Nature Biomedical Engineering最新文献_第10页

Identifying and reprogramming softness-driven cancer stem-like cells overcomes CAR-T cell resistance in solid tumours. 识别和重编程软驱动的癌症干细胞样细胞克服实体肿瘤中CAR-T细胞的抵抗。

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2026-07-06 DOI: 10.1038/s41551-026-01722-7

Yunjia Qu,Yuxuan Wang,Linshan Zhu,Fengyi Ma,Chi Woo Yoon,Xinyu Chen,Junhang Zhang,Carrie Bishop,Min Tang,Jiaxin Cui,Tianze Guo,Phuong Ho,W Martin Kast,Hongquan Xu,Qifa Zhou,Adam J Engler,Ning Wang,Longwei Liu,Shu Chien,Yingxiao Wang

{"title":"Identifying and reprogramming softness-driven cancer stem-like cells overcomes CAR-T cell resistance in solid tumours.","authors":"Yunjia Qu,Yuxuan Wang,Linshan Zhu,Fengyi Ma,Chi Woo Yoon,Xinyu Chen,Junhang Zhang,Carrie Bishop,Min Tang,Jiaxin Cui,Tianze Guo,Phuong Ho,W Martin Kast,Hongquan Xu,Qifa Zhou,Adam J Engler,Ning Wang,Longwei Liu,Shu Chien,Yingxiao Wang","doi":"10.1038/s41551-026-01722-7","DOIUrl":"https://doi.org/10.1038/s41551-026-01722-7","url":null,"abstract":"Solid tumours show substantial mechanical heterogeneity, yet how such cues influence the susceptibility of cancer cells to T cell-based therapies remains unclear. Here we discover that cancer cells grown on soft matrices are less sensitive to chimeric antigen receptor T cell cytotoxicity and exhibit elevated extracellular adenosine triphosphate and sustained calcium activity. To understand the mechanisms underlying this reduced killing, we sought to identify the cells that respond to mechanical softness. We engineered a doxycycline-gated calcium-activated transcriptional mechano-recorder that integrates softness-induced calcium activity over a defined recording window and converts this prior signalling history into a stable fluorescent output that persists for days. Unlike real-time calcium indicators, which report instantaneous calcium activity only at the moment of imaging, this recorder preserves a sortable transcriptional mark, enabling selective labelling and profiling of cells according to their past mechanosensing activity. Transcriptomic analyses showed that recorder-positive cells adopt a stem-like programme, including epithelial-mesenchymal transition, hypoxia responses, oncogenic signalling and elevated stemness markers, across cancer cell lines and patient-derived samples. To render these resistant cells targetable, we rewired the mechano-recorder into a mechano-reprogrammer by replacing the fluorescent output with the clinically validated antigen CD19, enabling softness-responsive cells to be recognized by CD19-directed T cells. This rewired system improved elimination of stem-like cancer cells in culture and animal models, converting mechanobiological resistance into therapeutic vulnerability.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"215 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148393342","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}

引用次数: 0

CD98hc-targeted antibody shuttles for central nervous system delivery with broad cross-species reactivity. 靶向cd98hc的抗体穿梭于中枢神经系统，具有广泛的跨物种反应性。

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2026-07-06 DOI: 10.1038/s41551-026-01718-3

Wen-Hao Wu,Neelan Sivaneri,Ece Akin,Cecilia J Spesia,Yu-Hui Huang,Layne G Bond,Dat L Q Doi,Jett Stad,Amani Djouadi,Yunxuan Xie,Hye Jin Lee,Na-Young Kwon,Colin F Greineder,Peter M Tessier

{"title":"CD98hc-targeted antibody shuttles for central nervous system delivery with broad cross-species reactivity.","authors":"Wen-Hao Wu,Neelan Sivaneri,Ece Akin,Cecilia J Spesia,Yu-Hui Huang,Layne G Bond,Dat L Q Doi,Jett Stad,Amani Djouadi,Yunxuan Xie,Hye Jin Lee,Na-Young Kwon,Colin F Greineder,Peter M Tessier","doi":"10.1038/s41551-026-01718-3","DOIUrl":"https://doi.org/10.1038/s41551-026-01718-3","url":null,"abstract":"Bispecific antibodies that target the blood-brain barrier (BBB) and mediate transport into the brain parenchyma are being used to increase the therapeutic potential of IgGs and other biologics. Nevertheless, antibodies specific for human BBB targets, such as CD98hc or transferrin receptor 1 (TfR1), typically either do not cross-react with orthologues from species commonly used in preclinical testing, such as mouse or cynomolgus monkey (cyno), or do so with relatively large differences in affinity. Here we address both limitations by using an active learning method to isolate anti-CD98hc antibodies with broad species cross-reactivity. Our approach starts from a fully human antibody that binds human and cynomolgus monkey CD98hc but lacks binding to mouse CD98hc and progressively evolves it through iterative mutagenesis and library optimization, resulting in a series of antibodies that recognize mouse, cyno and human CD98hc with similar affinities, possess similar epitopes, and display efficient and long-lived brain delivery. We expect these CD98hc-targeted CNS shuttles to accelerate clinical translation by eliminating the need for transgenic animals or surrogate antibodies.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"14 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148393341","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}

