Nature biotechnology最新文献

{"title":"Engineered bacterial siderophore production accelerates rock weathering for carbon removal.","authors":"Neil C Dalvie, Amogh P Jalihal, Abigail Fitzgibbon, Jan-Tobias Böhnke, Mohammed Hijaz, Quincey A Justman, Steven J Davis, Pamela A Silver, Michael Springer","doi":"10.1038/s41587-026-03288-w","DOIUrl":"10.1038/s41587-026-03288-w","url":null,"abstract":"<p><p>Silicate mineral weathering (dissolution) is a scalable strategy for capture and storage of CO₂ but is too slow for industrial deployment. Bacteria can accelerate mineral dissolution by secreting siderophores, molecules that solubilize iron released from the mineral. Here we investigate how to deploy siderophore-producing bacteria at scale to continuously enhance dissolution of the mineral olivine. We demonstrate that natural genetic regulation precludes continuous siderophore production in mineral bioreactors. To overcome this limitation, we engineer the marine bacterium Alteromonas macleodii for enhanced siderophore production, conferring a 2.6-fold increase in the rate of olivine dissolution. Life-cycle analysis indicated that renewable feedstocks and minimal replenishment of modified cells are critical to achieve net CO₂ removal at scale. With these guidelines, we constructed pilot-scale continuous mineral bioreactors that use unprocessed seawater and a renewable acetate feedstock to weather 4 kg of olivine. In reactors with engineered cells, we directly measured removal of 0.50 g CO₂ per day from the air through alkalinity generation.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":""},"PeriodicalIF":44.5,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148851278","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":"Precise genomic integration of large DNA fragments by donor-directed annealing using prime editing.","authors":"Hojun Jung, Bada Jeong, Yong-Woo Kim, Chanju Jung, Seoho Lee, Heesoo Uhm, Hyoungrak Kim, Ye Eun Oh, Yoonseo Park, Yeji Lee, Miseung Kang, Hyeon Woo Im, Doyoon Kim, Soyoon Lee, Yohan Kim, Kyungho Choi, Sangsu Bae","doi":"10.1038/s41587-026-03301-2","DOIUrl":"https://doi.org/10.1038/s41587-026-03301-2","url":null,"abstract":"<p><p>Replacing large-scale fragments in human cells remains a substantial challenge. Here, we present a programmable gene replacement tool, named prime assembly (PA), which adapts prime editors to produce one or two pairs of 3'-flaps on both the genome and donor DNA. These 3'-flaps anneal to each other precisely, similar to Gibson assembly in DNA oligonucleotides, allowing megabase-scale genomic excision and/or kilobase-scale donor insertion at the gene of interest. PA accepts DNA plasmids and linear double-stranded DNA as donors, ranging from 1.0 to 6.5 kb in size. We demonstrate an efficiency of up to 57.8% in replacing endogenous sequences with a 2.9-kb donor DNA fragment in HEK293T cells, with an accuracy of >90% for integrated PA fragments. Furthermore, PA enables site-specific chimeric antigen receptor integration with up to 28.1% efficiency in primary human T cells. When PA containing a GFP donor is delivered to mice by hydrodynamic injection, an average integration efficiency of 4.3% is measured in GFP-positive hepatocytes.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":""},"PeriodicalIF":44.5,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148851294","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":"Donor-complementary prime editing enables precise kilobase and library-compatible DNA insertions.","authors":"Yunzheng Fang, Jingyao Tang, Jiawei Xi, Binfeng Yang, Feng Zhang, Lingbo Wang","doi":"10.1038/s41587-026-03296-w","DOIUrl":"https://doi.org/10.1038/s41587-026-03296-w","url":null,"abstract":"<p><p>Methods for precise genomic DNA insertion that avoid double-strand breaks (DSBs) are constrained by limited throughput or the need for multistep editing. Here we report donor-complementary prime editing (DoPE), which combines a 3'-overhang double-stranded DNA (odsDNA) donor with a pair of overhang-complementary prime editing guide RNAs (opegRNAs) and a PE2* prime editor to achieve precise insertion of DNA sequences up to 12.5 kilobases (kb). Using one opegRNA pair and donor pools constructed from synthesized single-stranded oligonucleotides, we demonstrate in situ saturation mutagenesis across a targeted EGFP region at both amino acid and nucleotide resolutions. DoPE employing short (approximately 30-nucleotide) overhangs supports various insertions ranging from small fragments to those exceeding 10 kb. Furthermore, we replace mutant exons of PRKCSH, either individually or simultaneously, to correct diverse mutations, establishing a mutation-agnostic approach that corrects distinct alleles uniformly in vitro. Our study demonstrates DoPE as a one-step, DSB-free and library-compatible method for precise insertion of large DNA fragments without requiring recombinases or transposases.