{"title":"A live bacteria enzyme assay for identification of human disease mutations and drug screening","authors":"Donghui Choe, Bernhard O. Palsson","doi":"10.1038/s41551-025-01391-y","DOIUrl":"https://doi.org/10.1038/s41551-025-01391-y","url":null,"abstract":"<p>Advances in high-throughput sequencing have enabled the identification of genetic variations associated with human disease. However, deciphering the functional significance of these variations remains challenging. Here we propose an alternative approach that uses humanized <i>Escherichia coli</i> to study human genetic enzymopathies and to screen candidate drug effects on metabolic targets. By replacing selected <i>E. coli</i> metabolic enzymes with their human orthologues and their sequence variants, we demonstrate that the growth rate of <i>E. coli</i> reflects the in vivo activity of heterologously expressed human enzymes. This approach accurately reflected enzyme activities of known sequence variants, enabling rapid screening of causal sequence variations associated with human diseases. This approach bridges the gap between in vitro assays and cell-based assays. Our findings suggest that the proposed approach using a humanized <i>E. coli</i> strain holds promise for drug discovery, offering a high-throughput and cost-effective platform for identifying new compounds targeting human enzymes. Continued research and innovation in this field have the potential to impact the development and practice of precision medicine.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"35 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889905","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}
Yoojin Kim, Yeongju Yeo, Minju Kim, Yong-Wook Son, Joowon Kim, Koung Li Kim, Seohee Kim, Seokmin Oh, Yunha Kim, Hyowoo Lee, Hyun-Woo Park, Dongsoo Lee, Sung Jin Lee, Changmin Kang, Hongyoung Choi, Chan Soon Park, Seung-Pyo Lee, Wonhee Suh, Jae-Hyung Jang
{"title":"A highly mobile adeno-associated virus targeting vascular smooth muscle cells for the treatment of pulmonary arterial hypertension","authors":"Yoojin Kim, Yeongju Yeo, Minju Kim, Yong-Wook Son, Joowon Kim, Koung Li Kim, Seohee Kim, Seokmin Oh, Yunha Kim, Hyowoo Lee, Hyun-Woo Park, Dongsoo Lee, Sung Jin Lee, Changmin Kang, Hongyoung Choi, Chan Soon Park, Seung-Pyo Lee, Wonhee Suh, Jae-Hyung Jang","doi":"10.1038/s41551-025-01379-8","DOIUrl":"https://doi.org/10.1038/s41551-025-01379-8","url":null,"abstract":"<p>In pulmonary arterial hypertension (PAH), a phenotypic switch in pulmonary arterial smooth muscle cells (PASMCs) that is primarily caused by aberrant gene regulatory networks can lead to dysregulated vascular remodelling, heart failure or death. No curative therapies for PAH are currently available, presumably because of a lack of viral vectors specifically targeting PASMCs. Here we show that a highly mobile and PASMC-tropic adeno-associated virus variant developed via directed evolution overcomes physical barriers that inhibit its transfer from bronchial airways to vascular layers, ultimately boosting therapeutic efficacy in murine models of PAH. Intratracheal administration of the adeno-associated virus variant carrying a transgene for fibroblast growth factor 12—a key factor regulating the PASMC phenotype—suppressed pulmonary vascular remodelling, prevented the development of PAH in mice and reversed established PAH in rats. The variant’s mobility and enhanced tropism for PASMCs may enable curative treatments for PAH.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"18 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884825","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}
Alix Trouillet, Emilie Revol, Florent-Valéry Coen, Florian Fallegger, Aurélie Chanthany, Maude Delacombaz, Laurine Kolly, Ivan Furfaro, Florian Lanz, Vivek Kanumuri, Victor Adenis, Alejandro Garcia-Chavez, M. Christian Brown, Lukas Anschuetz, Jocelyne Bloch, Daniel J. Lee, Stéphanie P. Lacour
{"title":"High-resolution prosthetic hearing with a soft auditory brainstem implant in macaques","authors":"Alix Trouillet, Emilie Revol, Florent-Valéry Coen, Florian Fallegger, Aurélie Chanthany, Maude Delacombaz, Laurine Kolly, Ivan Furfaro, Florian Lanz, Vivek Kanumuri, Victor Adenis, Alejandro Garcia-Chavez, M. Christian Brown, Lukas Anschuetz, Jocelyne Bloch, Daniel J. Lee, Stéphanie P. Lacour","doi":"10.1038/s41551-025-01378-9","DOIUrl":"https://doi.org/10.1038/s41551-025-01378-9","url":null,"abstract":"<p>Individuals with compromised cochlear nerves are ineligible for cochlear implants and instead rely on auditory brainstem implants (ABIs). Most users of ABIs experience sound awareness, which aids in lip reading, yet not speech intelligibility. Here we engineered a dual-site (brainstem and cortex) implantable system, scaled to macaque anatomy, for the analysis of auditory perception evoked by electrical stimulation of the cochlear nucleus. A soft multichannel ABI, fabricated using thin-film processing, provided high-resolution auditory percepts, with spatially distinct stimulation sites eliciting cortical responses akin to frequency-specific tuning. Behavioural responses collected over several months were sufficiently precise to distinguish stimulations from adjacent channels. Soft multichannel ABIs may aid the rehabilitation of individuals with profound hearing loss who are ineligible for cochlear implants.