Nature Biomedical Engineering最新文献

{"title":"Reprogramming human B cells with custom heavy-chain antibodies","authors":"Geoffrey L. Rogers, Chun Huang, Atishay Mathur, Xiaoli Huang, Hsu-Yu Chen, Kalya Stanten, Heidy Morales, Chan-Hua Chang, Eric J. Kezirian, Paula M. Cannon","doi":"10.1038/s41551-024-01240-4","DOIUrl":"https://doi.org/10.1038/s41551-024-01240-4","url":null,"abstract":"<p>The immunoglobulin locus of B cells can be reprogrammed by genome editing to produce custom or non-natural antibodies that are not induced by immunization. However, current strategies for antibody reprogramming require complex expression cassettes and do not allow for customization of the constant region of the antibody. Here we show that human B cells can be edited at the immunoglobulin heavy-chain locus to express heavy-chain-only antibodies that support alterations to both the fragment crystallizable domain and the antigen-binding domain, which can be based on both antibody and non-antibody components. Using the envelope protein (Env) from the human immunodeficiency virus as a model antigen, we show that B cells edited to express heavy-chain antibodies to Env support the regulated expression of B cell receptors and antibodies through alternative splicing and that the cells respond to the Env antigen in a tonsil organoid model of immunization. This strategy allows for the reprogramming of human B cells to retain the potential for in vivo amplification while producing molecules with flexibility of composition beyond that of standard antibodies.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"34 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141737019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Radiotherapy-triggered reduction of platinum-based chemotherapeutic prodrugs in tumours","authors":"Qunfeng Fu,&nbsp;Shuren Zhang,&nbsp;Siyong Shen,&nbsp;Zhi Gu,&nbsp;Junyi Chen,&nbsp;Dongfan Song,&nbsp;Pengwei Sun,&nbsp;Chunhong Wang,&nbsp;Zhibin Guo,&nbsp;Yunlong Xiao,&nbsp;Yi Qin Gao,&nbsp;Zijian Guo,&nbsp;Zhibo Liu","doi":"10.1038/s41551-024-01239-x","DOIUrl":"10.1038/s41551-024-01239-x","url":null,"abstract":"Pt(II) drugs are a widely used chemotherapeutic, yet their side effects can be severe. Here we show that the radiation-induced reduction of Pt(IV) complexes to cytotoxic Pt(II) drugs is rapid, efficient and applicable in water, that it is mediated by hydrated electrons from water radiolysis and that the X-ray-induced release of Pt(II) drugs from an oxaliplatin prodrug in tumours inhibits their growth, as we show with nearly complete tumour regression in mice with subcutaneous human tumour xenografts. The combination of low-dose radiotherapy with a Pt(IV)-based antibody–trastuzumab conjugate led to the tumour-selective release of the chemotherapeutic in mice and to substantial therapeutic benefits. The radiation-induced local reduction of platinum prodrugs in the reductive tumour microenvironment may expand the utility of radiotherapy. Platinum-based chemotherapeutics can be locally released in tumours by leveraging the radiation-induced reduction of platinum prodrugs.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 11","pages":"1425-1435"},"PeriodicalIF":26.8,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Profiling protein–protein interactions to predict the efficacy of B-cell-lymphoma-2-homology-3 mimetics for acute myeloid leukaemia","authors":"Changju Chun,&nbsp;Ja Min Byun,&nbsp;Minkwon Cha,&nbsp;Hongwon Lee,&nbsp;Byungsan Choi,&nbsp;Hyunwoo Kim,&nbsp;Saem Hong,&nbsp;Yunseo Lee,&nbsp;Hayoung Park,&nbsp;Youngil Koh,&nbsp;Tae-Young Yoon","doi":"10.1038/s41551-024-01241-3","DOIUrl":"10.1038/s41551-024-01241-3","url":null,"abstract":"B-cell-lymphoma-2 (BCL2) homology-3 (BH3) mimetics are inhibitors of protein–protein interactions (PPIs) that saturate anti-apoptotic proteins in the BCL2 family to induce apoptosis in cancer cells. Despite the success of the BH3-mimetic ABT-199 for the treatment of haematological malignancies, only a fraction of patients respond to the drug and most patients eventually develop resistance to it. Here we show that the efficacy of ABT-199 can be predicted by profiling the rewired status of the PPI network of the BCL2 