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":""},"PeriodicalIF":44.5,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148851323","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":"Transferable genetic toolsets for nonmodel gut Clostridia enable in vivo reversible control of metabolite production.","authors":"Ting-Ting Li, Xi Chen, Fangzhao Wang, Yuelin Angelina Tang, Marissa Sim, Leyi Xiao, Wen-Bing Jin, Huiqing Shi, Jiayan Yoshii Ma, Xiaoyu Yang, Yaping Liu, Matthew T Sorbara, Chun-Jun Guo","doi":"10.1038/s41587-026-03269-z","DOIUrl":"https://doi.org/10.1038/s41587-026-03269-z","url":null,"abstract":"<p><p>Gut Clostridia species, including commensal members of the Clostridiaceae and Lachnospiraceae families, maintain microbiota homeostasis and influence human health and disease; however, adequate genetic toolsets to study abundant but nonmodel gut Clostridia are lacking. Here we present a set of transferable and modular genetic toolsets that function broadly across phylogenetically diverse gut Clostridia. We first identify a panel of strong constitutive promoters that drive robust gene expression across diverse clostridial strains. We then develop an inducible promoter system that enables precise, tunable gene regulation and facilitates the implementation of CRISPR-Cas gene-deletion systems. We apply this system for targeted and reversible control of trimethylamine and deoxycholic acid production, two microbiota-derived metabolites implicated in host lipid metabolism and diseases, in mice. This robust genetic toolkit for nonmodel gut Clostridia enables functional studies to causally link microbiota genes to host physiology and disease, paving the way for therapeutic genetic engineering of microbiota.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":""},"PeriodicalIF":44.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148819180","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":"Adaptive model-guided protein evolution with sparse data optimizes compact eukaryotic genome editors.","authors":"Shijie Wan, Jackson Gold, Pranay Vure, Casey S Mogilevsky, Ananya Talikoti, Tianrong Chen, Aman Gupta, Trisha Biswas, Zheng You, Vir Acharya, Pranam Chatterjee, Xiao Wang, Xue Gao","doi":"10.1038/s41587-026-03272-4","DOIUrl":"https://doi.org/10.1038/s41587-026-03272-4","url":null,"abstract":"<p><p>Efficient protein engineering is constrained by vast sequence space and limited experimental throughput, particularly for protein families that lack large mutational datasets. Here we combine Fanzor2 (Fz2) ortholog discovery, ωRNA scaffold engineering and EvoMax, a model-guided prioritization strategy for sparse-data engineering of compact eukaryotic Fz2 nucleases. EvoMax integrates iterative experimental profiling with Gaussian process regression, protein language models and inverse folding to navigate complex sequence-to-fitness landscapes. Applied to eukaryotic Fz2 nucleases, this strategy yielded a high-performance variant, FanzMAX v3-hLa, achieving up to 97% editing efficiency at the best-performing endogenous locus and a mean editing efficiency of ~33% across 19 endogenous loci, outperforming the established compact genome editors enNlovFz2 and enCnCas12f1 by more than 2.6-fold. In vivo editing of hPCSK9 in humanized mice supported the translational potential of optimized Fz2 editors. Together, these results establish EvoMax as an integrated strategy for engineering compact eukaryotic Fz2 genome editors and identify FanzMAX v3-hLa as a high-efficiency programmable nuclease for mammalian genome editing.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":""},"PeriodicalIF":44.5,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813695","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":"Bonsai reconstructs tree representations for distortion-free visualization and exploration of high-dimensional data","authors":"Daan H. de Groot, Sarah X. Morillo Leonardo, Mikhail Pachkov, Erik van Nimwegen","doi":"10.1038/s41587-026-03220-2","DOIUrl":"https://doi.org/10.1038/s41587-026-03220-2","url":null,"abstract":"Single-cell omics methods provide sparse, noisy measurements of high-dimensional cell states, whose underlying distributions remain poorly understood, raising an urgent need for exploratory analysis and visualization methods. However, current methods are ad hoc and uninterpretable, and they distort the structure in the data. We overcome these challenges by representing data on trees and present Bonsai, a method that reconstructs the most likely tree relating any set of high-dimensional objects with arbitrary heterogeneous measurement noise. Bonsai automatically regularizes noise, accurately recovers differentiation trajectories, preserves high-dimensional distances and improves nearest-neighbor identification. When applied to blood cell data, Bonsai not only accurately recovers known lineage relationships but also discovers a subtype of natural killer (NK) cells deriving from the myeloid lineage, pinpointing genes distinguishing myeloid NK from lymphoid NK cells. Bonsai has no tunable parameters, integrates downstream exploratory analyses methods with Bonsai-scout and scales to large datasets, making it applicable to visualizing the structure in any set of high-dimensional objects.