Bacterial biofilms, prevalent in human infections, present a major barrier to effective antibacterial therapy due to limited drug permeability and resistance. Here we introduce a 'trick-bacteria-with-bacteria' strategy that employs bacteria modified via calcium chloride treatment and antibiotic loading, followed by ultraviolet inactivation. These modified bacteria integrate selectively into biofilms of the same species, enabling targeted intra-biofilm drug release triggered by local pH and hydrogen peroxide. Species-specific integration is essential, as mismatched strains exhibit spatial segregation due to differences in surface adhesins and protein profiles. The strategy is effective against polymicrobial biofilms and demonstrated efficacy in treating biofilms formed by Staphylococcus aureus, Escherichia coli and Candida albicans. It also reinvigorates biofilm-associated macrophages by inducing the release of biofilm-derived l-arginine, enhancing immune responses. In vivo studies using subcutaneous and bone implant infection models showed stronger biofilm eradication and longer-term immunity in animals treated with modified bacteria compared with those treated with antibiotics, including resistance to re-infection. This approach could be adapted to modify infection-related bacteria from patients for personalized intra-biofilm drug delivery.
{"title":"Chemically modified and inactivated bacteria enable intra-biofilm drug delivery and long-term immunity against implant infections.","authors":"Chuang Yang,Qimanguli Saiding,Wei Chen,Soohwan An,Senfeng Zhao,Muhammad Muzamil Khan,Na Kong,Min Ge,Jianlin Shi,Han Lin,Wei Tao","doi":"10.1038/s41551-025-01600-8","DOIUrl":"https://doi.org/10.1038/s41551-025-01600-8","url":null,"abstract":"Bacterial biofilms, prevalent in human infections, present a major barrier to effective antibacterial therapy due to limited drug permeability and resistance. Here we introduce a 'trick-bacteria-with-bacteria' strategy that employs bacteria modified via calcium chloride treatment and antibiotic loading, followed by ultraviolet inactivation. These modified bacteria integrate selectively into biofilms of the same species, enabling targeted intra-biofilm drug release triggered by local pH and hydrogen peroxide. Species-specific integration is essential, as mismatched strains exhibit spatial segregation due to differences in surface adhesins and protein profiles. The strategy is effective against polymicrobial biofilms and demonstrated efficacy in treating biofilms formed by Staphylococcus aureus, Escherichia coli and Candida albicans. It also reinvigorates biofilm-associated macrophages by inducing the release of biofilm-derived l-arginine, enhancing immune responses. In vivo studies using subcutaneous and bone implant infection models showed stronger biofilm eradication and longer-term immunity in animals treated with modified bacteria compared with those treated with antibiotics, including resistance to re-infection. This approach could be adapted to modify infection-related bacteria from patients for personalized intra-biofilm drug delivery.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"36 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986524","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}
Pub Date : 2026-01-15DOI: 10.1038/s41551-025-01578-3
Xiaoqing Guo, Mohammad Alsharid, He Zhao, Yipei Wang, Jayne Lander, Aris T. Papageorghiou, J. Alison Noble
Freehand fetal ultrasound examinations require substantial clinical skill. Here we propose Sonomate (mate of a sonographer), an AI assistant to a user during fetal ultrasound examinations. Sonomate is based on aligning video features and text features derived from transcribed audio to facilitate real-time interactions between an ultrasound machine and a user. Our approach combines coarse-grained video–text alignment with fine-grained image–sentence alignment to build a robust visually grounded language model capable of understanding fetal ultrasound videos. To tackle the challenges associated with heterogeneous language and asynchronous content in real-world video–audio pairs, we design the anatomy-aware alignment and context label correction in the fine-grained alignment. Sonomate is effective at anatomy detection in fetal ultrasound images without the need for retraining on manually annotated data. Furthermore, Sonomate shows promising performance in visual question answering for both fetal ultrasound images and videos. Guardrails are built to ensure the safety of Sonomate during deployment. This advancement paves the way towards AI-assistive technology being used to support sonography training and enhanced diagnostic capabilities.