引用次数: 0

Rewiring tumour mechanosensing to overcome CAR T cell resistance. 重新布线肿瘤机械感应以克服CAR - T细胞耐药性。

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2026-07-06 DOI: 10.1038/s41551-026-01731-6

Maria Kalli,Triantafyllos Stylianopoulos

引用次数: 0

AI-orchestrated design–build–test–learn is the future of mammalian biodesign 人工智能策划的设计-构建-测试-学习是哺乳动物生物设计的未来。

IF 26.3 1区医学

Nature Biomedical Engineering Pub Date : 2026-07-06 DOI: 10.1038/s41551-026-01730-7

Jingjing Han, Martin Fussenegger

引用次数: 0

Lab-on-a-disc biosensing platform for folate level quantification. 用于叶酸水平定量的盘上实验室生物传感平台。

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2026-07-03 DOI: 10.1038/s41551-026-01715-6

Xiujun Fan,Songyue Chen,Guorui Chen,Zhaoqi Duan,Jun Chen

引用次数: 0

BoneCoT: multicentre validation of a whole-body skeleton foundation model for bone metastases guided by clinician-derived chain of thought. BoneCoT：由临床衍生的思维链引导的骨转移的全身骨骼基础模型的多中心验证。

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2026-07-02 DOI: 10.1038/s41551-026-01736-1

Hui Zhao,Ruipeng Zhang,Zhiyu Wang,Yifeng Gu,Shengyuan Xu,Sheng Wang,Yuehua Li

{"title":"BoneCoT: multicentre validation of a whole-body skeleton foundation model for bone metastases guided by clinician-derived chain of thought.","authors":"Hui Zhao,Ruipeng Zhang,Zhiyu Wang,Yifeng Gu,Shengyuan Xu,Sheng Wang,Yuehua Li","doi":"10.1038/s41551-026-01736-1","DOIUrl":"https://doi.org/10.1038/s41551-026-01736-1","url":null,"abstract":"Given the rising incidence of bone metastases, computed tomography is widely used worldwide as the initial imaging modality for their detection. Accurate diagnosis of bone metastases demands comprehensive evaluation, yet divergent interpretations among specialists can result in diagnostic discrepancies. In clinical practice, precision diagnosis of bone metastases necessitates multidisciplinary collaboration involving radiologists, pathologists and oncologists. Here, to meet the need for an automated tool that can deliver expert-level insights and predictions by jointly considering multidisciplinary information, we propose BoneCoT, a whole-body skeleton foundation model enhanced through a chain-of-thought (CoT) fine-tuning approach. We pretrained the model on 29.3 million computed tomography images from 30,267 patients across 12 skeletal sites and refined it over a graph of 26 clinically relevant tasks spanning diagnosis, complications, tumour type and biomarkers. Evaluated across 26 tasks and multicentre cohorts from 10 hospitals, BoneCoT outperformed state-of-the-art methods by 20% in area under the receiver operating characteristic curve. Critically, BoneCoT achieved a 40% area under the receiver operating characteristic curve improvement in distinguishing primary from metastatic lesions, significantly surpassing experienced radiologists. These findings show how clinician-derived reasoning can move artificial intelligence towards more integrated diagnostic assessment in complex disease.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"114 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148372697","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}

引用次数: 0

Derivation of functional retinal endothelial cells from human pluripotent stem cells for therapeutics and modelling 从人多能干细胞中衍生功能性视网膜内皮细胞用于治疗和建模。

IF 26.3 1区医学

Nature Biomedical Engineering Pub Date : 2026-06-30 DOI: 10.1038/s41551-026-01712-9

Ying-Yu Lin, Parker Esswein, Lucas Ramirez, Emily Warren, Julian Nicenboim, Sharon Gerecht

