Nature biotechnology最新文献_第7页

Dual SORT LNPs for multi-organ base editing 用于多器官碱基编辑的双排序LNPs

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-06-02 DOI: 10.1038/s41587-025-02675-z

Minjeong Kim, Eunice S. Song, Joseph C. Chen, Sumanta Chatterjee, Yehui Sun, Sang M. Lee, Shiying Wu, Priyanka Patel, Zeru Tian, Ariel Kantor, Brandon A. Wustman, David J. Lockhart, Daniel J. Siegwart

{"title":"Dual SORT LNPs for multi-organ base editing","authors":"Minjeong Kim, Eunice S. Song, Joseph C. Chen, Sumanta Chatterjee, Yehui Sun, Sang M. Lee, Shiying Wu, Priyanka Patel, Zeru Tian, Ariel Kantor, Brandon A. Wustman, David J. Lockhart, Daniel J. Siegwart","doi":"10.1038/s41587-025-02675-z","DOIUrl":"https://doi.org/10.1038/s41587-025-02675-z","url":null,"abstract":"Alpha-1 antitrypsin (A1AT) deficiency (AATD) is caused by a mutation in the SERPINA1 gene (PiZ allele), where misfolded A1AT liver accumulation leads to liver damage, and A1AT deficiency in the lungs results in emphysema due to unregulated neutrophil elastase activity. Base editing offers a potential cure for A1AT; however, effective treatment is hindered by the absence of dual-target delivery systems that can target key tissues. We developed Dual Selective ORgan-Targeting lipid nanoparticles (SORT LNPs) to deliver base editors to the liver and lungs. Dual SORT LNPs correct the PiZ mutation, achieving 40% correction editing in liver cells and 10% in lung AT2 cells. The liver maintains stable editing for 32 weeks, reducing Z-A1AT levels by over 80% and restoring a normal liver phenotype. In parallel, 89% neutrophil elastase inhibition is achieved in lung bronchoalveolar lavage fluid. Taken together, Dual SORT LNP therapy offers a promising approach for long-lasting genome correction for multi-organ diseases such as AATD.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"25 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193123","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

Large-scale discovery of chromatin dysregulation induced by oncofusions and other protein-coding variants. 大规模发现染色质失调是由同源基因融合和其他蛋白质编码变异引起的。

IF 33.1 1区生物学

Nature biotechnology Pub Date : 2025-06-01 Epub Date: 2024-07-24 DOI: 10.1038/s41587-024-02347-4

Max Frenkel, James E Corban, Margaux L A Hujoel, Zachary Morris, Srivatsan Raman

{"title":"Large-scale discovery of chromatin dysregulation induced by oncofusions and other protein-coding variants.","authors":"Max Frenkel, James E Corban, Margaux L A Hujoel, Zachary Morris, Srivatsan Raman","doi":"10.1038/s41587-024-02347-4","DOIUrl":"10.1038/s41587-024-02347-4","url":null,"abstract":"Population-scale databases have expanded to millions of protein-coding variants, yet insight into their mechanistic consequences has lagged. Here we present PROD-ATAC, a high-throughput method for discovering the effects of protein-coding variants on chromatin regulation. A pooled variant library is expressed in a disease-agnostic cell line, and single-cell assay for transposase-accessible chromatin resolves each variant's effect on the chromatin landscape. Using PROD-ATAC, we characterized the effects of more than 100 oncofusions (cancer-causing chimeric proteins) and controls and revealed that chromatin remodeling is common to fusions spanning an enormous range of fusion frequencies. Furthermore, fusion-induced dysregulation can be context agnostic, as observed mechanisms often overlapped with cancer and cell-type-specific prior knowledge. We also showed that gain-of-function activity is common among oncofusions. This work begins to outline a global map of fusion-induced chromatin alterations. We suggest that there might be convergent mechanisms among disparate oncofusions and shared modes of dysregulation among fusions present in tumors at different frequencies. PROD-ATAC is generalizable to any set of protein-coding variants.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":"996-1010"},"PeriodicalIF":33.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760014","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

