Nature Biomedical Engineering最新文献

Collagen-binding IL-12-armoured STEAP1 CAR-T cells reduce toxicity and treat prostate cancer in mouse models. 胶原结合il -12装甲STEAP1 CAR-T细胞在小鼠模型中降低毒性并治疗前列腺癌

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2025-10-23 DOI: 10.1038/s41551-025-01508-3

Koichi Sasaki,Vipul Bhatia,Yuta Asano,Jakob Bakhtiari,Pooja Kaur,Chuyi Wang,Takumi Matsuo,Olivier Dubois,Po-Chuan Chiu,Donny Gun,Charanjit Singh,Ioanna Panagi,Laurine Noblecourt,Maria Nikolaidi,Truman Chong,Gerardo Javier,Saul J Priceman,Aude G Chapuis,John K Lee,Jun Ishihara

{"title":"Collagen-binding IL-12-armoured STEAP1 CAR-T cells reduce toxicity and treat prostate cancer in mouse models.","authors":"Koichi Sasaki,Vipul Bhatia,Yuta Asano,Jakob Bakhtiari,Pooja Kaur,Chuyi Wang,Takumi Matsuo,Olivier Dubois,Po-Chuan Chiu,Donny Gun,Charanjit Singh,Ioanna Panagi,Laurine Noblecourt,Maria Nikolaidi,Truman Chong,Gerardo Javier,Saul J Priceman,Aude G Chapuis,John K Lee,Jun Ishihara","doi":"10.1038/s41551-025-01508-3","DOIUrl":"https://doi.org/10.1038/s41551-025-01508-3","url":null,"abstract":"Immunosuppressive microenvironments, the lack of immune infiltration, and antigen heterogeneity pose challenges for chimaeric antigen receptor (CAR)-T cell therapies applied to solid tumours. Previously, CAR-T cells were armoured with immunostimulatory molecules, such as interleukin 12 (IL-12), to overcome this issue, but faced high toxicity. Here we show that collagen-binding domain-fused IL-12 (CBD-IL-12) secreted from CAR-T cells to target human six transmembrane epithelial antigen of prostate 1 (STEAP1) is retained within murine prostate tumours. This leads to high intratumoural interferon-γ levels, without hepatotoxicity and infiltration of T cells into non-target organs compared with unmodified IL-12. Both innate and adaptive immune compartments are activated and recognize diverse tumour antigens after CBD-IL-12-armoured CAR-T cell treatment. A combination of CBD-IL-12-armoured CAR-T cells and immune checkpoint inhibitors eradicated large tumours in an established prostate cancer mouse model. In addition, human CBD-IL-12-armoured CAR-T cells showed potent anti-tumour efficacy in a 22Rv1 xenograft while reducing circulating IL-12 levels compared with unmodified IL-12-armoured CAR-T cells. CBD fusion to potent payloads for CAR-T therapy may remove obstacles to their clinical translation towards elimination of solid tumours.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"54 3 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338979","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

Comprehensive resistance profiling of chronic myeloid leukaemia associated ABL1 variants against five tyrosine kinase inhibitors using prime editing. 慢性髓系白血病相关ABL1变异对5种酪氨酸激酶抑制剂的综合耐药性分析

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2025-10-22 DOI: 10.1038/s41551-025-01531-4

Yusang Jung,Goosang Yu,Hyeong-Cheol Oh,Jueng-Hu Lee,Eunhye Jeon,Juhyeon Bae,Taebo Sim,Hyongbum Henry Kim

{"title":"Comprehensive resistance profiling of chronic myeloid leukaemia associated ABL1 variants against five tyrosine kinase inhibitors using prime editing.","authors":"Yusang Jung,Goosang Yu,Hyeong-Cheol Oh,Jueng-Hu Lee,Eunhye Jeon,Juhyeon Bae,Taebo Sim,Hyongbum Henry Kim","doi":"10.1038/s41551-025-01531-4","DOIUrl":"https://doi.org/10.1038/s41551-025-01531-4","url":null,"abstract":"There are four generations of tyrosine kinase inhibitors (TKIs) that target BCR-ABL1 mutations, a fusion oncogene, in chronic myeloid leukaemia, but predicting the resistance profiles of these TKIs for patients with ABL1 mutations is sometimes difficult, especially when the mutations are not included by clinical guidelines. Here we use prime editing to generate 97% (2,802/2,892) of all possible single-nucleotide variants in the sequence encoding the ABL1 kinase domain, which covers 98% (1,954/1,998) of all possible corresponding single amino acid variants. We evaluated their effects on resistance to five TKIs (imatinib, nilotinib, bosutinib, ponatinib and asciminib), spanning all four TKI generations by using K562 cells. We identified 361 pairs of resistance-conferring single amino acid variants and the corresponding TKIs. Our comprehensive resistance map will complement clinical guidelines in drug selection for patients with chronic myeloid leukaemia based on ABL1 mutations, facilitating precision medicine.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"39 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338980","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

