Mamand, Dara K. Mohammad, Wenyi Zheng, Rim Jawad Wiklander, Taras Sych, Antje M. Zickler, Xiuming Liang, Heena Sharma, Andrea Lavado, Jeremy Bost, Samantha Roudi, Giulia Corso, Angus J. Lennaárd, Manuchehr Abedi-Valugerdi, Imre Mäger, Evren Alici, Erdinc Sezgin, Joel Z. Nordin, Dhanu Gupta, André Görgens, Samir EL Andaloussi","doi":"10.1038/s41551-024-01214-6","DOIUrl":"10.1038/s41551-024-01214-6","url":null,"abstract":"Extracellular vesicles (EVs) function as natural delivery vectors and mediators of biological signals across tissues. Here, by leveraging these functionalities, we show that EVs decorated with an antibody-binding moiety specific for the fragment crystallizable (Fc) domain can be used as a modular delivery system for targeted cancer therapy. The Fc-EVs can be decorated with different types of immunoglobulin G antibody and thus be targeted to virtually any tissue of interest. Following optimization of the engineered EVs by screening Fc-binding and EV-sorting moieties, we show the targeting of EVs to cancer cells displaying the human epidermal receptor 2 or the programmed-death ligand 1, as well as lower tumour burden and extended survival of mice with subcutaneous melanoma tumours when systemically injected with EVs displaying an antibody for the programmed-death ligand 1 and loaded with the chemotherapeutic doxorubicin. EVs with Fc-binding domains may be adapted to display other Fc-fused proteins, bispecific antibodies and antibody–drug conjugates. Extracellular vesicles decorated with an antibody-binding moiety specific for the fragment crystallizable domain can be used as a modular delivery system for targeted cancer therapy.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 11","pages":"1453-1468"},"PeriodicalIF":26.8,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01214-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069432","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}
Pub Date : 2024-05-20DOI: 10.1038/s41551-024-01207-5
Alexander B. Silva, Jessie R. Liu, Sean L. Metzger, Ilina Bhaya-Grossman, Maximilian E. Dougherty, Margaret P. Seaton, Kaylo T. Littlejohn, Adelyn Tu-Chan, Karunesh Ganguly, David A. Moses, Edward F. Chang
Advancements in decoding speech from brain activity have focused on decoding a single language. Hence, the extent to which bilingual speech production relies on unique or shared cortical activity across languages has remained unclear. Here, we leveraged electrocorticography, along with deep-learning and statistical natural-language models of English and Spanish, to record and decode activity from speech-motor cortex of a Spanish–English bilingual with vocal-tract and limb paralysis into sentences in either language. This was achieved without requiring the participant to manually specify the target language. Decoding models relied on shared vocal-tract articulatory representations across languages, which allowed us to build a syllable classifier that generalized across a shared set of English and Spanish syllables. Transfer learning expedited training of the bilingual decoder by enabling neural data recorded in one language to improve decoding in the other language. Overall, our findings suggest shared cortical articulatory representations that persist after paralysis and enable the decoding of multiple languages without the need to train separate language-specific decoders. Multilingual articulatory representations in the speech-motor cortex of a participant with vocal-tract and limb paralysis enabled the development of a bilingual speech neuroprosthesis.