{"title":"A visually grounded language model for fetal ultrasound understanding","authors":"Xiaoqing Guo, Mohammad Alsharid, He Zhao, Yipei Wang, Jayne Lander, Aris T. Papageorghiou, J. Alison Noble","doi":"10.1038/s41551-025-01578-3","DOIUrl":"https://doi.org/10.1038/s41551-025-01578-3","url":null,"abstract":"Freehand fetal ultrasound examinations require substantial clinical skill. Here we propose Sonomate (mate of a sonographer), an AI assistant to a user during fetal ultrasound examinations. Sonomate is based on aligning video features and text features derived from transcribed audio to facilitate real-time interactions between an ultrasound machine and a user. Our approach combines coarse-grained video–text alignment with fine-grained image–sentence alignment to build a robust visually grounded language model capable of understanding fetal ultrasound videos. To tackle the challenges associated with heterogeneous language and asynchronous content in real-world video–audio pairs, we design the anatomy-aware alignment and context label correction in the fine-grained alignment. Sonomate is effective at anatomy detection in fetal ultrasound images without the need for retraining on manually annotated data. Furthermore, Sonomate shows promising performance in visual question answering for both fetal ultrasound images and videos. Guardrails are built to ensure the safety of Sonomate during deployment. This advancement paves the way towards AI-assistive technology being used to support sonography training and enhanced diagnostic capabilities.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"266 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968788","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}
Pub Date : 2026-01-15DOI: 10.1038/s41551-025-01583-6
Christopher Hughes,Xing Chen,Warren Grill,Takashi D Y Kozai
Sensation plays a pivotal role in the orchestration of our daily lives. Intracortical microstimulation (ICMS) can elicit artificial sensations in persons who have lost sensation due to neurological injury or disease. Despite ongoing clinical studies to assess the safety and efficacy of ICMS, the mechanisms underlying neural activation by ICMS and their implications for perception are not well understood. This Review delves into the current understanding of ICMS mechanisms, drawing parallels with physiological sensory processing in the cortex. We explore emerging approaches and note challenges to current technologies, including resolution and the tissue response to electrode insertion. We conclude by highlighting the basic principles of ICMS, lingering questions and important focus areas for continued development.
{"title":"Neural mechanisms underlying intracortical microstimulation for sensory restoration.","authors":"Christopher Hughes,Xing Chen,Warren Grill,Takashi D Y Kozai","doi":"10.1038/s41551-025-01583-6","DOIUrl":"https://doi.org/10.1038/s41551-025-01583-6","url":null,"abstract":"Sensation plays a pivotal role in the orchestration of our daily lives. Intracortical microstimulation (ICMS) can elicit artificial sensations in persons who have lost sensation due to neurological injury or disease. Despite ongoing clinical studies to assess the safety and efficacy of ICMS, the mechanisms underlying neural activation by ICMS and their implications for perception are not well understood. This Review delves into the current understanding of ICMS mechanisms, drawing parallels with physiological sensory processing in the cortex. We explore emerging approaches and note challenges to current technologies, including resolution and the tissue response to electrode insertion. We conclude by highlighting the basic principles of ICMS, lingering questions and important focus areas for continued development.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"3 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971966","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}
Senescent cell accumulation contributes to aging, and their clearance represents an effective anti-aging strategy. Current senolytic strategies focus on drug-mediated senescent cell clearance, but it is unknown whether a hypobaric condition can induce senescent cell death. Here we show that hypobaric pressure (HP) at -375 mmHg without hypoxia induces cells to undergo lysosome-dependent cell death (LDCD). Mechanistically, we unveil that HP activates transmembrane protein 59 (TMEM59) to induce cellular Ca2+ influx, which triggers calpain 2 to cleave lysosomal associated membrane protein 2 (LAMP2), leading to lysosomal membrane permeabilization and subsequent LDCD. Furthermore, given that senescent cells contain elevated numbers of lysosomes, we report intermittent HP treatment to specifically induce senescent cells to undergo LDCD and reduce the senescence-associated secretory phenotype. Eventually, we report that intermittent HP treatment can substantially extend the lifespan and rescue the osteoporosis phenotype in aged mice. This study reveals a previously unknown role of HP as a natural senolytic to eliminate senescent cells, and identifies TMEM59 as a new HP-activated ion channel protein.