A HO-1 gene knockout using a NanoCRISPR scaffold suppresses metastasis in mouse models. 在小鼠模型中，使用纳米crispr支架敲除HO-1基因抑制转移。

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2025-10-22 DOI: 10.1038/s41551-025-01518-1

Ning Wang,Zichao Luo,Chao Liu,Jialin Ma,Xinyue Wu,Qinjie Wu,Xiaogang Liu,Changyang Gong

{"title":"A HO-1 gene knockout using a NanoCRISPR scaffold suppresses metastasis in mouse models.","authors":"Ning Wang,Zichao Luo,Chao Liu,Jialin Ma,Xinyue Wu,Qinjie Wu,Xiaogang Liu,Changyang Gong","doi":"10.1038/s41551-025-01518-1","DOIUrl":"https://doi.org/10.1038/s41551-025-01518-1","url":null,"abstract":"Photodynamic therapy-induced immunogenic cell death has the potential to generate autologous cancer vaccines. However, the innate or evolved genetic tolerance of tumours limits the efficacy of this approach. Here we report the development of a heritable nanoplatform based on gene editing of haem oxygenase-1 (HO-1) using a NanoCRISPR/HO-1 scaffold. This platform effectively eliminates genetic tolerance to reactive oxygen species in tumours without causing adverse effects on main immune cells, resulting in a robust and durable immune response to autologous vaccine. This NanoCRISPR scaffold can inherit susceptibility to tumour progeny, transforming heterogeneous malignancies into a reactive oxyen species-sensitive phenotype. Moreover, the arginine-grafted polyethyleneimine module and CpG motif within the NanoCRISPR scaffold enhance the cancer-immune cycle by amplifying antigen generation, promoting T cell proliferation and activating adaptive immune response in cancer models. When combined with an αPD-L1 antibody, the NanoCRISPR scaffold-based heritable nanoplatform elicits antitumour immunity and durable immunological memory in vivo melanoma mouse models. This combinational therapy evokes a strong immune memory against tumour rechallenge, providing insights into the rational development of a cancer vaccine regimen.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"3 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339025","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

Targeting immunosuppressive myeloid cells via implant-mediated slow release of small molecules to prevent glioblastoma recurrence. 通过植入物介导的小分子缓释靶向免疫抑制骨髓细胞以防止胶质母细胞瘤复发。

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2025-10-22 DOI: 10.1038/s41551-025-01533-2

Yannik Kaiser,Christopher S Garris,Eliana Marinari,Hyung Shik Kim,Juhyun Oh,Martin Pedard,Elias A Halabi,Moonhyun Choi,Sepideh Parvanian,Rainer Kohler,Denis Migliorini,Ralph Weissleder

{"title":"Targeting immunosuppressive myeloid cells via implant-mediated slow release of small molecules to prevent glioblastoma recurrence.","authors":"Yannik Kaiser,Christopher S Garris,Eliana Marinari,Hyung Shik Kim,Juhyun Oh,Martin Pedard,Elias A Halabi,Moonhyun Choi,Sepideh Parvanian,Rainer Kohler,Denis Migliorini,Ralph Weissleder","doi":"10.1038/s41551-025-01533-2","DOIUrl":"https://doi.org/10.1038/s41551-025-01533-2","url":null,"abstract":"Glioblastoma is a highly aggressive brain tumour with a high risk of recurrence after surgery, even when combined with chemotherapy and radiotherapy. A major barrier to lasting treatment is the tumour's immunosuppressive environment, which is largely dominated by myeloid cells. Here we describe the development of a biodegradable implant to sustainably release immune-modulator small molecules to reprogram tumour-infiltrating myeloid cells toward a pro-inflammatory, antitumour phenotype in the surgical cavity after tumour removal. In immunocompetent mouse models, this therapy induces interleukin-12 expression in myeloid cells without systemic cytokine elevation, and increases the infiltration of CD8+ and CD4+ T cells. Over 50% of mice treated (in combination with radiotherapy and chemotherapy) remain tumour-free during the experimental course (80 days). We further treated human glioblastoma explants ex vivo with the therapy and observed increased interleukin-12 expression in tumour-infiltrating myeloid cells, supporting the translational potential of this strategy. This implantable system offers a promising approach to prevent glioblastoma recurrence by activating innate immunity and sustaining immune surveillance post-surgery.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"28 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339024","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

