Edo Kapetanovic, Cédric R. Weber, Marine Bruand, Daniel Pöschl, Jakub Kucharczyk, Elisabeth Hirth, Claudius Dietsche, Riyaz Khan, Bastian Wagner, Olivier Belli, Rodrigo Vazquez-Lombardi, Rocío Castellanos- Rueda, Raphael B. Di Roberto, Kevin Kalinka, Luca Raess, Kevin Ly, Shivam Rai, Petra S. Dittrich, Randall J. Platt, Elisa Oricchio, Sai T. Reddy
{"title":"Engineered allogeneic T cells decoupling T-cell-receptor and CD3 signalling enhance the antitumour activity of bispecific antibodies","authors":"Edo Kapetanovic, Cédric R. Weber, Marine Bruand, Daniel Pöschl, Jakub Kucharczyk, Elisabeth Hirth, Claudius Dietsche, Riyaz Khan, Bastian Wagner, Olivier Belli, Rodrigo Vazquez-Lombardi, Rocío Castellanos- Rueda, Raphael B. Di Roberto, Kevin Kalinka, Luca Raess, Kevin Ly, Shivam Rai, Petra S. Dittrich, Randall J. Platt, Elisa Oricchio, Sai T. Reddy","doi":"10.1038/s41551-024-01255-x","DOIUrl":"https://doi.org/10.1038/s41551-024-01255-x","url":null,"abstract":"<p>Bispecific antibodies (biAbs) used in cancer immunotherapies rely on functional autologous T cells, which are often damaged and depleted in patients with haematological malignancies and in other immunocompromised patients. The adoptive transfer of allogeneic T cells from healthy donors can enhance the efficacy of biAbs, but donor T cells binding to host-cell antigens cause an unwanted alloreactive response. Here we show that allogeneic T cells engineered with a T-cell receptor that does not convert antigen binding into cluster of differentiation 3 (CD3) signalling decouples antigen-mediated T-cell activation from T-cell cytotoxicity while preserving the surface expression of the T-cell-receptor–CD3 signalling complex as well as biAb-mediated CD3 signalling and T-cell activation. In mice with CD19<sup>+</sup> tumour xenografts, treatment with the engineered human cells in combination with blinatumomab (a clinically approved biAb) led to the recognition and clearance of tumour cells in the absence of detectable alloreactivity. Our findings support the development of immunotherapies combining biAbs and ‘off-the-shelf’ allogeneic T cells.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317022","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}
James G Shamul,Zhiyuan Wang,Hyeyeon Gong,Wenquan Ou,Alisa M White,Diogo P Moniz-Garcia,Shuo Gu,Alisa Morss Clyne,Alfredo Quiñones-Hinojosa,Xiaoming He
{"title":"Meta-analysis of the make-up and properties of in vitro models of the healthy and diseased blood-brain barrier.","authors":"James G Shamul,Zhiyuan Wang,Hyeyeon Gong,Wenquan Ou,Alisa M White,Diogo P Moniz-Garcia,Shuo Gu,Alisa Morss Clyne,Alfredo Quiñones-Hinojosa,Xiaoming He","doi":"10.1038/s41551-024-01250-2","DOIUrl":"https://doi.org/10.1038/s41551-024-01250-2","url":null,"abstract":"In vitro models of the human blood-brain barrier (BBB) are increasingly used to develop therapeutics that can cross the BBB for treating diseases of the central nervous system. Here we report a meta-analysis of the make-up and properties of transwell and microfluidic models of the healthy BBB and of BBBs in glioblastoma, Alzheimer's disease, Parkinson's disease and inflammatory diseases. We found that the type of model, the culture method (static or dynamic), the cell types and cell ratios, and the biomaterials employed as extracellular matrix are all crucial to recapitulate the low permeability and high expression of tight-junction proteins of the BBB, and to obtain high trans-endothelial electrical resistance. Specifically, for models of the healthy BBB, the inclusion of endothelial cells and pericytes as well as physiological shear stresses (~10-20 dyne cm-2) are necessary, and when astrocytes are added, astrocytes or pericytes should outnumber endothelial cells. We expect this meta-analysis to facilitate the design of increasingly physiological models of the BBB.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275158","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":"Non-viral targeted insertion of large payloads into T cells","authors":"Zsuzsanna Izsvák","doi":"10.1038/s41551-024-01252-0","DOIUrl":"https://doi.org/10.1038/s41551-024-01252-0","url":null,"abstract":"The nuclease Cas9 and DNA-repair pathway homology-mediated end joining can be leveraged to efficiently and non-virally integrate large DNA payloads into genomic target sites in primary T cells.