Nature biotechnology最新文献

{"title":"A light-inducible RNA base editor for precise gene expression","authors":"","doi":"10.1038/s41587-025-02621-z","DOIUrl":"https://doi.org/10.1038/s41587-025-02621-z","url":null,"abstract":"A lack of broadly applicable methods to precisely control therapeutic gene expression is a key challenge for gene therapies. We present a technology that offers a photoactivatable RNA base editor for tunable and reversible regulation of gene expression, with implications for improving the safety and efficacy of gene therapy.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"36 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736579","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":"Engineering a photoactivatable A-to-I RNA base editor for gene therapy in vivo","authors":"Huiying Li, Yuhao Qiu, Bowen Song, Xinyi Quan, Dan Zhang, Xinru Li, Jingyun Yang, Xiaohong Liu, Zhiyang Zeng, Ji Jing, Shuming Yin, Qi Dai, Liren Wang, Honghui Han, Haifeng Ye, Zhenliang Sun, Yiyun Cheng, Xueli Zhang, Bing Du, Mingyao Liu, Dali Li","doi":"10.1038/s41587-025-02610-2","DOIUrl":"https://doi.org/10.1038/s41587-025-02610-2","url":null,"abstract":"<p>Tunable and reversible regulation of exogenous and endogenous gene expression would be useful for improving the safety and efficacy of gene therapy. Current chemically inducible systems are limited by the rapid diffusion and extended metabolism of small molecules, and associated side effects. Here we develop a photoactivatable RNA adenosine base editor (PA-rABE) by harnessing a compact Cas13 variant and a split ADAR2 deaminase fused with the Magnets system, which is activated through blue-light-induced dimerization. PA-rABE achieves highly efficient editing on endogenous RNA with minimal bystander editing and off-target effects. By editing a phosphorylation site of the endogenous <i>CTNNB1</i> gene, PA-rABE stabilizes the β-catenin protein and activates Wnt signaling in vivo. Using adeno-associated virus vectors to deliver PA-rABE along with an h<i>F9</i> variant containing a premature termination codon, we show amelioration of clotting defects in hemophilia B mice upon illumination. In summary, PA-rABE offers a controlled RNA base-editing technology for diverse biomedical applications, enabling reversible and spatiotemporally specific modulation.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"49 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736750","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":"Sensitive detection of gene transfer in a microbial community","authors":"","doi":"10.1038/s41587-025-02639-3","DOIUrl":"https://doi.org/10.1038/s41587-025-02639-3","url":null,"abstract":"Gene transfer enables bacteria to adapt to their environment. To sensitively detect gene transfer, we created a synthetic biology tool that introduces an identifiable barcode into RNA when microbes exchange DNA. When applied in a wastewater community, high-throughput sequencing revealed which microbes in the community participated in gene transfer.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"15 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723134","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 transcriptomic imaging of an intact organism using volumetric DNA microscopy","authors":"Nianchao Qian, Joshua A. Weinstein","doi":"10.1038/s41587-025-02613-z","DOIUrl":"https://doi.org/10.1038/s41587-025-02613-z","url":null,"abstract":"<p>Lymphatic, nervous and tumor tissues exhibit complex physiology arising from three-dimensional interactions within genetically unique microenvironments. Here we develop a technology capable of volumetrically imaging transcriptomes, genotypes and morphologies in a single measurement, without relying on prior knowledge of spatial organization or genetic sequences. Our method extends DNA microscopy into three dimensions at scales involving 10⁷ molecules by forming a distributed intermolecular network of proximal unique DNA barcodes tagging complementary DNA molecules inside the specimen. After sequencing the DNA-encoded network, an image of molecular positions is inferred using geodesic spectral embeddings, a dimensionality reduction approach that we show to be especially suitable for this data-inverse problem. Applying whole-transcriptome volumetric DNA microscopy to intact zebrafish embryos, we demonstrate that three-dimensional image inference recapitulates zebrafish morphology and known gene expression patterns, capturing the spatial organization of gene sequences. Our extension of spatial genetic measurements to three dimensions, independent of prior templates, opens the door to detailed joint resolution of genomics and morphology in biological tissues.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"34 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712833","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":"Volumetric imaging using a distributed molecular network","authors":"","doi":"10.1038/s41587-025-02640-w","DOIUrl":"https://doi.org/10.1038/s41587-025-02640-w","url":null,"abstract":"We introduce volumetric DNA microscopy, a technique that enables three-dimensional imaging of tissue morphology and gene expression in a single measurement. This feat is achieved by forming a huge intermolecular network of DNA barcodes within an intact specimen and encoding their pairwise proximities into a DNA sequence library.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"57 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712832","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":"Induced proximity at the cell surface","authors":"Nicholas A. Till, Muthukumar Ramanathan, Carolyn R. Bertozzi","doi":"10.1038/s41587-025-02592-1","DOIUrl":"https://doi.org/10.1038/s41587-025-02592-1","url":null,"abstract":"<p>Molecular proximity is a governing principle of biology that is essential to normal and disease-related biochemical pathways. At the cell surface, protein–protein proximity regulates receptor activation, inhibition and protein recycling and degradation. Induced proximity is a molecular engineering principle in which bifunctional molecules are designed to bring two protein targets into close contact, inducing a desired biological outcome. Researchers use this engineering principle for therapeutic purposes and to interrogate fundamental biological mechanisms. This Review focuses on the use of induced proximity at the cell surface for diverse applications, such as targeted protein degradation, receptor inhibition and activating intracellular signaling cascades. We see a rich future for proximity-based modulation of cell surface protein activity both in basic and translational science.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"99 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702898","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":"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}