{"title":"Derivation of functional retinal endothelial cells from human pluripotent stem cells for therapeutics and modelling","authors":"Ying-Yu Lin, Parker Esswein, Lucas Ramirez, Emily Warren, Julian Nicenboim, Sharon Gerecht","doi":"10.1038/s41551-026-01712-9","DOIUrl":"10.1038/s41551-026-01712-9","url":null,"abstract":"Retinal microvascular diseases involve a compromised inner blood–retina barrier (iBRB), which remains poorly understood. A renewable source of human iBRB endothelium is thus vital for advancing eye research and treatment development. Here we differentiated human induced pluripotent stem cells into retinal endothelial cells (iRECs) via the Wnt–β-catenin pathway, namely Norrin–Frizzled4 signalling. These iRECs show genetic, protein and functional fidelity as well as unique retinal features. When injected into oxygen-induced retinopathy mice, iRECs integrated into the host vascular network and revascularized the ischaemic eye, rescuing the tissue. In microphysiological models, iRECs form perfusable microvascular networks that recapitulate iBRB morphology and phenotype in both healthy and diabetic states while also physiologically organizing and interacting with induced pluripotent stem cell-derived retinal pericytes. Our study establishes functional human iRECs and microphysiological iBRB models that facilitate mechanistic studies aimed at identifying therapeutic targets and promoting the revascularization of injured retinas, thereby supporting treatment advancement. Treatment of induced pluripotent stem cells with Norrin and vitronectin, and subsequent cell sorting and maturation, generates retinal-like endothelial cells that can regenerate retinal vasculature in an oxygen-induced retinopathy mouse and recapitulate enhanced inner blood–retinal barrier properties when co-cultured with retinal-like pericytes.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"10 10","pages":"2094-2115"},"PeriodicalIF":26.3,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13526318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361770","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}

引用次数: 0

Engineered circular RNA compatible with complete nucleoside modification and rolling circle translation through a Cap-independent translation enhancer. 工程环状RNA兼容完全核苷修饰和滚动环翻译通过帽独立的翻译增强子。

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2026-06-29 DOI: 10.1038/s41551-026-01725-4

Xinyue Wang,Qian Pan,Jie Yin,Haomeng Kou,Xinyuan Liao,Chi Zhang,Yanyan Wang,Shengnan She,Ligaoyue Zhang,Wanjia Wang,Shan Qin,Xiaohong Xia,Jing Li,Fei Gao,Xinyang Li,Yong Cao,Liang Qu

{"title":"Engineered circular RNA compatible with complete nucleoside modification and rolling circle translation through a Cap-independent translation enhancer.","authors":"Xinyue Wang,Qian Pan,Jie Yin,Haomeng Kou,Xinyuan Liao,Chi Zhang,Yanyan Wang,Shengnan She,Ligaoyue Zhang,Wanjia Wang,Shan Qin,Xiaohong Xia,Jing Li,Fei Gao,Xinyang Li,Yong Cao,Liang Qu","doi":"10.1038/s41551-026-01725-4","DOIUrl":"https://doi.org/10.1038/s41551-026-01725-4","url":null,"abstract":"Circular RNA (circRNA) exhibits extended stability and enhanced protein expression, and its translational efficiency and immunogenicity can be improved through nucleoside modification and rolling circle translation (RCT). However, it remains challenging to produce protein-encoding circRNA with modified nucleosides. Here we identified a cap-independent translation enhancer (CITE) element from black beetle virus, termed BBV, which could drive the translation of nucleoside-modified RNA and RCT of engineered circRNA. In addition, we developed a system to produce 'scarless' circRNA via in vitro transcription (IVT). The resulting circRNA vaccine outperformed m1ψ-mRNA vaccine in inhibiting tumour growth in mice. With nucleoside modification, circRNA exhibited reduced expression of pro-inflammatory cytokines. Further, nucleoside-modified circRNA encoding glucagon-like peptide-1 (GLP-1) peptides reduced blood glucose levels with efficacy comparable to that of commercial semaglutide, and ameliorated liver damage in obese mice. Moreover, nucleoside-modified circRNA encoding myelin oligodendrocyte glycoprotein (MOG35-55) peptides induced immune tolerance and alleviated disease progression in an experimental autoimmune encephalomyelitis (EAE) murine model. Collectively, we established a nucleoside-modified circRNA platform that facilitated efficient translation with minimal immunogenicity, expanding the application scenarios of circRNA beyond vaccines.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"29 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349054","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}

引用次数: 0

Off‑the‑shelf, engineered non-living stem cell strategy for advancing cellular therapies. 现成的、工程化的非活干细胞策略，用于推进细胞治疗。

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2026-06-29 DOI: 10.1038/s41551-026-01697-5

Tiep Tien Nguyen,Nhu-Nam Nguyen,Linh Nguyen,Kim-Phuong Phan,Junhyeung Park,Jong-Hyuk Sung,Simmyung Yook,Hu-Lin Jiang,Jee-Heon Jeong

