Nature biotechnology最新文献

{"title":"Specific and efficient RNA A-to-I editing through cleavage of an ADAR inhibitor","authors":"Guangye Li, Guo Chen, Guo-Hua Yuan, Jia Wei, Qingyang Ni, Jing Wu, Bei Yang, Li Yang, Jia Chen","doi":"10.1038/s41587-025-02591-2","DOIUrl":"https://doi.org/10.1038/s41587-025-02591-2","url":null,"abstract":"<p>RNA editing can be a promising therapeutic approach. However, ectopic expression of RNA editing enzymes has been shown to trigger off-target editing. Here we identified adenosine deaminase acting on RNA (ADAR) inhibitors (ADIs) that suppress the activity of the fused ADAR2 deamination domain (ADAR2_DD). Using these specific ADIs, we develop an RNA transformer adenosine base editor (RtABE) with high specificity. Fusing ADI to ADAR2_DD, RtABE remains inactive until it binds to its target site. After binding to the target site, ADI is cleaved from ADAR2_DD, and RtABE becomes active. RtABE can induce efficient editing in broad sequence contexts, including UAN, AAN, CAN and GAN. Using an adeno-associated virus for delivery of RtABE enables therapeutic RNA correction and restoration of α-<span>l</span>-iduronidase activity in Hurler syndrome mice with no substantial off-target editing. RtABE is a specific and efficient RNA editing system with a broad scope that may be a better alternative to existing RNA editing tools.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"16 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lengthy delays in H5N1 genome submissions to GISAID","authors":"Sarah P. Otto, Sean Vidal Edgerton","doi":"10.1038/s41587-025-02636-6","DOIUrl":"https://doi.org/10.1038/s41587-025-02636-6","url":null,"abstract":"<p>Real-time surveillance of viral genomes enables the detection of new variants, the assessment of their impact on infectivity and disease severity, the estimation of rates of spread and routes of transmission using new phylogenetic tools, and evidence-based decision making by public health authorities, but it requires access to timely genomic information. Up-to-date genomic information also facilitates rapid, collaborative and interdisciplinary research and evidence-based public health responses (for example, vaccine development and deployment). Viral genetic changes have enabled transmission of the highly pathogenic avian influenza H5N1 to hundreds of species of birds and mammals^1,2,3, leading to repeated animal-to-human transmission events, including 72 reported to the World Health Organization in 2024 (ref. ⁴). Two recent reports describe patients with severe respiratory infections in Canada⁵ and the United States⁶ with viruses that were polymorphic for genetic changes previously predicted by deep mutational scanning to improve binding to human cells⁷. While these changes may have facilitated within-host viral replication, efficient human-to-human transmission of H5N1 has yet to be observed. However, this may change at any time. Real-time reporting of current H5N1 genomes is crucial, yet we find extensive delays of 7.5 months between H5N1 sample collection and submission to the Global Initiative on Sharing All Influenza Data (GISAID) repository for virus data and associated metadata^8,9.</p><p>Early on in the COVID-19 pandemic, a previous study¹⁰ highlighted lengthy delays in SARS-CoV-2 sequence submissions to GISAID, with an average of 48 days between sample collection and submission. This global analysis highlighted countries with rapid data sharing practices and pointed out others that lagged behind. Many countries subsequently improved pipelines for data submission, with collection-to-submission times (CST) now down to 30 days for samples submitted to GISAID in 2024. As an example, Canada had a CST of 88 days early in the pandemic¹⁰, but now has a median CST for SARS-CoV-2 sequences of only 16 days. Such dramatic improvements aided global efforts to track variants and to monitor the spread and public health impacts of COVID-19 over the last few years.