{"title":"Intermittent hypobaric pressure induces selective senescent cell death and alleviates age-related osteoporosis.","authors":"Bowen Meng,Yan Qu,Benyi Yang,Chaoran Fu,Yifan He,Jing Li,Rentao Wan,Xin Li,Zhulin Xue,Zeyuan Cao,Meng Hao,Xiao Zhang,Zhe An,Fen Chen,Ruibao Ren,Xueli Mao,Yang Cao,Songtao Shi","doi":"10.1038/s41551-025-01584-5","DOIUrl":"https://doi.org/10.1038/s41551-025-01584-5","url":null,"abstract":"Senescent cell accumulation contributes to aging, and their clearance represents an effective anti-aging strategy. Current senolytic strategies focus on drug-mediated senescent cell clearance, but it is unknown whether a hypobaric condition can induce senescent cell death. Here we show that hypobaric pressure (HP) at -375 mmHg without hypoxia induces cells to undergo lysosome-dependent cell death (LDCD). Mechanistically, we unveil that HP activates transmembrane protein 59 (TMEM59) to induce cellular Ca2+ influx, which triggers calpain 2 to cleave lysosomal associated membrane protein 2 (LAMP2), leading to lysosomal membrane permeabilization and subsequent LDCD. Furthermore, given that senescent cells contain elevated numbers of lysosomes, we report intermittent HP treatment to specifically induce senescent cells to undergo LDCD and reduce the senescence-associated secretory phenotype. Eventually, we report that intermittent HP treatment can substantially extend the lifespan and rescue the osteoporosis phenotype in aged mice. This study reveals a previously unknown role of HP as a natural senolytic to eliminate senescent cells, and identifies TMEM59 as a new HP-activated ion channel protein.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"15 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968531","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}
Pub Date : 2026-01-14DOI: 10.1038/s41551-025-01597-0
Justin C Rolando,Anton Thieme,Nicole E Weckman,Nayoung Kim,Helena de Puig,Xiao Tan,Emily Cotnoir,Vishnu Chaturvedi,James J Collins,David R Walt
Candida auris, an increasingly prevalent fungal pathogen, requires both rapid identification and antifungal susceptibility testing to enable proper treatment. This study introduces digital SHERLOCK (dSHERLOCK), a platform that combines CRISPR/Cas nucleic acid detection, single-template quantification and real-time kinetics monitoring. Assays implemented on this platform display excellent sensitivity to C. auris from major clades 1-4, while maintaining specificity when challenged with common environmental and pathogenic fungi. dSHERLOCK detects C. auris within 20 min in minimally processed swab samples and achieves sensitive quantification (1 c.f.u. µl-1) within 40 min. To address antifungal susceptibility testing, we develop assays that detect mutations that are commonly associated with azole and echinocandin multidrug resistance. We use machine learning and real-time monitoring of reaction kinetics to achieve highly accurate simultaneous quantification of mutant and wild-type FKS1 SNP alleles in fungal populations with mixed antifungal susceptibility, which would be misdiagnosed as completely susceptible or resistant under standard reaction conditions. Our platform's use of commercially available materials and common laboratory equipment makes C. auris diagnostics widely deployable in global healthcare settings.