{"title":"A bilingual speech neuroprosthesis driven by cortical articulatory representations shared between languages","authors":"Alexander B. Silva, Jessie R. Liu, Sean L. Metzger, Ilina Bhaya-Grossman, Maximilian E. Dougherty, Margaret P. Seaton, Kaylo T. Littlejohn, Adelyn Tu-Chan, Karunesh Ganguly, David A. Moses, Edward F. Chang","doi":"10.1038/s41551-024-01207-5","DOIUrl":"10.1038/s41551-024-01207-5","url":null,"abstract":"Advancements in decoding speech from brain activity have focused on decoding a single language. Hence, the extent to which bilingual speech production relies on unique or shared cortical activity across languages has remained unclear. Here, we leveraged electrocorticography, along with deep-learning and statistical natural-language models of English and Spanish, to record and decode activity from speech-motor cortex of a Spanish–English bilingual with vocal-tract and limb paralysis into sentences in either language. This was achieved without requiring the participant to manually specify the target language. Decoding models relied on shared vocal-tract articulatory representations across languages, which allowed us to build a syllable classifier that generalized across a shared set of English and Spanish syllables. Transfer learning expedited training of the bilingual decoder by enabling neural data recorded in one language to improve decoding in the other language. Overall, our findings suggest shared cortical articulatory representations that persist after paralysis and enable the decoding of multiple languages without the need to train separate language-specific decoders. Multilingual articulatory representations in the speech-motor cortex of a participant with vocal-tract and limb paralysis enabled the development of a bilingual speech neuroprosthesis.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 8","pages":"977-991"},"PeriodicalIF":26.8,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069430","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}
Technology for spatial multi-omics aids the discovery of new insights into cellular functions and disease mechanisms. Here we report the development and applicability of multi-omics in situ pairwise sequencing (MiP-seq), a method for the simultaneous detection of DNAs, RNAs, proteins and biomolecules at subcellular resolution. Compared with other in situ sequencing methods, MiP-seq enhances decoding capacity and reduces sequencing and imaging costs while maintaining the efficacy of detection of gene mutations, allele-specific expression and RNA modifications. MiP-seq can be integrated with in vivo calcium imaging and Raman imaging, which enabled us to generate a spatial multi-omics atlas of mouse brain tissues and to correlate gene expression with neuronal activity and cellular biochemical fingerprints. We also report a sequential dilution strategy for resolving optically crowded signals during in situ sequencing. High-throughput in situ pairwise sequencing may facilitate the multidimensional analysis of molecular and functional maps of tissues. A spatial multi-omics method with high decoding capacity and reduced sequencing and imaging costs enhances the high-throughput detection of gene mutations, allele-specific expression and RNA modifications in tissue samples.
{"title":"Spatial multi-omics at subcellular resolution via high-throughput in situ pairwise sequencing","authors":"Xiaofeng Wu, Weize Xu, Lulu Deng, Yue Li, Zhongchao Wang, Leqiang Sun, Anran Gao, Haoqi Wang, Xiaodan Yang, Chengchao Wu, Yanyan Zou, Keji Yan, Zhixiang Liu, Lingkai Zhang, Guohua Du, Liyao Yang, Da Lin, Junqiu Yue, Ping Wang, Yunyun Han, Zhenfang Fu, Jinxia Dai, Gang Cao","doi":"10.1038/s41551-024-01205-7","DOIUrl":"10.1038/s41551-024-01205-7","url":null,"abstract":"Technology for spatial multi-omics aids the discovery of new insights into cellular functions and disease mechanisms. Here we report the development and applicability of multi-omics in situ pairwise sequencing (MiP-seq), a method for the simultaneous detection of DNAs, RNAs, proteins and biomolecules at subcellular resolution. Compared with other in situ sequencing methods, MiP-seq enhances decoding capacity and reduces sequencing and imaging costs while maintaining the efficacy of detection of gene mutations, allele-specific expression and RNA modifications. MiP-seq can be integrated with in vivo calcium imaging and Raman imaging, which enabled us to generate a spatial multi-omics atlas of mouse brain tissues and to correlate gene expression with neuronal activity and cellular biochemical fingerprints. We also report a sequential dilution strategy for resolving optically crowded signals during in situ sequencing. High-throughput in situ pairwise sequencing may facilitate the multidimensional analysis of molecular and functional maps of tissues. A spatial multi-omics method with high decoding capacity and reduced sequencing and imaging costs enhances the high-throughput detection of gene mutations, allele-specific expression and RNA modifications in tissue samples.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 7","pages":"872-889"},"PeriodicalIF":26.8,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140919582","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}
Pub Date : 2024-05-10DOI: 10.1038/s41551-024-01210-w
Robert Ohlendorf, Nan Li, Valerie Doan Phi Van, Miriam Schwalm, Yuting Ke, Miranda Dawson, Ying Jiang, Sayani Das, Brenna Stallings, Wen Ting Zheng, Alan Jasanoff
Bioluminescent probes are widely used to monitor biomedically relevant processes and cellular targets in living animals. However, the absorption and scattering of visible light by tissue drastically limit the depth and resolution of the detection of luminescence. Here we show that bioluminescent sources can be detected with magnetic resonance imaging by leveraging the light-mediated activation of vascular cells expressing a photosensitive bacterial enzyme that causes the conversion of bioluminescent emission into local changes in haemodynamic contrast. In the brains of rats with photosensitized vasculature, we used magnetic resonance imaging to volumetrically map bioluminescent xenografts and cell populations virally transduced to express luciferase. Detecting bioluminescence-induced haemodynamic signals from photosensitized vasculature will extend the applications of bioluminescent probes. Bioluminescent sources can be detected with magnetic resonance imaging by leveraging the light-mediated activation of vascular cells expressing a photosensitive bacterial enzyme that causes alterations in local haemodynamic contrast.