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"57 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-dimensional imaging using combinatorial channel multiplexing and deep learning","authors":"Raz Ben-Uri, Lior Ben Shabat, Dana Shainshein, Omer Bar-Tal, Yuval Bussi, Noa Maimon, Tal Keidar Haran, Idan Milo, Inna Goliand, Yoseph Addadi, Tomer Meir Salame, Alexander Rochwarger, Christian M. Schürch, Shai Bagon, Ofer Elhanani, Leeat Keren","doi":"10.1038/s41587-025-02585-0","DOIUrl":"https://doi.org/10.1038/s41587-025-02585-0","url":null,"abstract":"<p>Understanding tissue structure and function requires tools that quantify the expression of multiple proteins at single-cell resolution while preserving spatial information. Current imaging technologies use a separate channel for each protein, limiting throughput and scalability. Here, we present combinatorial multiplexing (CombPlex), a combinatorial staining platform coupled with an algorithmic framework to exponentially increase the number of measured proteins. Every protein can be imaged in several channels and every channel contains agglomerated images of several proteins. These combinatorically compressed images are then decompressed to individual protein images using deep learning. We achieve accurate reconstruction when compressing the stains of 22 proteins to five imaging channels. We demonstrate the approach both in fluorescence microscopy and in mass-based imaging and show successful application across multiple tissues and cancer types. CombPlex can escalate the number of proteins measured by any imaging modality, without the need for specialized instrumentation.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"34 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging base excision repair for efficient adenine base editing of mitochondrial DNA","authors":"Yuhang Fan, Wenchao Xu, Bao-Qing Gao, Huichao Qin, Xiaoyi Wu, Jia Wei, Qingyang Ni, Lina Zhou, Jiangchao Xiang, Jing Wu, Bei Yang, Li Yang, Jia Chen","doi":"10.1038/s41587-025-02608-w","DOIUrl":"https://doi.org/10.1038/s41587-025-02608-w","url":null,"abstract":"<p>Transcription activator-like effector-linked deaminases (TALEDs) use their single-stranded DNA (ssDNA)-specific adenosine deaminase TadA8e to mediate A-to-G editing in mitochondrial DNA (mtDNA). The working mechanism of this process is unknown, hindering the development of more effective TALEDs. Here we reveal that TALED-mediated A-to-G editing relies on the formation of an ssDNA region through base excision repair (BER), which is triggered by double-stranded DNA-specific cytidine deaminase (DddA)-induced C-to-U deamination. We develop a series of enhanced TALEDs (eTALED6s) with increased editing efficiency by replacing DddA with the high-activity variant DddA6 and fusing human uracil DNA glycosylase to TadA8e. By further engineering TadA8e, the resulting eTALED6Rs induces efficient on-target editing with reduced bystander editing and off-target editing at the DNA and RNA levels. Lastly, we use eTALED6 and eTALED6R to install a pathogenic mutation in mtDNA. Revealing the mechanism of TALED-mediated A-to-G editing demonstrates that enhancing BER increases editing efficiency.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"57 19 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Protein Design Archive (PDA): insights from 40 years of protein design","authors":"Marta Chronowska, Michael J. Stam, Derek N. Woolfson, Luigi F. Di Costanzo, Christopher W. Wood","doi":"10.1038/s41587-025-02607-x","DOIUrl":"https://doi.org/10.1038/s41587-025-02607-x","url":null,"abstract":"<p>While natural proteins are incredibly diverse biomacromolecules, they present only a subset of the sequence and structural space that is chemically possible¹. The field of protein design has the potential to illuminate the unexplored regions of this space, to deepen our understanding of sequence–structure–function relationships, and to enable the development of novel proteins that could be used to address societal challenges.</p><p>Protein design has evolved dramatically over the past 40 years from rational design to contemporary data-driven approaches. The field has now reached milestones such as the design of small-molecule² and protein³ binders, entirely novel folds^4,5,6, and has been recognized with a Nobel Prize. However, it can be difficult to identify current challenges and opportunities within the field as no easily searchable resource provides an overview of proteins that have been designed to date. Such a resource would improve our ability to learn from previous efforts and guide the development of future design methods.