Enhancing siRNA efficacy in vivo with extended nucleic acid backbones. 利用扩展核酸骨架增强 siRNA 在体内的功效。

IF 33.1 1区生物学

Nature biotechnology Pub Date : 2025-06-01 Epub Date: 2024-08-01 DOI: 10.1038/s41587-024-02336-7

Ken Yamada, Vignesh N Hariharan, Jillian Caiazzi, Rachael Miller, Chantal M Ferguson, Ellen Sapp, Hassan H Fakih, Qi Tang, Nozomi Yamada, Raymond C Furgal, Joseph D Paquette, Annabelle Biscans, Brianna M Bramato, Nicholas McHugh, Ashley Summers, Clemens Lochmann, Bruno M D C Godinho, Samuel Hildebrand, Samuel O Jackson, Dimas Echeverria, Matthew R Hassler, Julia F Alterman, Marian DiFiglia, Neil Aronin, Anastasia Khvorova

{"title":"Enhancing siRNA efficacy in vivo with extended nucleic acid backbones.","authors":"Ken Yamada, Vignesh N Hariharan, Jillian Caiazzi, Rachael Miller, Chantal M Ferguson, Ellen Sapp, Hassan H Fakih, Qi Tang, Nozomi Yamada, Raymond C Furgal, Joseph D Paquette, Annabelle Biscans, Brianna M Bramato, Nicholas McHugh, Ashley Summers, Clemens Lochmann, Bruno M D C Godinho, Samuel Hildebrand, Samuel O Jackson, Dimas Echeverria, Matthew R Hassler, Julia F Alterman, Marian DiFiglia, Neil Aronin, Anastasia Khvorova","doi":"10.1038/s41587-024-02336-7","DOIUrl":"10.1038/s41587-024-02336-7","url":null,"abstract":"Therapeutic small interfering RNA (siRNA) requires sugar and backbone modifications to inhibit nuclease degradation. However, metabolic stabilization by phosphorothioate (PS), the only backbone chemistry used clinically, may be insufficient for targeting extrahepatic tissues. To improve oligonucleotide stabilization, we report the discovery, synthesis and characterization of extended nucleic acid (exNA) consisting of a methylene insertion between the 5'-C and 5'-OH of a nucleoside. exNA incorporation is compatible with common oligonucleotide synthetic protocols and the PS backbone, provides stabilization against 3' and 5' exonucleases and is tolerated at multiple oligonucleotide positions. A combined exNA-PS backbone enhances resistance to 3' exonuclease by ~32-fold over the conventional PS backbone and by >1,000-fold over the natural phosphodiester backbone, improving tissue exposure, tissue accumulation and efficacy in mice, both systemically and in the brain. The improved efficacy and durability imparted by exNA may enable therapeutic interventions in extrahepatic tissues, both with siRNA and with other oligonucleotides such as CRISPR guide RNA, antisense oligonucleotides, mRNA and tRNA.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":"904-913"},"PeriodicalIF":33.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875452","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

Anatomy of the 23andMe fall and implications for consumer genomics 剖析23andMe的衰落及其对消费者基因组学的影响

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-05-29 DOI: 10.1038/s41587-025-02683-z

Yaniv Erlich, Dina Zielinski

引用次数: 0

Self-supervised learning from small-molecule mass spectrometry data 从小分子质谱数据中进行自我监督学习

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-05-23 DOI: 10.1038/s41587-025-02677-x

Wout Bittremieux, William Stafford Noble

引用次数: 0

Self-supervised learning of molecular representations from millions of tandem mass spectra using DreaMS 使用DreaMS对数百万串联质谱的分子表征进行自我监督学习

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-05-23 DOI: 10.1038/s41587-025-02663-3

Roman Bushuiev, Anton Bushuiev, Raman Samusevich, Corinna Brungs, Josef Sivic, Tomáš Pluskal