family via single-molecule pull-down and co-immunoprecipitation to quantify more than 20 types of PPI from a total of only 1.2 × 106 cells per sample. By comparing the obtained multidimensional data with BH3-mimetic efficacies determined ex vivo, we constructed a model for predicting the efficacy of ABT-199 that designates two complexes of the BCL2 protein family as the primary mediators of drug effectiveness and resistance, and applied it to prospectively assist therapeutic decision-making for patients with acute myeloid leukaemia. The characterization of PPI complexes in clinical specimens opens up opportunities for individualized protein-complex-targeting therapies. The efficacy of a B-cell-lymphoma-2-homology-3 mimetic can be predicted by profiling the rewired status of the network of interactions among proteins of the B-cell-lymphoma-2 family via single-molecule pull-down and co-immunoprecipitation.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 11","pages":"1379-1395"},"PeriodicalIF":26.8,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01241-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optical microscopy and transcriptomics reveal the origins of fluorescence in glioma surgery","authors":"","doi":"10.1038/s41551-024-01218-2","DOIUrl":"10.1038/s41551-024-01218-2","url":null,"abstract":"Fluorescence guidance is utilized to increase the chances of complete tumour resection while balancing preservation of neurological function in glioma surgery. A multimodal optical microscope capable of imaging the histology and fluorescence of fresh human brain specimens revealed an unexpected pattern of fluorophore accumulation and a new means of visualizing macrophages during surgery.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 6","pages":"670-671"},"PeriodicalIF":26.8,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141584254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic optimization of prime editing for the efficient functional correction of CFTR F508del in human airway epithelial cells","authors":"Alexander A. Sousa, Colin Hemez, Lei Lei, Soumba Traore, Katarina Kulhankova, Gregory A. Newby, Jordan L. Doman, Keyede Oye, Smriti Pandey, Philip H. Karp, Paul B. McCray, David R. Liu","doi":"10.1038/s41551-024-01233-3","DOIUrl":"https://doi.org/10.1038/s41551-024-01233-3","url":null,"abstract":"<p>Prime editing (PE) enables precise and versatile genome editing without requiring double-stranded DNA breaks. Here we describe the systematic optimization of PE systems to efficiently correct human cystic fibrosis (CF) transmembrane conductance regulator (<i>CFTR</i>) F508del, a three-nucleotide deletion that is the predominant cause of CF. By combining six efficiency optimizations for PE—engineered PE guide RNAs, the PEmax architecture, the transient expression of a dominant-negative mismatch repair protein, strategic silent edits, PE6 variants and proximal ‘dead’ single-guide RNAs—we increased correction efficiencies for <i>CFTR</i> F508del from less than 0.5% in HEK293T cells to 58% in immortalized bronchial epithelial cells (a 140-fold improvement) and to 25% in patient-derived airway epithelial cells. The optimizations also resulted in minimal off-target editing, in edit-to-indel ratios 3.5-fold greater than those achieved by nuclease-mediated homology-directed repair, and in the functional restoration of CFTR ion channels to over 50% of wild-type levels (similar to those achieved via combination treatment with elexacaftor, tezacaftor and ivacaftor) in primary airway cells. Our findings support the feasibility of a durable one-time treatment for CF.