{"title":"Digital CRISPR-based diagnostics for quantification of Candida auris and resistance mutations.","authors":"Justin C Rolando,Anton Thieme,Nicole E Weckman,Nayoung Kim,Helena de Puig,Xiao Tan,Emily Cotnoir,Vishnu Chaturvedi,James J Collins,David R Walt","doi":"10.1038/s41551-025-01597-0","DOIUrl":"https://doi.org/10.1038/s41551-025-01597-0","url":null,"abstract":"Candida auris, an increasingly prevalent fungal pathogen, requires both rapid identification and antifungal susceptibility testing to enable proper treatment. This study introduces digital SHERLOCK (dSHERLOCK), a platform that combines CRISPR/Cas nucleic acid detection, single-template quantification and real-time kinetics monitoring. Assays implemented on this platform display excellent sensitivity to C. auris from major clades 1-4, while maintaining specificity when challenged with common environmental and pathogenic fungi. dSHERLOCK detects C. auris within 20 min in minimally processed swab samples and achieves sensitive quantification (1 c.f.u. µl-1) within 40 min. To address antifungal susceptibility testing, we develop assays that detect mutations that are commonly associated with azole and echinocandin multidrug resistance. We use machine learning and real-time monitoring of reaction kinetics to achieve highly accurate simultaneous quantification of mutant and wild-type FKS1 SNP alleles in fungal populations with mixed antifungal susceptibility, which would be misdiagnosed as completely susceptible or resistant under standard reaction conditions. Our platform's use of commercially available materials and common laboratory equipment makes C. auris diagnostics widely deployable in global healthcare settings.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"17 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968532","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}
Pub Date : 2026-01-13DOI: 10.1038/s41551-025-01588-1
Jamie I. Scott, Zhiming Cheng, Emily J. Thompson, Utsa Karmakar, Verity Cowell, Maya David, Doireann Gordon, Lorena Mendive-Tapia, Alexander Le Saint-Grant, Pia Volkmer, Cher S. Chuah, Phoebe Lau, Adriano G. Rossi, Wouter B. Nagengast, Doron Shabat, Gwo-Tzer Ho, Marc Vendrell
The diagnosis and monitoring of inflammatory bowel disease (IBD) relies on histologic and endoscopic analysis, as well as measurements of generic markers of inflammation. However, there are no specific tests that report on T cell-mediated immune responses as a key driver of IBD pathogenesis. Here we detect increasing granzyme A (GzmA) in gut biopsies and confirm that CD8+ T cells secrete its active form to induce interleukin (IL)-8. We then rationally design a non-invasive chemiluminescence assay for measuring active GzmA in stool supernatants from patients with IBD. For our assay, we synthesize peptide-based GzmA-specific inhibitors and chemiluminescent reporters and use them to characterize biosamples from ~150 human patients with IBD and healthy controls. Our results demonstrate that GzmA activity is an indicator of gut inflammation that can enhance the identification of patients with IBD over existing tests and potentially act as a mechanistic biomarker for the dominance of T cell activity. We envision that the selectivity and sensitivity of our GzmA activity-based optical assay will accelerate the design of additional biomedical approaches to enhance precision medicine in IBD.
{"title":"A chemiluminescence assay targeting granzyme A activity for monitoring inflammatory bowel disease","authors":"Jamie I. Scott, Zhiming Cheng, Emily J. Thompson, Utsa Karmakar, Verity Cowell, Maya David, Doireann Gordon, Lorena Mendive-Tapia, Alexander Le Saint-Grant, Pia Volkmer, Cher S. Chuah, Phoebe Lau, Adriano G. Rossi, Wouter B. Nagengast, Doron Shabat, Gwo-Tzer Ho, Marc Vendrell","doi":"10.1038/s41551-025-01588-1","DOIUrl":"https://doi.org/10.1038/s41551-025-01588-1","url":null,"abstract":"The diagnosis and monitoring of inflammatory bowel disease (IBD) relies on histologic and endoscopic analysis, as well as measurements of generic markers of inflammation. However, there are no specific tests that report on T cell-mediated immune responses as a key driver of IBD pathogenesis. Here we detect increasing granzyme A (GzmA) in gut biopsies and confirm that CD8+ T cells secrete its active form to induce interleukin (IL)-8. We then rationally design a non-invasive chemiluminescence assay for measuring active GzmA in stool supernatants from patients with IBD. For our assay, we synthesize peptide-based GzmA-specific inhibitors and chemiluminescent reporters and use them to characterize biosamples from ~150 human patients with IBD and healthy controls. Our results demonstrate that GzmA activity is an indicator of gut inflammation that can enhance the identification of patients with IBD over existing tests and potentially act as a mechanistic biomarker for the dominance of T cell activity. We envision that the selectivity and sensitivity of our GzmA activity-based optical assay will accelerate the design of additional biomedical approaches to enhance precision medicine in IBD.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"39 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956334","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}