CCR5-targeted allogeneic gamma-delta CD19 chimeric antigen receptor T cells for HIV-associated B cell-malignancy immunotherapy. 靶向ccr5的异体γ - δ CD19嵌合抗原受体T细胞用于hiv相关B细胞恶性免疫治疗。

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2025-10-21 DOI: 10.1038/s41551-025-01527-0

Ángel Ramírez-Fernández,Alexander J Dimitri,Fang Chen,Robert Bartoszek,Gregory M Chen,Laura Córdoba-Espejo,Yuqi Zhou,Yun-Hsin Tang,Chien-Ting Lin,Reyes Acosta,John Scholler,Guido Ghilardi,Patrizia Porazzi,Mireia Pellicer,Núria Profitós-Pelejà,Stefan K Barta,Anne Chew,Julie K Jadlowsky,Vanessa E Gonzalez,Donald L Siegel,Bruce L Levine,Gaël Roué,Marco Ruella,Michael T Lotze,Carl H June,James L Riley,Joseph A Fraietta

{"title":"CCR5-targeted allogeneic gamma-delta CD19 chimeric antigen receptor T cells for HIV-associated B cell-malignancy immunotherapy.","authors":"Ángel Ramírez-Fernández,Alexander J Dimitri,Fang Chen,Robert Bartoszek,Gregory M Chen,Laura Córdoba-Espejo,Yuqi Zhou,Yun-Hsin Tang,Chien-Ting Lin,Reyes Acosta,John Scholler,Guido Ghilardi,Patrizia Porazzi,Mireia Pellicer,Núria Profitós-Pelejà,Stefan K Barta,Anne Chew,Julie K Jadlowsky,Vanessa E Gonzalez,Donald L Siegel,Bruce L Levine,Gaël Roué,Marco Ruella,Michael T Lotze,Carl H June,James L Riley,Joseph A Fraietta","doi":"10.1038/s41551-025-01527-0","DOIUrl":"https://doi.org/10.1038/s41551-025-01527-0","url":null,"abstract":"Immune-based cell therapy offers a promising approach to cancer treatment. While autologous chimeric antigen receptor (CAR) T cells have shown success, production is time-consuming, costly and patient specific. Gamma-delta (γδ) T cells are promising for 'off-the-shelf' CAR T cell therapy. However, clinical translation of γδ CAR T cells is hampered by low frequency, resistance to genetic manipulation and advanced differentiation after expansion, limiting therapeutic feasibility. Here we demonstrate a method for in vitro activation and expansion of peripheral blood γδ T cells, facilitating high rates of gene editing and efficient CAR integration. Using artificial antigen-presenting cells, we produce minimally differentiated, highly functional γδ CAR T cells. By targeting a US Food and Drug Administration-approved CD19 CAR to the CCR5 locus, we generate CCR5-deficient γδ CD19 CAR T cells (γδ CCR5KI-CAR19), which demonstrated resistance to HIV-mediated depletion and robust antitumour responses against B cell lymphoma and leukaemia. γδ CCR5KI-CAR19 T cells enable the immunotherapy of HIV-associated B cell malignancies. These studies provide preclinical evidence supporting large-scale development of potent allogeneic γδ CAR T cells for diverse immunotherapies.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"18 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338533","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

Targeting circulating mechanoresponsive monocytes and macrophages to reduce fibrosis. 靶向循环机械反应性单核细胞和巨噬细胞减少纤维化。

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2025-10-21 DOI: 10.1038/s41551-025-01479-5

Kellen Chen,Michelle Griffin,Dominic Henn,Katharina S Berryman,Dharshan Sivaraj,Hudson C Kussie,Clark A Bonham,Eamonn McKenna,Maria Gracia Mora Pinos,Abdelrahman M Alsharif,Fidel Saenz,Nicholas E Matthews,Maisam Jafri,Jonathan P Yasmeh,Mimi R Borrelli,Savana Huskins,Sydney Steele,Amelia B Knochel,Mansi Singh,Andrew C Hostler,Melissa Leeolou,William W Hahn,David Perrault,Darren Abbas,Nicholas Guardino,Benjamin Thomas,Janos A Barrera,Chikage Noishiki,Artem A Trotsyuk,Jagannath Padmanabhan,Michael Januszyk,Mohammad Khreiss,Michael T Longaker,Geoffrey C Gurtner