{"title":"Self-supervised learning of molecular representations from millions of tandem mass spectra using DreaMS","authors":"Roman Bushuiev, Anton Bushuiev, Raman Samusevich, Corinna Brungs, Josef Sivic, Tomáš Pluskal","doi":"10.1038/s41587-025-02663-3","DOIUrl":"https://doi.org/10.1038/s41587-025-02663-3","url":null,"abstract":"Characterizing biological and environmental samples at a molecular level primarily uses tandem mass spectroscopy (MS/MS), yet the interpretation of tandem mass spectra from untargeted metabolomics experiments remains a challenge. Existing computational methods for predictions from mass spectra rely on limited spectral libraries and on hard-coded human expertise. Here we introduce a transformer-based neural network pre-trained in a self-supervised way on millions of unannotated tandem mass spectra from our GNPS Experimental Mass Spectra (GeMS) dataset mined from the MassIVE GNPS repository. We show that pre-training our model to predict masked spectral peaks and chromatographic retention orders leads to the emergence of rich representations of molecular structures, which we named Deep Representations Empowering the Annotation of Mass Spectra (DreaMS). Further fine-tuning the neural network yields state-of-the-art performance across a variety of tasks. We make our new dataset and model available to the community and release the DreaMS Atlas—a molecular network of 201 million MS/MS spectra constructed using DreaMS annotations.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"56 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122573","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

Deep-learning-based single-domain and multidomain protein structure prediction with D-I-TASSER 基于深度学习的D-I-TASSER蛋白单域和多域结构预测

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-05-23 DOI: 10.1038/s41587-025-02654-4

Wei Zheng, Qiqige Wuyun, Yang Li, Quancheng Liu, Xiaogen Zhou, Chunxiang Peng, Yiheng Zhu, Lydia Freddolino, Yang Zhang

{"title":"Deep-learning-based single-domain and multidomain protein structure prediction with D-I-TASSER","authors":"Wei Zheng, Qiqige Wuyun, Yang Li, Quancheng Liu, Xiaogen Zhou, Chunxiang Peng, Yiheng Zhu, Lydia Freddolino, Yang Zhang","doi":"10.1038/s41587-025-02654-4","DOIUrl":"https://doi.org/10.1038/s41587-025-02654-4","url":null,"abstract":"The dominant success of deep learning techniques on protein structure prediction has challenged the necessity and usefulness of traditional force field-based folding simulations. We proposed a hybrid approach, deep-learning-based iterative threading assembly refinement (D-I-TASSER), which constructs atomic-level protein structural models by integrating multisource deep learning potentials with iterative threading fragment assembly simulations. D-I-TASSER introduces a domain splitting and assembly protocol for the automated modeling of large multidomain protein structures. Benchmark tests and the most recent critical assessment of protein structure prediction, 15 experiments demonstrate that D-I-TASSER outperforms AlphaFold2 and AlphaFold3 on both single-domain and multidomain proteins. Large-scale folding experiments further show that D-I-TASSER could fold 81% of protein domains and 73% of full-chain sequences in the human proteome with results highly complementary to recently released models by AlphaFold2. These results highlight a new avenue to integrate deep learning with classical physics-based folding simulations for high-accuracy protein structure and function predictions that are usable in genome-wide applications.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"1 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122574","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 multi-kingdom genetic barcoding system for precise clone isolation 用于精确克隆分离的多界遗传条形码系统

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-05-21 DOI: 10.1038/s41587-025-02649-1

Soh Ishiguro, Kana Ishida, Rina C. Sakata, Minori Ichiraku, Ren Takimoto, Rina Yogo, Yusuke Kijima, Hideto Mori, Mamoru Tanaka, Samuel King, Shoko Tarumoto, Taro Tsujimura, Omar Bashth, Nanami Masuyama, Arman Adel, Hiromi Toyoshima, Motoaki Seki, Ju Hee Oh, Anne-Sophie Archambault, Keiji Nishida, Akihiko Kondo, Satoru Kuhara, Hiroyuki Aburatani, Ramon I. Klein Geltink, Takuya Yamamoto, Nika Shakiba, Yasuhiro Takashima, Nozomu Yachie