Pub Date : 2026-01-13DOI: 10.1038/s41551-025-01596-1
Hui Zhang, Xinyue Yu, Fuhua Yang, Jinying An, Lin Su, Yuqing Liu, Mi Zhang, Ruiyan Fan, Hongli Yang, Xiaorong Li, Xiaomin Zhang
Small extracellular vesicles have been widely studied for their therapeutic properties and ability to deliver bioactive molecules. In addition to secretory vesicles, cells contain small intracellular vesicles involved in physiological and metabolic processes, whose therapeutic potential remains unexplored. Here we developed protocols to isolate small intracellular vesicles from multiple cell types and systematically compared their molecular and functional profiles to extracellular vesicles. Intracellular vesicles are smaller, yield higher quantities and demonstrate enhanced cellular uptake in both in vitro and in vivo models. Molecular profiling revealed that intracellular vesicles are enriched in proteins associated with the endoplasmic reticulum and Golgi apparatus, possess distinct microRNA signatures linked to intracellular membrane systems, and contain elevated levels of phospholipids such as phosphatidylcholine and phosphatidylethanolamine. Vesicles derived from umbilical cord mesenchymal stem cells showed superior therapeutic efficacy in a model of retinal degeneration by reducing endoplasmic reticulum stress and delivering neuroprotective factors. In addition, intracellular vesicles exhibited enhanced drug-loading capacity and efficient delivery of lipophilic compounds to the retina. These findings position intracellular vesicles as promising candidates for therapeutic applications.
{"title":"Small intracellular vesicles outperform small extracellular vesicles in uptake, drug delivery and retinal neuroprotection","authors":"Hui Zhang, Xinyue Yu, Fuhua Yang, Jinying An, Lin Su, Yuqing Liu, Mi Zhang, Ruiyan Fan, Hongli Yang, Xiaorong Li, Xiaomin Zhang","doi":"10.1038/s41551-025-01596-1","DOIUrl":"https://doi.org/10.1038/s41551-025-01596-1","url":null,"abstract":"Small extracellular vesicles have been widely studied for their therapeutic properties and ability to deliver bioactive molecules. In addition to secretory vesicles, cells contain small intracellular vesicles involved in physiological and metabolic processes, whose therapeutic potential remains unexplored. Here we developed protocols to isolate small intracellular vesicles from multiple cell types and systematically compared their molecular and functional profiles to extracellular vesicles. Intracellular vesicles are smaller, yield higher quantities and demonstrate enhanced cellular uptake in both in vitro and in vivo models. Molecular profiling revealed that intracellular vesicles are enriched in proteins associated with the endoplasmic reticulum and Golgi apparatus, possess distinct microRNA signatures linked to intracellular membrane systems, and contain elevated levels of phospholipids such as phosphatidylcholine and phosphatidylethanolamine. Vesicles derived from umbilical cord mesenchymal stem cells showed superior therapeutic efficacy in a model of retinal degeneration by reducing endoplasmic reticulum stress and delivering neuroprotective factors. In addition, intracellular vesicles exhibited enhanced drug-loading capacity and efficient delivery of lipophilic compounds to the retina. These findings position intracellular vesicles as promising candidates for therapeutic applications.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"4 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956333","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}
Adoptive T cell transfer therapy remains limited by the inability to monitor live tumour cell dynamics during treatment. Here we introduce a real-time, label-free phenotyping system that integrates electrical impedance spectroscopy, Raman spectroscopy and microscopy to analyse live tumour cells undergoing therapy. This system enables simultaneous tracking of metabolic activity, membrane integrity and cytoplasmic properties at single-cell resolution. First, analysis of glycolysis reveals that tumour-infiltrating lymphocytes suppress lactate production early, reducing tumour aggressiveness, while chimaeric antigen receptor T cells trigger tumour silent escape early and delay metabolic inhibition until later stages, culminating in cell death. Second, membrane profiling shows early phospholipid and cholesterol depletion under tumour-infiltrating lymphocyte treatment, with partial recovery, whereas chimaeric antigen receptor T cells cause progressive and irreversible membrane damage. Third, cytoplasmic analysis identifies early protein structural disruption and ionic imbalance under tumour-infiltrating lymphocyte therapy, while chimaeric antigen receptor T cells trigger delayed metabolic collapse and cytoplasmic contraction. These findings uncover distinct immune killing mechanisms and escape phases, offering mechanistic insights into tumour-immune interactions and informing the design of personalized therapeutic strategies.