{"title":"Imaging bioluminescence by detecting localized haemodynamic contrast from photosensitized vasculature","authors":"Robert Ohlendorf, Nan Li, Valerie Doan Phi Van, Miriam Schwalm, Yuting Ke, Miranda Dawson, Ying Jiang, Sayani Das, Brenna Stallings, Wen Ting Zheng, Alan Jasanoff","doi":"10.1038/s41551-024-01210-w","DOIUrl":"10.1038/s41551-024-01210-w","url":null,"abstract":"Bioluminescent probes are widely used to monitor biomedically relevant processes and cellular targets in living animals. However, the absorption and scattering of visible light by tissue drastically limit the depth and resolution of the detection of luminescence. Here we show that bioluminescent sources can be detected with magnetic resonance imaging by leveraging the light-mediated activation of vascular cells expressing a photosensitive bacterial enzyme that causes the conversion of bioluminescent emission into local changes in haemodynamic contrast. In the brains of rats with photosensitized vasculature, we used magnetic resonance imaging to volumetrically map bioluminescent xenografts and cell populations virally transduced to express luciferase. Detecting bioluminescence-induced haemodynamic signals from photosensitized vasculature will extend the applications of bioluminescent probes. Bioluminescent sources can be detected with magnetic resonance imaging by leveraging the light-mediated activation of vascular cells expressing a photosensitive bacterial enzyme that causes alterations in local haemodynamic contrast.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 6","pages":"775-786"},"PeriodicalIF":26.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140902916","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}
Pub Date : 2024-05-07DOI: 10.1038/s41551-024-01208-4
Di Yin, Yiye Zhong, Sikai Ling, Sicong Lu, Xiaoyuan Wang, Zhuofan Jiang, Jie Wang, Yao Dai, Xiaolong Tian, Qijing Huang, Xingbo Wang, Junsong Chen, Ziying Li, Yang Li, Zhijue Xu, Hewei Jiang, Yuqing Wu, Yi Shi, Quanjun Wang, Jianjiang Xu, Wei Hong, Heng Xue, Hang Yang, Yan Zhang, Lintai Da, Ze-guang Han, Sheng-ce Tao, Ruijiao Dong, Tianlei Ying, Jiaxu Hong, Yujia Cai
Messenger RNA vaccines lack specificity for dendritic cells (DCs)—the most effective cells at antigen presentation. Here we report the design and performance of a DC-targeting virus-like particle pseudotyped with an engineered Sindbis-virus glycoprotein that recognizes a surface protein on DCs, and packaging mRNA encoding for the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or for the glycoproteins B and D of herpes simplex virus 1. Injection of the DC-targeting SARS-CoV-2 mRNA vaccine in the footpad of mice led to substantially higher and durable antigen-specific immunoglobulin-G titres and cellular immune responses than untargeted virus-like particles and lipid–nanoparticle formulations. The vaccines also protected the mice from infection with SARS-CoV-2 or with herpes simplex virus 1. Virus-like particles with preferential uptake by DCs may facilitate the development of potent prophylactic and therapeutic vaccines.