{"title":"Targeting circulating mechanoresponsive monocytes and macrophages to reduce fibrosis.","authors":"Kellen Chen,Michelle Griffin,Dominic Henn,Katharina S Berryman,Dharshan Sivaraj,Hudson C Kussie,Clark A Bonham,Eamonn McKenna,Maria Gracia Mora Pinos,Abdelrahman M Alsharif,Fidel Saenz,Nicholas E Matthews,Maisam Jafri,Jonathan P Yasmeh,Mimi R Borrelli,Savana Huskins,Sydney Steele,Amelia B Knochel,Mansi Singh,Andrew C Hostler,Melissa Leeolou,William W Hahn,David Perrault,Darren Abbas,Nicholas Guardino,Benjamin Thomas,Janos A Barrera,Chikage Noishiki,Artem A Trotsyuk,Jagannath Padmanabhan,Michael Januszyk,Mohammad Khreiss,Michael T Longaker,Geoffrey C Gurtner","doi":"10.1038/s41551-025-01479-5","DOIUrl":"https://doi.org/10.1038/s41551-025-01479-5","url":null,"abstract":"In response to injury, a variety of different cells are recruited to sites of injury to facilitate healing. Recent studies have examined the importance of the heterogeneity of tissue resident fibroblasts and mechanical signalling pathways in healing and fibrosis. However, tissue repair and the inflammatory response also involves blood cells that are recruited from the circulation. Here we identify mechanoresponsive myeloid subpopulations present in scar and unwounded skin. We then modulate these subpopulations by manipulating mechanical strain in vivo and in vitro and find that specifically targeting myeloid mechanical signalling is sufficient to reduce the pro-fibrotic myeloid subpopulations and restore the native, anti-inflammatory subpopulations. In addition, myeloid-specific mechanotransduction ablation also downregulates downstream pro-fibrotic fibroblast transcriptional profiles, reducing scar formation. As inflammatory cells circulate and home to injury sites during the initial healing phases in all organs, focusing on mechanoresponsive myeloid subpopulations may generate additional directions for systemic immunomodulatory therapies to target fibrosis and other diseases across other internal organ systems.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"12 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338534","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

Targeting myeloid cell-mediated fibrosis through FAK. 通过FAK靶向髓细胞介导的纤维化。

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2025-10-21 DOI: 10.1038/s41551-025-01482-w

Maya Ezzo,Boris Hinz

引用次数: 0

Engineering a macromolecular JAK inhibitor for treating acute inflammation and endotoxaemia. 设计用于治疗急性炎症和内毒素血症的大分子JAK抑制剂。

IF 28.1 1区医学

Nature Biomedical Engineering Pub Date : 2025-10-17 DOI: 10.1038/s41551-025-01521-6

Min Zhou,Yan Wang,Bin Yang,Yang Zhang,Ling Zhong,Kaiyao Hu,Wendan Pu,Gaoxing Luo,Jianxiang Zhang

{"title":"Engineering a macromolecular JAK inhibitor for treating acute inflammation and endotoxaemia.","authors":"Min Zhou,Yan Wang,Bin Yang,Yang Zhang,Ling Zhong,Kaiyao Hu,Wendan Pu,Gaoxing Luo,Jianxiang Zhang","doi":"10.1038/s41551-025-01521-6","DOIUrl":"https://doi.org/10.1038/s41551-025-01521-6","url":null,"abstract":"Uncontrolled and sustained inflammation is inextricably associated with the pathogenesis of numerous diseases. However, there is still demand for effective and safe anti-inflammatory therapies. Here we report a potent anti-inflammatory macromolecular therapy named HPL, created by conjugating polyethylene glycol and luminol onto a multivalent and hydrolysable cyclic structure. Leveraging its amphiphilic nature, HPL can spontaneously self-assemble into micelles capable of targeting inflamed tissues and localizing in inflammatory cells. In mice with acute lung, kidney and liver injuries, as well as endotoxaemia, HPL shows anti-inflammatory effects that rivals or surpasses those of two commonly used anti-inflammatory drugs. HPL micelles can act as bioactive and inflammation-responsive carriers for site-specific delivery to release anti-inflammatory drugs. Mechanistically, HPL exerts its anti-inflammatory activity mainly by inhibiting the IL-6/JAK2/STAT3 signalling pathway. HPL shows favourable safety profiles in mice at doses at least 5-fold higher than those used in therapeutic studies. These findings suggest that HPL holds great promise as a highly potent, cost-effective and safe JAK2 inhibitor for treating various diseases associated with inflammation.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"16 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311252","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

Autonomous ultrasound with UltraBot 使用UltraBot的自主超声波。

IF 26.8 1区医学

Nature Biomedical Engineering Pub Date : 2025-10-17 DOI: 10.1038/s41551-025-01546-x

Rita Strack

引用次数: 0

Managing haemodynamic instability in spinal cord injury 脊髓损伤血流动力学不稳定的处理。

IF 26.8 1区医学

Nature Biomedical Engineering Pub Date : 2025-10-17 DOI: 10.1038/s41551-025-01547-w

Sadra Bakhshandeh

引用次数: 0