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"29 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141566303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Localization of protoporphyrin IX during glioma-resection surgery via paired stimulated Raman histology and fluorescence microscopy","authors":"Mustafa Nasir-Moin,&nbsp;Lisa Irina Wadiura,&nbsp;Vlad Sacalean,&nbsp;Devin Juros,&nbsp;Misha Movahed-Ezazi,&nbsp;Emily K. Lock,&nbsp;Andrew Smith,&nbsp;Matthew Lee,&nbsp;Hannah Weiss,&nbsp;Michael Müther,&nbsp;Daniel Alber,&nbsp;Sujay Ratna,&nbsp;Camila Fang,&nbsp;Eric Suero-Molina,&nbsp;Sönke Hellwig,&nbsp;Walter Stummer,&nbsp;Karl Rössler,&nbsp;Johannes A. Hainfellner,&nbsp;Georg Widhalm,&nbsp;Barbara Kiesel,&nbsp;David Reichert,&nbsp;Mario Mischkulnig,&nbsp;Rajan Jain,&nbsp;Jakob Straehle,&nbsp;Nicolas Neidert,&nbsp;Oliver Schnell,&nbsp;Jürgen Beck,&nbsp;Jay Trautman,&nbsp;Steve Pastore,&nbsp;Donato Pacione,&nbsp;Dimitris Placantonakis,&nbsp;Eric Karl Oermann,&nbsp;John G. Golfinos,&nbsp;Todd C. Hollon,&nbsp;Matija Snuderl,&nbsp;Christian W. Freudiger,&nbsp;Dieter Henrik Heiland,&nbsp;Daniel A. Orringer","doi":"10.1038/s41551-024-01217-3","DOIUrl":"10.1038/s41551-024-01217-3","url":null,"abstract":"The most widely used fluorophore in glioma-resection surgery, 5-aminolevulinic acid (5-ALA), is thought to cause the selective accumulation of fluorescent protoporphyrin IX (PpIX) in tumour cells. Here we show that the clinical detection of PpIX can be improved via a microscope that performs paired stimulated Raman histology and two-photon excitation fluorescence microscopy (TPEF). We validated the technique in fresh tumour specimens from 115 patients with high-grade gliomas across four medical institutions. We found a weak negative correlation between tissue cellularity and the fluorescence intensity of PpIX across all imaged specimens. Semi-supervised clustering of the TPEF images revealed five distinct patterns of PpIX fluorescence, and spatial transcriptomic analyses of the imaged tissue showed that myeloid cells predominate in areas where PpIX accumulates in the intracellular space. Further analysis of external spatially resolved metabolomics, transcriptomics and RNA-sequencing datasets from glioblastoma specimens confirmed that myeloid cells preferentially accumulate and metabolize PpIX. Our findings question 5-ALA-induced fluorescence in glioma cells and show how 5-ALA and TPEF imaging can provide a window into the immune microenvironment of gliomas. The clinical detection of fluorescent protoporphyrin IX during glioma-resection surgery can be improved via a microscope that pairs stimulated Raman histology and two-photon excitation fluorescence microscopy.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 6","pages":"672-688"},"PeriodicalIF":26.8,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141566304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensing and guiding cell-state transitions by using genetically encoded endoribonuclease-mediated microRNA sensors","authors":"Lei Wang, Wenlong Xu, Shun Zhang, Gregory C. Gundberg, Christine R. Zheng, Zhengpeng Wan, Kamila Mustafina, Fabio Caliendo, Hayden Sandt, Roger Kamm, Ron Weiss","doi":"10.1038/s41551-024-01229-z","DOIUrl":"https://doi.org/10.1038/s41551-024-01229-z","url":null,"abstract":"<p>Precisely sensing and guiding cell-state transitions via the conditional genetic activation of appropriate differentiation factors is challenging. Here we show that desired cell-state transitions can be guided via genetically encoded sensors, whereby endogenous cell-state-specific miRNAs regulate the translation of a constitutively transcribed endoribonuclease, which, in turn, controls the translation of a gene of interest. We used this approach to monitor several cell-state transitions, to enrich specific cell types and to automatically guide the multistep differentiation of human induced pluripotent stem cells towards a haematopoietic lineage via endothelial cells as an intermediate state. Such conditional activation of gene expression is durable and resistant to epigenetic silencing and could facilitate the monitoring of cell-state transitions in physiological and pathological conditions and eventually the ‘rewiring’ of cell-state transitions for applications in organoid-based disease modelling, cellular therapies and regenerative medicine.