{"title":"Dendritic-cell-targeting virus-like particles as potent mRNA vaccine carriers","authors":"Di Yin, Yiye Zhong, Sikai Ling, Sicong Lu, Xiaoyuan Wang, Zhuofan Jiang, Jie Wang, Yao Dai, Xiaolong Tian, Qijing Huang, Xingbo Wang, Junsong Chen, Ziying Li, Yang Li, Zhijue Xu, Hewei Jiang, Yuqing Wu, Yi Shi, Quanjun Wang, Jianjiang Xu, Wei Hong, Heng Xue, Hang Yang, Yan Zhang, Lintai Da, Ze-guang Han, Sheng-ce Tao, Ruijiao Dong, Tianlei Ying, Jiaxu Hong, Yujia Cai","doi":"10.1038/s41551-024-01208-4","DOIUrl":"https://doi.org/10.1038/s41551-024-01208-4","url":null,"abstract":"<p>Messenger RNA vaccines lack specificity for dendritic cells (DCs)—the most effective cells at antigen presentation. Here we report the design and performance of a DC-targeting virus-like particle pseudotyped with an engineered Sindbis-virus glycoprotein that recognizes a surface protein on DCs, and packaging mRNA encoding for the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or for the glycoproteins B and D of herpes simplex virus 1. Injection of the DC-targeting SARS-CoV-2 mRNA vaccine in the footpad of mice led to substantially higher and durable antigen-specific immunoglobulin-G titres and cellular immune responses than untargeted virus-like particles and lipid–nanoparticle formulations. The vaccines also protected the mice from infection with SARS-CoV-2 or with herpes simplex virus 1. Virus-like particles with preferential uptake by DCs may facilitate the development of potent prophylactic and therapeutic vaccines.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"25 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845223","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}
Pub Date : 2024-05-06DOI: 10.1038/s41551-024-01206-6
Jipeng Yan, Biao Huang, Johanna Tonko, Matthieu Toulemonde, Joseph Hansen-Shearer, Qingyuan Tan, Kai Riemer, Konstantinos Ntagiantas, Rasheda A. Chowdhury, Pier D. Lambiase, Roxy Senior, Meng-Xing Tang
Myocardial microvasculature and haemodynamics are indicative of potential microvascular diseases for patients with symptoms of coronary heart disease in the absence of obstructive coronary arteries. However, imaging microvascular structure and flow within the myocardium is challenging owing to the small size of the vessels and the constant movement of the patient’s heart. Here we show the feasibility of transthoracic ultrasound localization microscopy for imaging myocardial microvasculature and haemodynamics in explanted pig hearts and in patients in vivo. Through a customized data-acquisition and processing pipeline with a cardiac phased-array probe, we leveraged motion correction and tracking to reconstruct the dynamics of microcirculation. For four patients, two of whom had impaired myocardial function, we obtained super-resolution images of myocardial vascular structure and flow using data acquired within a breath hold. Myocardial ultrasound localization microscopy may facilitate the understanding of myocardial microcirculation and the management of patients with cardiac microvascular diseases. Transthoracic ultrasound localization microscopy enables super-resolution imaging of myocardial microvasculature and haemodynamics in patients with impaired myocardial function using data acquired within a breath hold.