{"title":"Real-time multimodal phenotyping reveals distinct tumour cell dynamics and immune escape mechanisms in T cell therapies.","authors":"Shengjie Chen,Kunru Yu,Shengsen Zhang,Xiaoliang Guo,Rong Zhu","doi":"10.1038/s41551-025-01582-7","DOIUrl":"https://doi.org/10.1038/s41551-025-01582-7","url":null,"abstract":"Adoptive T cell transfer therapy remains limited by the inability to monitor live tumour cell dynamics during treatment. Here we introduce a real-time, label-free phenotyping system that integrates electrical impedance spectroscopy, Raman spectroscopy and microscopy to analyse live tumour cells undergoing therapy. This system enables simultaneous tracking of metabolic activity, membrane integrity and cytoplasmic properties at single-cell resolution. First, analysis of glycolysis reveals that tumour-infiltrating lymphocytes suppress lactate production early, reducing tumour aggressiveness, while chimaeric antigen receptor T cells trigger tumour silent escape early and delay metabolic inhibition until later stages, culminating in cell death. Second, membrane profiling shows early phospholipid and cholesterol depletion under tumour-infiltrating lymphocyte treatment, with partial recovery, whereas chimaeric antigen receptor T cells cause progressive and irreversible membrane damage. Third, cytoplasmic analysis identifies early protein structural disruption and ionic imbalance under tumour-infiltrating lymphocyte therapy, while chimaeric antigen receptor T cells trigger delayed metabolic collapse and cytoplasmic contraction. These findings uncover distinct immune killing mechanisms and escape phases, offering mechanistic insights into tumour-immune interactions and informing the design of personalized therapeutic strategies.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"23 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956023","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}
Amidst the chronic issue of opioid misuse, finding an alternative to pharmaceutical pain control following surgical interventions stands as a major hurdle. Conventional non-pharmacological pain control technologies often rely on rigid stimulators linking internal and external body components, thereby imposing nerve burden and additional interventions for the removal. Here we introduce a bioresorbable triboelectric nerve cuff activated via ultrasounds for pain control. The targeted nerves are enveloped around polymers with opposite triboelectric properties that vibrate upon ultrasound stimulation, generating an alternating triboelectric field parallel to the nerve for pain modulation. In vivo testing in rat and porcine models demonstrates that the fully implanted neurostimulator exerts no discernible impact on gait and yields immediate pain relief. Application of the implant until full resorbing caused no adverse effects in the nerve or surrounding muscle tissue, and behavioural analysis confirmed its effective pain control. The implantable pain control system might offer a drug-free alternative to pain management strategies, helping prevent drug abuse.