{"title":"A multi-kingdom genetic barcoding system for precise clone isolation","authors":"Soh Ishiguro, Kana Ishida, Rina C. Sakata, Minori Ichiraku, Ren Takimoto, Rina Yogo, Yusuke Kijima, Hideto Mori, Mamoru Tanaka, Samuel King, Shoko Tarumoto, Taro Tsujimura, Omar Bashth, Nanami Masuyama, Arman Adel, Hiromi Toyoshima, Motoaki Seki, Ju Hee Oh, Anne-Sophie Archambault, Keiji Nishida, Akihiko Kondo, Satoru Kuhara, Hiroyuki Aburatani, Ramon I. Klein Geltink, Takuya Yamamoto, Nika Shakiba, Yasuhiro Takashima, Nozomu Yachie","doi":"10.1038/s41587-025-02649-1","DOIUrl":"https://doi.org/10.1038/s41587-025-02649-1","url":null,"abstract":"Cell-tagging strategies with DNA barcodes have enabled the analysis of clone size dynamics and clone-restricted transcriptomic landscapes in heterogeneous populations. However, isolating a target clone that displays a specific phenotype from a complex population remains challenging. Here we present a multi-kingdom genetic barcoding system, CloneSelect, which enables a target cell clone to be triggered to express a reporter gene for isolation through barcode-specific CRISPR base editing. In CloneSelect, cells are first stably tagged with DNA barcodes and propagated so that their subpopulation can be subjected to a given experiment. A clone that shows a phenotype or genotype of interest at a given time can then be isolated from the initial or subsequent cell pools stored during the experiment using CRISPR base editing. CloneSelect is scalable and compatible with single-cell RNA sequencing. We demonstrate the versatility of CloneSelect in human embryonic kidney 293T cells, mouse embryonic stem cells, human pluripotent stem cells, yeast cells and bacterial cells.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"45 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103958","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

Beyond cell atlases: spatial biology reveals mechanisms behind disease 超越细胞图谱：空间生物学揭示疾病背后的机制

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-05-21 DOI: 10.1038/s41587-025-02699-5

引用次数: 0

Retargeted retrotransposons insert multi-kilobase cargo at new sites 重靶向逆转录转座子在新的位点插入数千个碱基的货物

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-05-16 DOI: 10.1038/s41587-025-02682-0

Iris Marchal

{"title":"Retargeted retrotransposons insert multi-kilobase cargo at new sites","authors":"Iris Marchal","doi":"10.1038/s41587-025-02682-0","DOIUrl":"https://doi.org/10.1038/s41587-025-02682-0","url":null,"abstract":"Site-specific retroelements, such as R2 retrotransposons, have potential as programmable genome-editing systems, but so far have only been used for targeted insertion at genomic safe-harbor loci. In a paper now published in Nature, Fell et al. profile the evolution of site-specific retrotransposon families to gain insight into target site preferences, which they then used to engineer reprogramming.By surveying 4,464 animal assemblies derived from Genbank, the authors discovered several new site-specific retrotransposon families, including families with multiple integration preferences and with differing 5′ and 3′ site predictions, which might indicate retargeting mechanisms. They zoned in on a retrotransposon from the zebra finch (Taeniopygia guttata), called R2Tg, for biochemical profiling and characterized its activity in mammalian cells, which showed that R2Tg can insert payloads by reverse transcription of RNA and nicking of genomic DNA. Notably, the authors found that R2Tg can be retargeted by engineering the payload, which allowed scarless insertion of the payload at new genomic sites. The activity of the reprogrammed R2Tg was enhanced by fusing it with CRISPR–Cas9 nickase.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"16 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066955","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