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"17 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846443","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}
Matthias R. Kollert, Martin Krämer, Nicholas M. Brisson, Victoria Schemenz, Serafeim Tsitsilonis, Taimoor H. Qazi, Peter Fratzl, Viola Vogel, Jürgen R. Reichenbach, Georg N. Duda
{"title":"Water and ions binding to extracellular matrix drives stress relaxation, aiding MRI detection of swelling-associated pathology","authors":"Matthias R. Kollert, Martin Krämer, Nicholas M. Brisson, Victoria Schemenz, Serafeim Tsitsilonis, Taimoor H. Qazi, Peter Fratzl, Viola Vogel, Jürgen R. Reichenbach, Georg N. Duda","doi":"10.1038/s41551-025-01369-w","DOIUrl":"https://doi.org/10.1038/s41551-025-01369-w","url":null,"abstract":"<p>Swelling-associated changes in extracellular matrix (ECM) occur in many pathological conditions involving inflammation or oedema. Here we show that alterations in the proportion of loosely bound water in ECM correlate with changes in ECM elasticity and stress relaxation, owing to the strength of water binding to ECM being primarily governed by osmolality and the electrostatic properties of proteoglycans. By using mechanical testing and small-angle X-ray scattering, as well as magnetic resonance imaging (MRI) to detect changes in loosely bound water, we observed that enhanced water binding manifests as greater resistance to compression (mechanical or osmotic), resulting from increased electrostatic repulsion between negatively charged proteoglycans rather than axial contraction in collagen fibrils. This indicates that electrostatic contributions of proteoglycans regulate elasticity and stress relaxation independently of hydration. Our ex vivo experiments in osmotically modulated tendon elucidate physical causes of MRI signal alterations, in agreement with pilot in vivo MRI of inflammatory Achilles tendinopathy. We suggest that the strength of water binding to ECM regulates cellular niches and can be exploited to enhance MRI-informed diagnostics of swelling-associated tissue pathology.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"108 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831751","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}
{"title":"An implantable hydrogel-based phononic crystal for continuous and wireless monitoring of internal tissue strains","authors":"Ye Tian, Yueying Yang, Hanchuan Tang, Jiaxin Wang, Na Li, Yifan Cheng, Tianyu Kang, Jiarui Tang, Mengyuan Zhou, Wei Chen, Yan Yu, Xinqi Liu, Xurui Liu, Liqun Xu, Zhouping Yin, Jianfeng Zang","doi":"10.1038/s41551-025-01374-z","DOIUrl":"https://doi.org/10.1038/s41551-025-01374-z","url":null,"abstract":"<p>Conventional implantable electronic sensors for continuous monitoring of internal tissue strains are yet to match the biomechanics of tissues while maintaining biodegradability, biocompatibility and wireless monitoring capability. Here we present a two-dimensional phononic crystal composed of periodic air columns in soft hydrogel, which was named ultrasonic metagel, and we demonstrate its use as implantable sensor for continuous and wireless monitoring of internal tissue strains. The metagel’s deformation shifts its ultrasonic bandgap, which can be wirelessly detected by an external ultrasonic probe. We demonstrate ex vivo the ability of the metagel sensor for monitoring tissue strains on porcine tendon, wounded tissue and heart. In live pigs, we further demonstrate the ability of the metagel to monitor tendon stretching, respiration and heartbeat, working stably during 30 days of implantation, and we loaded the metagel with growth factors to achieve different healing rates in subcutaneous wounds. The metagel results almost completely degraded 12 weeks after implantation. Our finding highlights the clinical potential of the ultrasonic sensor for tendon rehabilitation monitoring and drug delivery efficacy evaluation.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"6 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827144","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}
Xi Tian, Michael E. Werner, Kyle C. Roche, Ariel D. Hanson, Henry P. Foote, Stephanie K. Yu, Samuel B. Warner, Jonathan A. Copp, Haydee Lara, Eliane L. Wauthier, Joseph M. Caster, Laura E. Herring, Longzhen Zhang, Joel E. Tepper, David S. Hsu, Tian Zhang, Lola M. Reid, Andrew Z. Wang