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234456","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":"In situ formation of biomolecular condensates as intracellular drug reservoirs for augmenting chemotherapy","authors":"Tingxizi Liang, Yuxiang Dong, Irina Cheng, Ping Wen, Fengqin Li, Feng Liu, Qing Wu, En Ren, Peifeng Liu, Hongjun Li, Zhen Gu","doi":"10.1038/s41551-024-01254-y","DOIUrl":"https://doi.org/10.1038/s41551-024-01254-y","url":null,"abstract":"<p>Biomolecular condensates, which arise from liquid–liquid phase separation within cells, may provide a means of enriching and prolonging the retention of small-molecule drugs within cells. Here we report a method for the controlled in situ formation of biomolecular condensates as reservoirs for the enrichment and retention of chemotherapeutics in cancer cells, and show that the approach can be leveraged to enhance antitumour efficacies in mice with drug-resistant tumours. The method involves histones as positively charged proteins and doxorubicin-intercalated DNA strands bioorthogonally linked via a click-to-release reaction between <i>trans</i>-cyclooctene and tetrazine groups. The reaction temporarily impaired the phase separation of histones in vitro, favoured the initiation of liquid–liquid phase separation within cells and led to the formation of biomolecular condensates that were sufficiently large to be retained within tumour cells. The controlled formation of biomolecular condensates as drug reservoirs within cells may offer new options for boosting the efficacies of cancer therapies.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175025","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}
Yifan Wang, Benjamin R. Schrank, Wen Jiang, Betty Y. S. Kim
{"title":"Learning what keeps nanomedicines in tumours","authors":"Yifan Wang, Benjamin R. Schrank, Wen Jiang, Betty Y. S. Kim","doi":"10.1038/s41551-024-01251-1","DOIUrl":"https://doi.org/10.1038/s41551-024-01251-1","url":null,"abstract":"An analysis of histopathological data from mouse and human tumours via machine learning reveals that the densities of blood vessels and tumour-associated macrophages are predictive features of the degree of tumoural accumulation of polymeric and liposomal nanomedicines.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175024","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}
Benedict Edward Mc Larney, Ali Yasin Sonay, Elana Apfelbaum, Nermin Mostafa, Sébastien Monette, Dana Goerzen, Nicole Aguirre, Rüdiger M. Exner, Christine Habjan, Elizabeth Isaac, Ngan Bao Phung, Magdalena Skubal, Mijin Kim, Anuja Ogirala, Darren Veach, Daniel A. Heller, Jan Grimm
{"title":"A pan-cancer dye for solid-tumour screening, resection and wound monitoring via short-wave and near-infrared fluorescence imaging","authors":"Benedict Edward Mc Larney, Ali Yasin Sonay, Elana Apfelbaum, Nermin Mostafa, Sébastien Monette, Dana Goerzen, Nicole Aguirre, Rüdiger M. Exner, Christine Habjan, Elizabeth Isaac, Ngan Bao Phung, Magdalena Skubal, Mijin Kim, Anuja Ogirala, Darren Veach, Daniel A. Heller, Jan Grimm","doi":"10.1038/s41551-024-01248-w","DOIUrl":"10.1038/s41551-024-01248-w","url":null,"abstract":"The efficacy of fluorescence-guided surgery in facilitating the real-time delineation of tumours depends on the optical contrast of tumour tissue over healthy tissue. Here we show that CJ215—a commercially available, renally cleared carbocyanine dye sensitive to apoptosis, and with an absorption and emission spectra suitable for near-infrared fluorescence imaging (wavelengths of 650–900 nm) and shortwave infrared (SWIR) fluorescence imaging (900–1,700 nm)—can facilitate fluorescence-guided tumour screening, tumour resection and the assessment of wound healing. In tumour models of either murine or human-derived breast, prostate and colon cancers and of fibrosarcoma, and in a model of intraperitoneal carcinomatosis, imaging of CJ215 with ambient light allowed for the delineation of nearly all tumours within 24 h after intravenous injection of the dye, which was minimally taken up by healthy organs. At later timepoints, CJ215 provided tumour-to-muscle contrast ratios up to 100 and tumour-to-liver contrast ratios up to 18. SWIR fluorescence imaging with the dye also allowed for quantifiable non-contact wound monitoring through commercial bandages. CJ215 may be compatible with existing and emerging clinical solutions. A commercial near-infrared dye that is sensitive to apoptosis and that provides high tumour-to-muscle and tumour-to-liver contrast ratios facilitates fluorescence-guided tumour screening, tumour resection and the assessment of wound healing.