{"title":"Off‑the‑shelf, engineered non-living stem cell strategy for advancing cellular therapies.","authors":"Tiep Tien Nguyen,Nhu-Nam Nguyen,Linh Nguyen,Kim-Phuong Phan,Junhyeung Park,Jong-Hyuk Sung,Simmyung Yook,Hu-Lin Jiang,Jee-Heon Jeong","doi":"10.1038/s41551-026-01697-5","DOIUrl":"https://doi.org/10.1038/s41551-026-01697-5","url":null,"abstract":"Non-living cell therapeutics have become crucial for treating diverse disease conditions. However, ineffective manufacturing processes, significant cellular content loss and structural damage reduce therapeutic efficacy. Here we present a translational approach for designing 'off-the-shelf' highly efficient active lyophilized tannic-acid-engineered non-living cells (HealTEC) with distinct features. Our strategy is customizable and integrates cellular function enhancement, high-dose tannic acid-induced cell inactivation, low-temperature cellular matter condensation and advanced lyophilization. By leveraging it, we engineer mesenchymal stem cell-derived HealTEC as a bio-reservoir platform, enabling formulations enriched in immunomodulatory factors for ulcerative colitis, enriched in angiogenic factors for hindlimb ischaemia or loaded with drug nanoparticles for asthma. Importantly, the HealTEC formulations exhibit high therapeutic stability after long-term storage at mild conditions. Furthermore, HealTEC injections induce much lower immunogenicity than living cell injections, both in the short term and long term. HealTEC technology presents the potential for upscaling cell manufacture, commercialization and reshaping worldwide clinical demands.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"30 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349336","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}

引用次数: 0

The evolving role of cytokines for CAR-T cell manufacturing and beyond 细胞因子在CAR-T细胞制造及其他方面的进化作用。

IF 26.3 1区医学

Nature Biomedical Engineering Pub Date : 2026-06-29 DOI: 10.1038/s41551-026-01703-w

Mar Guaza-Lasheras, Johanna Nimmerfroh, Dominic Schwarz, Tanja D. de Gruijl, Jessica Hartmann, Christian Klein, Heinz Läubli, Michal Lotem, Joerg Mittelstaet, Christophe Paget, Sine Reker Hadrup, Sonja Schallenberg, Per Thor Straten, Sebastian Theurich, Dario Venetz, Alfred Zippelius, Laurence Zitvogel, Sebastian Kobold

{"title":"The evolving role of cytokines for CAR-T cell manufacturing and beyond","authors":"Mar Guaza-Lasheras, Johanna Nimmerfroh, Dominic Schwarz, Tanja D. de Gruijl, Jessica Hartmann, Christian Klein, Heinz Läubli, Michal Lotem, Joerg Mittelstaet, Christophe Paget, Sine Reker Hadrup, Sonja Schallenberg, Per Thor Straten, Sebastian Theurich, Dario Venetz, Alfred Zippelius, Laurence Zitvogel, Sebastian Kobold","doi":"10.1038/s41551-026-01703-w","DOIUrl":"10.1038/s41551-026-01703-w","url":null,"abstract":"Chimeric antigen receptor (CAR)-T cells represent a recent clinically validated modality in cancer therapy and beyond. However, broad industrial implementation faces technological, logistical, regulatory and financial challenges. A major bottleneck is the ex vivo production process, where cytokines are essential and product-determining constituents. To better understand the complexity of cytokine utilization throughout the production process, we rigorously reviewed the existing literature, including extended manufacturing parameters from 292 available clinical reports. We found a progressive reduction of interleukin-2 exposure, driven by its association with unfavourable cell characteristics. Preclinically, this catalysed the evaluation of alternative cytokines with potential to preserve naive phenotypes, support cell expansion and enhance the efficacy of CAR-T cells. Here we illustrate the evolving use of cytokines, reveal non-standardized clinical CAR-T cell manufacturing parameters, and summarize preclinical and next-generation concepts, which may improve manufacturing efficiency, cost-effectiveness and therapeutic outcomes. Our observations may further guide the development of cytokine-armouring strategies to promote in-patient expansion and persistence, even as innovations such as shortened manufacturing and in vivo engineering techniques could reduce reliance on cytokines during ex vivo culture. This Perspective explores the use of cytokines during CAR-T cell manufacturing and how their use has changed over time. It further synthesizes data from clinical trials to discuss future improvements in manufacturing and therapeutic outcomes.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"10 9","pages":"1811-1827"},"PeriodicalIF":26.3,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349007","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}

引用次数: 0