{"title":"Transthoracic ultrasound localization microscopy of myocardial vasculature in patients","authors":"Jipeng Yan, Biao Huang, Johanna Tonko, Matthieu Toulemonde, Joseph Hansen-Shearer, Qingyuan Tan, Kai Riemer, Konstantinos Ntagiantas, Rasheda A. Chowdhury, Pier D. Lambiase, Roxy Senior, Meng-Xing Tang","doi":"10.1038/s41551-024-01206-6","DOIUrl":"10.1038/s41551-024-01206-6","url":null,"abstract":"Myocardial microvasculature and haemodynamics are indicative of potential microvascular diseases for patients with symptoms of coronary heart disease in the absence of obstructive coronary arteries. However, imaging microvascular structure and flow within the myocardium is challenging owing to the small size of the vessels and the constant movement of the patient’s heart. Here we show the feasibility of transthoracic ultrasound localization microscopy for imaging myocardial microvasculature and haemodynamics in explanted pig hearts and in patients in vivo. Through a customized data-acquisition and processing pipeline with a cardiac phased-array probe, we leveraged motion correction and tracking to reconstruct the dynamics of microcirculation. For four patients, two of whom had impaired myocardial function, we obtained super-resolution images of myocardial vascular structure and flow using data acquired within a breath hold. Myocardial ultrasound localization microscopy may facilitate the understanding of myocardial microcirculation and the management of patients with cardiac microvascular diseases. Transthoracic ultrasound localization microscopy enables super-resolution imaging of myocardial microvasculature and haemodynamics in patients with impaired myocardial function using data acquired within a breath hold.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 6","pages":"689-700"},"PeriodicalIF":26.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01206-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845389","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}
Pub Date : 2024-05-06DOI: 10.1038/s41551-024-01209-3
Alexander J. Najibi, Ryan S. Lane, Miguel C. Sobral, Giovanni Bovone, Shawn Kang, Benjamin R. Freedman, Joel Gutierrez Estupinan, Alberto Elosegui-Artola, Christina M. Tringides, Maxence O. Dellacherie, Katherine Williams, Hamza Ijaz, Sören Müller, Shannon J. Turley, David J. Mooney
Following immunization, lymph nodes dynamically expand and contract. The mechanical and cellular changes enabling the early-stage expansion of lymph nodes have been characterized, yet the durability of such responses and their implications for adaptive immunity and vaccine efficacy are unknown. Here, by leveraging high-frequency ultrasound imaging of the lymph nodes of mice, we report more potent and persistent lymph-node expansion for animals immunized with a mesoporous silica vaccine incorporating a model antigen than for animals given bolus immunization or standard vaccine formulations such as alum, and that durable and robust lymph-node expansion was associated with vaccine efficacy and adaptive immunity for 100 days post-vaccination in a mouse model of melanoma. Immunization altered the mechanical and extracellular-matrix properties of the lymph nodes, drove antigen-dependent proliferation of immune and stromal cells, and altered the transcriptional features of dendritic cells and inflammatory monocytes. Strategies that robustly maintain lymph-node expansion may result in enhanced vaccination outcomes. Durable and robust lymph-node expansion is associated with the efficacy of therapeutic vaccination, as shown in mice immunized via a biomaterial-based vaccine.
{"title":"Durable lymph-node expansion is associated with the efficacy of therapeutic vaccination","authors":"Alexander J. Najibi, Ryan S. Lane, Miguel C. Sobral, Giovanni Bovone, Shawn Kang, Benjamin R. Freedman, Joel Gutierrez Estupinan, Alberto Elosegui-Artola, Christina M. Tringides, Maxence O. Dellacherie, Katherine Williams, Hamza Ijaz, Sören Müller, Shannon J. Turley, David J. Mooney","doi":"10.1038/s41551-024-01209-3","DOIUrl":"10.1038/s41551-024-01209-3","url":null,"abstract":"Following immunization, lymph nodes dynamically expand and contract. The mechanical and cellular changes enabling the early-stage expansion of lymph nodes have been characterized, yet the durability of such responses and their implications for adaptive immunity and vaccine efficacy are unknown. Here, by leveraging high-frequency ultrasound imaging of the lymph nodes of mice, we report more potent and persistent lymph-node expansion for animals immunized with a mesoporous silica vaccine incorporating a model antigen than for animals given bolus immunization or standard vaccine formulations such as alum, and that durable and robust lymph-node expansion was associated with vaccine efficacy and adaptive immunity for 100 days post-vaccination in a mouse model of melanoma. Immunization altered the mechanical and extracellular-matrix properties of the lymph nodes, drove antigen-dependent proliferation of immune and stromal cells, and altered the transcriptional features of dendritic cells and inflammatory monocytes. Strategies that robustly maintain lymph-node expansion may result in enhanced vaccination outcomes. Durable and robust lymph-node expansion is associated with the efficacy of therapeutic vaccination, as shown in mice immunized via a biomaterial-based vaccine.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 10","pages":"1226-1242"},"PeriodicalIF":26.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01209-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845381","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}
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