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"49 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell–drug conjugates","authors":"Yanfang Wang,&nbsp;Jiaqi Shi,&nbsp;Minhang Xin,&nbsp;Anna R. Kahkoska,&nbsp;Jinqiang Wang,&nbsp;Zhen Gu","doi":"10.1038/s41551-024-01230-6","DOIUrl":"10.1038/s41551-024-01230-6","url":null,"abstract":"By combining living cells with therapeutics, cell–drug conjugates can potentiate the functions of both components, particularly for applications in drug delivery and therapy. The conjugates can be designed to persist in the bloodstream, undergo chemotaxis, evade surveillance by the immune system, proliferate, or maintain or transform their cellular phenotypes. In this Review, we discuss strategies for the design of cell–drug conjugates with specific functions, the techniques for their preparation, and their applications in the treatment of cancers, autoimmune diseases and other pathologies. We also discuss the translational challenges and opportunities of this class of drug-delivery systems and therapeutics. This Review discusses strategies for the design of cell–drug conjugates, the techniques for their preparation, and their translational applications, particularly for the treatment of cancers and autoimmune diseases.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 11","pages":"1347-1365"},"PeriodicalIF":26.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategies for the development of metalloimmunotherapies","authors":"Xiaoqi Sun,&nbsp;Xingwu Zhou,&nbsp;Xiaoyue Shi,&nbsp;Omar A. Abed,&nbsp;Xinran An,&nbsp;Yu Leo Lei,&nbsp;James J. Moon","doi":"10.1038/s41551-024-01221-7","DOIUrl":"10.1038/s41551-024-01221-7","url":null,"abstract":"Metal ions play crucial roles in the regulation of immune pathways. In fact, metallodrugs have a long record of accomplishment as effective treatments for a wide range of diseases. Here we argue that the modulation of interactions of metal ions with molecules and cells involved in the immune system forms the basis of a new class of immunotherapies. By examining how metal ions modulate the innate and adaptive immune systems, as well as host–microbiota interactions, we discuss strategies for the development of such metalloimmunotherapies for the treatment of cancer and other immune-related diseases. This Perspective examines how metal ions modulate the immune system and host–microbiota interactions, and proposes strategies for the development of metal-ion-based immunotherapies.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 9","pages":"1073-1091"},"PeriodicalIF":26.8,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141444954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A miniaturized mesoscope for the large-scale single-neuron-resolved imaging of neuronal activity in freely behaving mice","authors":"Yuanlong Zhang,&nbsp;Lekang Yuan,&nbsp;Qiyu Zhu,&nbsp;Jiamin Wu,&nbsp;Tobias Nöbauer,&nbsp;Rujin Zhang,&nbsp;Guihua Xiao,&nbsp;Mingrui Wang,&nbsp;Hao Xie,&nbsp;Zengcai Guo,&nbsp;Qionghai Dai,&nbsp;Alipasha Vaziri","doi":"10.1038/s41551-024-01226-2","DOIUrl":"10.1038/s41551-024-01226-2","url":null,"abstract":"Exploring the relationship between neuronal dynamics and ethologically relevant behaviour involves recording neuronal-population activity using technologies that are compatible with unrestricted animal behaviour. However, head-mounted microscopes that accommodate weight limits to allow for free animal behaviour typically compromise field of view, resolution or depth range, and are susceptible to movement-induced artefacts. Here we report a miniaturized head-mounted fluorescent mesoscope that we systematically optimized for calcium imaging at single-neuron resolution, for increased fields of view and depth of field, and for robustness against motion-generated artefacts. Weighing less than 2.5 g, the mesoscope enabled recordings of neuronal-population activity at up to 16 Hz, with 4 μm resolution over 300 μm depth-of-field across a field of view of 3.6 × 3.6 mm2 in the cortex of freely moving mice. We used the mesoscope to record large-scale neuronal-population activity in socially interacting mice during free exploration and during fear-conditioning experiments, and to investigate neurovascular coupling across multiple cortical regions. An optimized head-mounted fluorescent mesoscope enables large-scale calcium imaging at single-neuron resolution in freely moving mice, facilitating neurobehavioural studies during social interactions and fear-conditioning experiments.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 6","pages":"754-774"},"PeriodicalIF":26.8,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}