Nature biotechnology最新文献_第9页

Improved RNA base editing with guide RNAs mimicking highly edited endogenous ADAR substrates 利用模拟高度编辑的内源性ADAR底物的引导RNA改进RNA碱基编辑

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-04-03 DOI: 10.1038/s41587-025-02628-6

Yuanfan Sun, Yong Cao, Yulong Song, Jin Li, Yongheng Hou, Wen Huang, Guodong Xie, Wenbing Yang, Rui Zhang

{"title":"Improved RNA base editing with guide RNAs mimicking highly edited endogenous ADAR substrates","authors":"Yuanfan Sun, Yong Cao, Yulong Song, Jin Li, Yongheng Hou, Wen Huang, Guodong Xie, Wenbing Yang, Rui Zhang","doi":"10.1038/s41587-025-02628-6","DOIUrl":"https://doi.org/10.1038/s41587-025-02628-6","url":null,"abstract":"Adenosine deaminase acting on RNA (ADAR)-mediated RNA base editing offers a safer alternative to genome editing for specific clinical applications because of nonpermanent editing of targets. Current guide RNA (gRNA) designs feature a fully complementary specificity domain with an A–C mismatch at the targeted adenosine. However, perfectly matched dsRNA is not the most effective ADAR substrate. Here we introduce MIRROR (mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides), an approach that implements structural motifs derived from highly edited inverted Alu repeats in human tissues to enable rational gRNA design for ADAR recruitment. We demonstrated that MIRROR is applicable to both short chemically synthesized gRNAs with modifications and long biologically generated gRNAs and surpasses current state-of-the-art approaches in both gRNA forms. It enhances editing efficiency by up to 5.7-fold in multiple human cell types and primary hepatocytes from an alpha-1 antitrypsin deficiency mouse model. Our findings improve programmable RNA editing in vitro and in vivo by rational design through the screening of highly edited natural substrate mimics.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"57 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766563","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}

引用次数: 0

Openness guides discovery 开放引导发现

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-04-02 DOI: 10.1038/s41587-025-02635-7

Itai Yanai, Martin J. Lercher

{"title":"Openness guides discovery","authors":"Itai Yanai, Martin J. Lercher","doi":"10.1038/s41587-025-02635-7","DOIUrl":"https://doi.org/10.1038/s41587-025-02635-7","url":null,"abstract":"In reality, research projects grow through an evolutionary process. Variation — the substrate of evolution — is provided through the emergence of new questions and avenues of investigation. The research team must then choose which directions to pursue, a process akin to natural selection1. Along with this evolution at the macro-scale, a much more orderly process is required at the micro-scale. Within each step, thoughtful study design leads to robust experiments and analyses. This complementarity between evolution and design best encapsulates the process of discovery: in ‘night science’ we evolve ideas for the next step, while ‘day science’ tests them2.A project’s evolutionary history is generally obscured in the resulting scientific publication. The publication’s function is to justify and communicate the project’s main results; it is not a historical account. Instead of recounting all of the project’s dried-up branches, publications zoom in on a single lineage in its evolution: the steps that led to the most interesting result (Fig. 1c). Publications typically describe the discovery as it ideally should have happened, reporting only the evidence relevant to the proposed claims3.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"37 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758447","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}

引用次数: 0

The emerging landscape of engineered bacteria cancer therapies 工程菌癌症疗法的新兴前景

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-04-01 DOI: 10.1038/s41587-025-02623-x

Edward R. Ballister, Alexander Michels, Rosa L. Vincent, Lior Kreindler, Sreyan Chowdhury, Samik Upadhaya, Ana Rosa Saez-Ibañez, Tao Tu, Juraj Gottweis, Tal Danino

引用次数: 0

Circular RNA aptamers targeting neuroinflammation ameliorate Alzheimer disease phenotypes in mouse models 靶向神经炎症的环状RNA适体改善小鼠模型中的阿尔茨海默病表型

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-03-31 DOI: 10.1038/s41587-025-02624-w

Xin Feng, Bo-Wen Jiang, Si-Nan Zhai, Chu-Xiao Liu, Hao Wu, Bang-Qi Zhu, Meng-Yuan Wei, Jia Wei, Li Yang, Ling-Ling Chen

{"title":"Circular RNA aptamers targeting neuroinflammation ameliorate Alzheimer disease phenotypes in mouse models","authors":"Xin Feng, Bo-Wen Jiang, Si-Nan Zhai, Chu-Xiao Liu, Hao Wu, Bang-Qi Zhu, Meng-Yuan Wei, Jia Wei, Li Yang, Ling-Ling Chen","doi":"10.1038/s41587-025-02624-w","DOIUrl":"https://doi.org/10.1038/s41587-025-02624-w","url":null,"abstract":"Alzheimer disease (AD) therapy may benefit from optimized approaches to inhibit neuroinflammation. Small-molecule inhibitors of the proinflammatory molecule double-stranded RNA (dsRNA)-activated protein kinase R (PKR) have efficacy in AD models but their utility is compromised by adverse side effects. Here, we target PKR in two mouse models of AD using circular RNAs containing short double-stranded regions (ds-cRNAs), which are structurally similar to what we used previously to target PKR in psoriasis models. We show that the intrahippocampal injection of ds-cRNAs to neurons and microglia by adeno-associated virus (AAV) effectively dampens excessive PKR activity with minimal toxicity, accompanied by reduced neuroinflammation and amyloid-β plaques. We also deliver ds-cRNAs to the whole brain through intravenous injection of AAV-PHP.eB, which crosses the blood–brain barrier, resulting in neuroprotection and enhanced capability of spatial learning and memory in AD mouse models. The delivery of ds-cRNAs at different progressive stages of AD alleviates disease phenotypes, with therapeutic effects sustained for at least 6 months after a single administration.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"4 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736577","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}

引用次数: 0

A light-inducible RNA base editor for precise gene expression 用于精确基因表达的光诱导RNA碱基编辑器

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-03-31 DOI: 10.1038/s41587-025-02621-z

引用次数: 0

Engineering a photoactivatable A-to-I RNA base editor for gene therapy in vivo 设计用于体内基因治疗的光激活a -to- i RNA碱基编辑器

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-03-31 DOI: 10.1038/s41587-025-02610-2

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

{"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":"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 CTNNB1 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 hF9 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.","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}

引用次数: 0

Sensitive detection of gene transfer in a microbial community 微生物群落中基因转移的灵敏检测

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-03-28 DOI: 10.1038/s41587-025-02639-3

引用次数: 0

Spatial transcriptomic imaging of an intact organism using volumetric DNA microscopy 空间转录组成像的一个完整的有机体使用体积DNA显微镜

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-03-27 DOI: 10.1038/s41587-025-02613-z

Nianchao Qian, Joshua A. Weinstein

{"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":"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.","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}

引用次数: 0

Volumetric imaging using a distributed molecular network 使用分布式分子网络的体积成像

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-03-27 DOI: 10.1038/s41587-025-02640-w

引用次数: 0

Induced proximity at the cell surface 在细胞表面诱导接近

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-03-26 DOI: 10.1038/s41587-025-02592-1

Nicholas A. Till, Muthukumar Ramanathan, Carolyn R. Bertozzi

引用次数: 0