{"title":"Author Correction: Organ-specific metastases obtained by culturing colorectal cancer cells on tissue-specific decellularized scaffolds","authors":"Xi Tian, Michael E. Werner, Kyle C. Roche, Ariel D. Hanson, Henry P. Foote, Stephanie K. Yu, Samuel B. Warner, Jonathan A. Copp, Haydee Lara, Eliane L. Wauthier, Joseph M. Caster, Laura E. Herring, Longzhen Zhang, Joel E. Tepper, David S. Hsu, Tian Zhang, Lola M. Reid, Andrew Z. Wang","doi":"10.1038/s41551-025-01383-y","DOIUrl":"https://doi.org/10.1038/s41551-025-01383-y","url":null,"abstract":"<p>Correction to: <i>Nature Biomedical Engineering</i> https://doi.org/10.1038/s41551-018-0231-0, published online 23 April 2018.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"245 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806110","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}
{"title":"Site-directed antibody conjugation via ubiquitination","authors":"","doi":"10.1038/s41551-025-01368-x","DOIUrl":"https://doi.org/10.1038/s41551-025-01368-x","url":null,"abstract":"The method uses ubiquitin biochemistry in vitro to achieve rapid and site-specific protein conjugation to generate homogeneous multimeric antibody conjugates. It addresses limitations of traditional conjugation methods, and it may aid the development of antibody therapies and vaccines.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"35 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805683","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}
{"title":"In vivo generation of tolerogenic APCs using PDL1 mRNA-loaded nanoparticles","authors":"","doi":"10.1038/s41551-025-01384-x","DOIUrl":"https://doi.org/10.1038/s41551-025-01384-x","url":null,"abstract":"We have developed a versatile method for generating tolerogenic antigen-presenting cells in vivo by delivering mRNA encoding PDL1 via lipid nanoparticles. These tolerogenic antigen-presenting cells selectively target and suppress activated T cells while sparing naive T cells, preventing autoimmune disease progression in mouse models.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"10 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806009","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}
Angela F. el Hebieshy, Zacharias Wijfjes, Camille M. Le Gall, Jim Middelburg, Kim E. de Roode, Felix L. Fennemann, Marjolein Sluijter, Thorbald van Hall, Douwe J. Dijkstra, Leendert A. Trouw, Floris J. van Dalen, Andrea Rodgers Furones, Johan M. S. van der Schoot, Ian Derksen, Hans de Haard, Bas van der Woning, Cami M. P. Talavera Ormeño, Bjorn R. van Doodewaerd, Carl G. Figdor, Gerbrand J. van der Heden van Noort, Paul W. H. I. Parren, Sandra Heskamp, Huib Ovaa, Martijn Verdoes, Ferenc A. Scheeren
{"title":"Site-directed multivalent conjugation of antibodies to ubiquitinated payloads","authors":"Angela F. el Hebieshy, Zacharias Wijfjes, Camille M. Le Gall, Jim Middelburg, Kim E. de Roode, Felix L. Fennemann, Marjolein Sluijter, Thorbald van Hall, Douwe J. Dijkstra, Leendert A. Trouw, Floris J. van Dalen, Andrea Rodgers Furones, Johan M. S. van der Schoot, Ian Derksen, Hans de Haard, Bas van der Woning, Cami M. P. Talavera Ormeño, Bjorn R. van Doodewaerd, Carl G. Figdor, Gerbrand J. van der Heden van Noort, Paul W. H. I. Parren, Sandra Heskamp, Huib Ovaa, Martijn Verdoes, Ferenc A. Scheeren","doi":"10.1038/s41551-024-01342-z","DOIUrl":"https://doi.org/10.1038/s41551-024-01342-z","url":null,"abstract":"<p>Antibody conjugates are the foundation of a wide range of diagnostic and therapeutic applications. Although many antibody-conjugation techniques are robust and efficient, obtaining homogeneous multimeric conjugation products remains challenging. Here we report a modular and versatile technique for the site-directed multivalent conjugation of antibodies via the small-protein ubiquitin. Specifically, multiple ubiquitin fusions with antibodies, antibody fragments, nanobodies, peptides or small molecules such as fluorescent dyes can be conjugated to antibodies and nanobodies within 30 min. The technique, which we named ‘ubi-tagging’, allowed us to efficiently generate a bispecific T-cell engager as well as nanobodies conjugated to dendritic-cell-targeted antigens that led to potent T-cell responses. Using both recombinant ubi-tagged proteins and synthetic ubiquitin derivatives allows for the iterative, site-directed and multivalent conjugation of antibodies and nanobodies to a plethora of molecular moieties.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"1 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805684","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}
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