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"125 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769242","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-throughput synthesis of DNA fragments by molecular self-assembly of overlapping oligonucleotides","authors":"Zhiguang Wu, Zhengyang Sun, Shuangying Jiang, Yaqi Wang, Tanxi Bai, Cheng Zeng, Zelin Cai, Chenghao Su, Xiandi Zhang, Yunan Chen, Yue Shen, Chenyou Zhu, Ye Xiang, Fang Fang, Ninuo Xia, Dongsheng Liu, Junbiao Dai, Bryan Wei","doi":"10.1038/s41587-026-03266-2","DOIUrl":"https://doi.org/10.1038/s41587-026-03266-2","url":null,"abstract":"The limitations of DNA synthesis technologies are a fundamental bottleneck in synthetic biology. Here we present a high-throughput gene synthesis method driven by hybridization, called Molecular Self-Assembly Induced Cloning. Molecular Self-Assembly Induced Cloning overcomes molecular crosstalk and oligo misalignment across genes by coupling orthogonal self-assembly of overlapping DNA segments in vitro with the DNA repair machineries of host cells in vivo. Cellular uptake of the assembled target fragments serves as templates for recovery and cloning. We adopt microchip-based oligonucleotide synthesis, enabling the production of over 1,000 distinct gene fragments in a simple one-pot reaction. Near-zero misalignment is an indispensable feature of the parallel synthesis, with oligo synthesis errors remaining at a constant but controllable level. We also construct massive variant libraries of the industrial enzyme PETase and discover higher-potency variants than the gold standard enzyme.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"52 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769244","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":"Massive-scale parallel gene synthesis with oligonucleotide hybridization.","authors":"","doi":"10.1038/s41587-026-03290-2","DOIUrl":"https://doi.org/10.1038/s41587-026-03290-2","url":null,"abstract":"","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":""},"PeriodicalIF":44.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795654","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":"A blinded, prospective benchmark of in silico antibody discovery anchored to experimental affinity and developability","authors":"M. Frank Erasmus, Daniel Bedinger, Elizabeth Hopkins, Ginger Ferguson, Justine Strickler, Christilyn P. Graff, Samantha R. Summers, Stacy L. Capehart, Joshua D. Slocum, Crystal Richardson, Sumit Kumar, Zhifei Sun, Yujie Shang, Jixian Zhang, Ming Gu, Lixia Yi, Alon Wellner, Shuangjia Zheng, Wei Lu, Pietro Sormanni, Matthew Greenig, Haiping Zhang, Brendan T. Mann, Mahdi Baghbanzadeh, Ali Rahnavard, Gregory L. Moore, Huaiyu Sun, Ying Ding, Alex Nisthal, Jitendra Kanodia, Matthew J. Bernett, Aurélien Pélissier, Yanjun Shao, Maria Rodriguez Martinez, Karthik Ramesh, Horacio Nastri, Andreas Evers, Anhar Abdelatif, Andrew J. Bordner, Mykola Bordyuh, Lim Heo, Brian A. Kidd, H. Serhat Tetikol, Shuai Wei, Jung-Eun Shin, Ryan Peckner, Leigh Manley, Ajitesh Lunge, Yashas Devasurmutt, Bora Guloglu, Liviu Copoiu, Miles McGibbon, Monica L. Fernandez-Quintero, Nitesh Mishra, Sean M. Callaghan, Olivia M. Swanson","doi":"10.1038/s41587-026-03238-6","DOIUrl":"https://doi.org/10.1038/s41587-026-03238-6","url":null,"abstract":"Experimentally validated prospective, blinded benchmarks are needed to separate durable advances from hype in computational antibody design. Here AIntibody, a challenge inspired by the Critical Assessment of Structure Prediction, tests 511 artificial intelligence (AI)-designed or predicted antibodies from 29 organizations on three tasks: in silico affinity maturation from phase 1 sequencing outputs, affinity ranking within heavy-chain complementarity-determining region 3 (HCDR3) clusters of a selection output and CDR design of proteins not included in a selection output. Validated with diverse experimental assays, several groups produced developable antibodies with affinities <100 pM. However, these successes were exceptions that did not transfer across tasks. Affinity-matured antibodies were modeled effectively. Except for one model, predicting high-affinity clones from clustered HCDR3 datasets was worse than random clone picking. Out-of-library design was highly variable for most method submissions, with many failing to outperform standard selections. The AIntibody challenge shows that AI can optimize antibodies in defined, biologically grounded regimes, in addition to highlighting critical gaps including affinity prediction and library-inspired antibody design and cross-task generalization.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"187 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769243","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":"From reading to writing.","authors":"","doi":"10.1038/s41587-026-03300-3","DOIUrl":"https://doi.org/10.1038/s41587-026-03300-3","url":null,"abstract":"","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":""},"PeriodicalIF":44.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795641","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}