{"title":"Wireless and bioresorbable triboelectric nerve block system for postoperative pain control.","authors":"Young-Jun Kim,So-Hee Kim,Byung-Joon Park,Jinyoung Jeon,Donghyeon Kang,Youngwook Chung,Joon-Ha Hwang,Hong-Joon Yoon,Kyu Hyoung Lee,Byung-Ok Choi,Sang-Woo Kim","doi":"10.1038/s41551-025-01579-2","DOIUrl":"https://doi.org/10.1038/s41551-025-01579-2","url":null,"abstract":"Amidst the chronic issue of opioid misuse, finding an alternative to pharmaceutical pain control following surgical interventions stands as a major hurdle. Conventional non-pharmacological pain control technologies often rely on rigid stimulators linking internal and external body components, thereby imposing nerve burden and additional interventions for the removal. Here we introduce a bioresorbable triboelectric nerve cuff activated via ultrasounds for pain control. The targeted nerves are enveloped around polymers with opposite triboelectric properties that vibrate upon ultrasound stimulation, generating an alternating triboelectric field parallel to the nerve for pain modulation. In vivo testing in rat and porcine models demonstrates that the fully implanted neurostimulator exerts no discernible impact on gait and yields immediate pain relief. Application of the implant until full resorbing caused no adverse effects in the nerve or surrounding muscle tissue, and behavioural analysis confirmed its effective pain control. The implantable pain control system might offer a drug-free alternative to pain management strategies, helping prevent drug abuse.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"1 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937761","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}
Pub Date : 2026-01-08DOI: 10.1038/s41551-025-01576-5
Dachao Tang, Chi Zhang, Weizhi Zhang, Funian Lu, Leming Xiao, Xinhe Huang, Jiangyi Shao, Dan Liu, Shanshan Fu, Miaoying Zhao, Luoying Zhang, Da Jia, Han-Ming Shen, Chaoyang Sun, Gang Chen, Bin Liu, Di Peng, Yu Xue
Profiling molecular panorama from massive omics data identifies regulatory networks in cells but requires mechanistic interpretation and experimental follow up. Here we combine deep learning and large language model reasoning to develop a hybrid workflow for omics interpretation, called LyMOI. LyMOI incorporates GPT-3.5 for biological knowledge reasoning and a large graph model with graph convolutional networks (GCNs). The large graph model integrates evolutionarily conserved protein interactions and uses hierarchical fine-tuning to predict context-specific molecular regulators from multi-omics data. GPT-3.5 then generates machine chain-of-thought (CoT) to mechanistically interpret their roles in biological systems. Focusing on autophagy, LyMOI mechanistically interprets 1.3 TB transcriptomic, proteomic and phosphoproteomic data and expands the knowledge of autophagy regulators. We also show that LyMOI highlights two human oncoproteins, CTSL and FAM98A, for enhancing autophagy upon treatment with disulfiram (DSF), an antitumour agent. Silencing these genes in vitro attenuates DSF-mediated autophagy and suppresses cancer cell proliferation. Strikingly, DSF treatment with Z-FY-CHO, a CTSL-specific inhibitor previously used for preventing SARS-CoV-2 infection, potently inhibits tumour growth in vivo.
{"title":"A deep learning and large language hybrid workflow for omics interpretation","authors":"Dachao Tang, Chi Zhang, Weizhi Zhang, Funian Lu, Leming Xiao, Xinhe Huang, Jiangyi Shao, Dan Liu, Shanshan Fu, Miaoying Zhao, Luoying Zhang, Da Jia, Han-Ming Shen, Chaoyang Sun, Gang Chen, Bin Liu, Di Peng, Yu Xue","doi":"10.1038/s41551-025-01576-5","DOIUrl":"https://doi.org/10.1038/s41551-025-01576-5","url":null,"abstract":"Profiling molecular panorama from massive omics data identifies regulatory networks in cells but requires mechanistic interpretation and experimental follow up. Here we combine deep learning and large language model reasoning to develop a hybrid workflow for omics interpretation, called LyMOI. LyMOI incorporates GPT-3.5 for biological knowledge reasoning and a large graph model with graph convolutional networks (GCNs). The large graph model integrates evolutionarily conserved protein interactions and uses hierarchical fine-tuning to predict context-specific molecular regulators from multi-omics data. GPT-3.5 then generates machine chain-of-thought (CoT) to mechanistically interpret their roles in biological systems. Focusing on autophagy, LyMOI mechanistically interprets 1.3 TB transcriptomic, proteomic and phosphoproteomic data and expands the knowledge of autophagy regulators. We also show that LyMOI highlights two human oncoproteins, CTSL and FAM98A, for enhancing autophagy upon treatment with disulfiram (DSF), an antitumour agent. Silencing these genes in vitro attenuates DSF-mediated autophagy and suppresses cancer cell proliferation. Strikingly, DSF treatment with Z-FY-CHO, a CTSL-specific inhibitor previously used for preventing SARS-CoV-2 infection, potently inhibits tumour growth in vivo.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"43 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919983","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}
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