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":26.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158748","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}
Fujian Lu, Carter Liou, Qing Ma, Zexuan Wu, Bingqing Xue, Yu Xia, Shutao Xia, Michael A. Trembley, Anna Ponek, Wenjun Xie, Kevin Shani, Raul H. Bortolin, Maksymilian Prondzynski, Paul Berkson, Xiaoran Zhang, Francisco J. Naya, Kenneth C. Bedi, Kenneth B. Margulies, Donghui Zhang, Kevin K. Parker, William T. Pu
{"title":"Virally delivered CMYA5 enhances the assembly of cardiac dyads","authors":"Fujian Lu, Carter Liou, Qing Ma, Zexuan Wu, Bingqing Xue, Yu Xia, Shutao Xia, Michael A. Trembley, Anna Ponek, Wenjun Xie, Kevin Shani, Raul H. Bortolin, Maksymilian Prondzynski, Paul Berkson, Xiaoran Zhang, Francisco J. Naya, Kenneth C. Bedi, Kenneth B. Margulies, Donghui Zhang, Kevin K. Parker, William T. Pu","doi":"10.1038/s41551-024-01253-z","DOIUrl":"https://doi.org/10.1038/s41551-024-01253-z","url":null,"abstract":"<p>Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) lack nanoscale structures essential for efficient excitation–contraction coupling. Such nanostructures, known as dyads, are frequently disrupted in heart failure. Here we show that the reduced expression of cardiomyopathy-associated 5 (CMYA5), a master protein that establishes dyads, contributes to dyad disorganization in heart failure and to impaired dyad assembly in hiPSC-CMs, and that a miniaturized form of CMYA5 suitable for delivery via an adeno-associated virus substantially improved dyad architecture and normalized cardiac function under pressure overload. In hiPSC-CMs, the miniaturized form of CMYA5 increased contractile forces, improved Ca<sup>2+</sup> handling and enhanced the alignment of sarcomere Z-lines with ryanodine receptor 2, a protein that mediates the sarcoplasmic release of stored Ca<sup>2+</sup>. Our findings clarify the mechanisms responsible for impaired dyad structure in diseased cardiomyocytes, and suggest strategies for promoting dyad assembly and stability in heart disease and during the derivation of hiPSC-CMs.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137988","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":"Engineering signalling pathways in mammalian cells","authors":"Anna V. Leopold, Vladislav V. Verkhusha","doi":"10.1038/s41551-024-01237-z","DOIUrl":"https://doi.org/10.1038/s41551-024-01237-z","url":null,"abstract":"<p>In mammalian cells, signalling pathways orchestrate cellular growth, differentiation and survival, as well as many other processes that are essential for the proper functioning of cells. Here we describe cutting-edge genetic-engineering technologies for the rewiring of signalling networks in mammalian cells. Specifically, we describe the recombination of native pathway components, cross-kingdom pathway transplantation, and the development of de novo signalling within cells and organelles. We also discuss how, by designing signalling pathways, mammalian cells can acquire new properties, such as the capacity for photosynthesis, the ability to detect cancer and senescent cell markers or to synthesize hormones or metabolites in response to chemical or physical stimuli. We also review the applications of mammalian cells in biocomputing. Technologies for engineering signalling pathways in mammalian cells are advancing basic cellular biology, biomedical research and drug discovery.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137990","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}
Yannan Chen, Shradha Chauhan, Cheng Gong, Hannah Dayton, Cong Xu, Estanislao Daniel De La Cruz, Yu-Young Wesley Tsai, Malika S. Datta, Gorazd B. Rosoklija, Andrew J. Dwork, J. John Mann, Maura Boldrini, Kam W. Leong, Lars E. P. Dietrich, Raju Tomer