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"214 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial genomics of AAV vectors reveals mechanism of transcriptional crosstalk that enables targeted delivery of large genetic cargo","authors":"Gerard M. Coughlin, Máté Borsos, Bre’Anna H. Barcelona, Nathan Appling, Acacia M. H. Mayfield, Elisha D. Mackey, Rana A. Eser, Cameron R. Jackson, Xinhong Chen, Sripriya Ravindra Kumar, Viviana Gradinaru","doi":"10.1038/s41587-025-02565-4","DOIUrl":"https://doi.org/10.1038/s41587-025-02565-4","url":null,"abstract":"<p>Cell-type-specific regulatory elements such as enhancers can direct expression of recombinant adeno-associated viruses (AAVs) to specific cell types, but this approach is limited by the relatively small packaging capacity of AAVs. In this study, we used spatial genomics to show that transcriptional crosstalk between individual AAV genomes provides a general method for cell-type-specific expression of large cargo by separating distally acting regulatory elements into a second AAV genome. We identified and profiled transcriptional crosstalk in AAV genomes carrying 11 different enhancers active in mouse brain. We developed spatial genomics methods to identify and localize AAV genomes and their concatemeric forms in cultured cells and in tissue, and we demonstrate here that transcriptional crosstalk is dependent upon concatemer formation. Finally, we leveraged transcriptional crosstalk to drive expression of a 3.2-kb Cas9 cargo in a cell-type-specific manner with systemically administered engineered AAVs, and we demonstrate AAV-delivered, minimally invasive, cell-type-specific gene editing in wild-type mice that recapitulates known disease phenotypes.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"11 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Information storage across a microbial community using universal RNA barcoding","authors":"Prashant B. Kalvapalle, August Staubus, Matthew J. Dysart, Lauren Gambill, Kiara Reyes Gamas, Li Chieh Lu, Jonathan J. Silberg, Lauren B. Stadler, James Chappell","doi":"10.1038/s41587-025-02593-0","DOIUrl":"https://doi.org/10.1038/s41587-025-02593-0","url":null,"abstract":"<p>Gene transfer can be studied using genetically encoded reporters or metagenomic sequencing but these methods are limited by sensitivity when used to monitor the mobile DNA host range in microbial communities. To record information about gene transfer across a wastewater microbiome, a synthetic catalytic RNA was used to barcode a highly conserved segment of ribosomal RNA (rRNA). By writing information into rRNA using a ribozyme and reading out native and modified rRNA using amplicon sequencing, we find that microbial community members from 20 taxonomic orders participate in plasmid conjugation with an <i>Escherichia coli</i> donor strain and observe differences in 16S rRNA barcode signal across amplicon sequence variants. Multiplexed rRNA barcoding using plasmids with pBBR1 or ColE1 origins of replication reveals differences in host range. This autonomous RNA-addressable modification provides information about gene transfer without requiring translation and will enable microbiome engineering across diverse ecological settings and studies of environmental controls on gene transfer and cellular uptake of extracellular materials.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"24 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143640967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biotech news from around the world","authors":"","doi":"10.1038/s41587-025-02599-8","DOIUrl":"10.1038/s41587-025-02599-8","url":null,"abstract":"","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"43 3","pages":"294-294"},"PeriodicalIF":33.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143640520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Philanthropic giants join forces over antimicrobial resistance","authors":"","doi":"10.1038/s41587-025-02620-0","DOIUrl":"10.1038/s41587-025-02620-0","url":null,"abstract":"","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"43 3","pages":"289-289"},"PeriodicalIF":33.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143640521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2H24 biotech job picture","authors":"Michael Francisco","doi":"10.1038/s41587-025-02586-z","DOIUrl":"10.1038/s41587-025-02586-z","url":null,"abstract":"A semiannual snapshot of job expansions, reductions and availability in the biotech and pharma sectors.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"43 3","pages":"451-451"},"PeriodicalIF":33.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143640524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}