{"title":"Low-cost and scalable projected light-sheet microscopy for the high-resolution imaging of cleared tissue and living samples","authors":"Yannan Chen, Shradha Chauhan, Cheng Gong, Hannah Dayton, Cong Xu, Estanislao Daniel De La Cruz, Yu-Young Wesley Tsai, Malika S. Datta, Gorazd B. Rosoklija, Andrew J. Dwork, J. John Mann, Maura Boldrini, Kam W. Leong, Lars E. P. Dietrich, Raju Tomer","doi":"10.1038/s41551-024-01249-9","DOIUrl":"10.1038/s41551-024-01249-9","url":null,"abstract":"Light-sheet fluorescence microscopy (LSFM) is a widely used technique for imaging cleared tissue and living samples. However, high-performance LSFM systems are typically expensive and not easily scalable. Here we introduce a low-cost, scalable and versatile LSFM framework, which we named ‘projected light-sheet microscopy’ (pLSM), with high imaging performance and small device and computational footprints. We characterized the capabilities of pLSM, which repurposes readily available consumer-grade components, optimized optics, over-network control architecture and software-driven light-sheet modulation, by performing high-resolution mapping of cleared mouse brains and of post-mortem pathological human brain samples, and via the molecular phenotyping of brain and blood-vessel organoids derived from human induced pluripotent stem cells. We also report a method that leverages pLSM for the live imaging of the dynamics of sparsely labelled multi-layered bacterial pellicle biofilms at an air–liquid interface. pLSM can make high-resolution LSFM for biomedical applications more accessible, affordable and scalable. A light-sheet fluorescence microscope leveraging consumer-grade components as well as optimized optics and software facilitates the high-resolution imaging of cleared and living samples at scale with lower costs.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":26.8,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090115","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}
Michael Tong, Nathan Palmer, Amir Dailamy, Aditya Kumar, Hammza Khaliq, Sangwoo Han, Emma Finburgh, Madeleine Wing, Camilla Hong, Yichen Xiang, Katelyn Miyasaki, Andrew Portell, Joseph Rainaldi, Amanda Suhardjo, Sami Nourreddine, Wei Leong Chew, Ester J Kwon, Prashant Mali
{"title":"Robust genome and cell engineering via in vitro and in situ circularized RNAs.","authors":"Michael Tong, Nathan Palmer, Amir Dailamy, Aditya Kumar, Hammza Khaliq, Sangwoo Han, Emma Finburgh, Madeleine Wing, Camilla Hong, Yichen Xiang, Katelyn Miyasaki, Andrew Portell, Joseph Rainaldi, Amanda Suhardjo, Sami Nourreddine, Wei Leong Chew, Ester J Kwon, Prashant Mali","doi":"10.1038/s41551-024-01245-z","DOIUrl":"10.1038/s41551-024-01245-z","url":null,"abstract":"<p><p>Circularization can improve RNA persistence, yet simple and scalable approaches to achieve this are lacking. Here we report two methods that facilitate the pursuit of circular RNAs (cRNAs): cRNAs developed via in vitro circularization using group II introns, and cRNAs developed via in-cell circularization by the ubiquitously expressed RtcB protein. We also report simple purification protocols that enable high cRNA yields (40-75%) while maintaining low immune responses. These methods and protocols facilitate a broad range of applications in stem cell engineering as well as robust genome and epigenome targeting via zinc finger proteins and CRISPR-Cas9. Notably, cRNAs bearing the encephalomyocarditis internal ribosome entry enabled robust expression and persistence compared with linear capped RNAs in cardiomyocytes and neurons, which highlights the utility of cRNAs in these non-dividing cells. We also describe genome targeting via deimmunized Cas9 delivered as cRNA and a long-range multiplexed protein engineering methodology for the combinatorial screening of deimmunized protein variants that enables compatibility between persistence of expression and immunogenicity in cRNA-delivered proteins. The cRNA toolset will aid research and the development of therapeutics.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":26.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073377","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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