Combination vaccines promise to simplify immunization schedules and improve coverage, but remain technically challenging owing to antigen compatibility, immunogenic balance and formulation complexity. Here we report a modular strategy that uses a single-component nanobody binder to noncovalently attach diverse antigens to intact particles from the licensed hepatitis E vaccine. To identify a suitable binder, an alpaca was immunized with the vaccine, and nanobodies were screened via phage display. One nanobody, P1-5B, selectively bound recessed, non-immunodominant sites on the particle surface and enabled stable antigen display without disrupting native immunogenicity. Using this binder, we generated three vaccine formulations displaying five to eleven antigens, including variants from SARS-2 coronavirus, influenza virus and respiratory syncytial virus. These multivalent particles exhibited high-affinity assembly, preserved solubility and induced neutralizing titres up to three log units higher than soluble antigens. In mice, hamsters and non-human primates, the candidate vaccines conferred robust protection and showed a favourable safety profile. This approach introduces a scalable, plug-and-display system for rapid development of customizable combination vaccines.
{"title":"Nanobody-based combination vaccine using licensed protein nanoparticles protects animals against respiratory and viral infections.","authors":"Tingting Li,Wenhui Xue,Sibo Zhang,Hong Wang,Miaolin Lan,Limin Zhang,Min Lin,Ming Zhou,Dong Ying,Yarong Zeng,Lingyan Cui,Yifan Yin,Huiqing Chen,Jian Ma,Chang Liu,Jijing Chen,Chen Wang,Zihao Yu,Yanling Chen,Yangtao Wu,Hongjing Liu,Hai Li,Yuyun Zhang,Jinjin Li,Zhen Lu,Zihao Chen,Yali Zhang,Lunzhi Yuan,Lizhi Zhou,Qingbing Zheng,Hai Yu,Jun Zhang,Tong Cheng,Junyu Chen,Yixin Chen,Yi Guan,Zizheng Zheng,Ying Gu,Ningshao Xia,Shaowei Li","doi":"10.1038/s41551-025-01529-y","DOIUrl":"https://doi.org/10.1038/s41551-025-01529-y","url":null,"abstract":"Combination vaccines promise to simplify immunization schedules and improve coverage, but remain technically challenging owing to antigen compatibility, immunogenic balance and formulation complexity. Here we report a modular strategy that uses a single-component nanobody binder to noncovalently attach diverse antigens to intact particles from the licensed hepatitis E vaccine. To identify a suitable binder, an alpaca was immunized with the vaccine, and nanobodies were screened via phage display. One nanobody, P1-5B, selectively bound recessed, non-immunodominant sites on the particle surface and enabled stable antigen display without disrupting native immunogenicity. Using this binder, we generated three vaccine formulations displaying five to eleven antigens, including variants from SARS-2 coronavirus, influenza virus and respiratory syncytial virus. These multivalent particles exhibited high-affinity assembly, preserved solubility and induced neutralizing titres up to three log units higher than soluble antigens. In mice, hamsters and non-human primates, the candidate vaccines conferred robust protection and showed a favourable safety profile. This approach introduces a scalable, plug-and-display system for rapid development of customizable combination vaccines.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"33 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357629","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 : 2025-10-24DOI: 10.1038/s41551-025-01530-5
Liam C Kealy,Kim L Good-Jacobson
{"title":"Non-covalent assembly of multiple epitopes onto a single nanoparticle.","authors":"Liam C Kealy,Kim L Good-Jacobson","doi":"10.1038/s41551-025-01530-5","DOIUrl":"https://doi.org/10.1038/s41551-025-01530-5","url":null,"abstract":"","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"106 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357628","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}
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.
免疫抑制微环境、缺乏免疫浸润和抗原异质性对嵌合抗原受体(CAR)-T细胞治疗应用于实体肿瘤提出了挑战。以前，CAR-T细胞被免疫刺激分子（如白细胞介素12 (IL-12)）包裹以克服这一问题，但面临高毒性。本研究表明，CAR-T细胞分泌的靶向人前列腺6跨膜上皮抗原（STEAP1）的胶原结合结构域融合IL-12 （CBD-IL-12）在小鼠前列腺肿瘤中保留。与未修饰的IL-12相比，这导致高肿瘤内干扰素-γ水平，没有肝毒性和T细胞浸润到非靶器官。在cbd - il -12装甲CAR-T细胞治疗后，先天和适应性免疫区均被激活并识别多种肿瘤抗原。在一个已建立的前列腺癌小鼠模型中，cbd - il -12装甲CAR-T细胞和免疫检查点抑制剂的组合根除了大肿瘤。此外，与未经修饰的IL-12装甲CAR-T细胞相比，人类cbd -IL-12装甲CAR-T细胞在22Rv1异种移植物中显示出强大的抗肿瘤功效，同时降低循环IL-12水平。CBD融合到CAR-T治疗的有效载荷可能会消除它们在消除实体肿瘤的临床转化中的障碍。
{"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}
Pub Date : 2025-10-22DOI: 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
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.
{"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}
Pub Date : 2025-10-22DOI: 10.1038/s41551-025-01518-1
Ning Wang,Zichao Luo,Chao Liu,Jialin Ma,Xinyue Wu,Qinjie Wu,Xiaogang Liu,Changyang Gong
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.
{"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}
Pub Date : 2025-10-22DOI: 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
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.
{"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}
Pub Date : 2025-10-21DOI: 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
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.
免疫细胞疗法为癌症治疗提供了一种很有前途的方法。虽然自体嵌合抗原受体（CAR） T细胞已经取得了成功，但生产过程耗时、成本高且患者特异性强。γ - δ (γδ) T细胞有望用于“现成的”CAR - T细胞治疗。然而，γδ CAR - T细胞的临床翻译受到低频、对基因操作的抗性和扩增后的晚期分化的阻碍，限制了治疗的可行性。在这里，我们展示了一种体外激活和扩增外周血γδ T细胞的方法，促进了高速率的基因编辑和高效的CAR整合。利用人工抗原呈递细胞，我们生产了分化程度最低、功能强大的γδ CAR - T细胞。通过将美国食品和药物管理局批准的CD19 CAR靶向CCR5位点，我们产生了CCR5缺陷的γδ CD19 CAR - T细胞（γδ CCR5KI-CAR19），其表现出对hiv介导的衰竭的抵抗和对B细胞淋巴瘤和白血病的强大抗肿瘤反应。γδ CCR5KI-CAR19 T细胞能够免疫治疗hiv相关的B细胞恶性肿瘤。这些研究为大规模开发有效的同种异体γδ CAR - T细胞用于多种免疫疗法提供了临床前证据。
{"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}
Pub Date : 2025-10-21DOI: 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
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.
{"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}
Pub Date : 2025-10-17DOI: 10.1038/s41551-025-01521-6
Min Zhou,Yan Wang,Bin Yang,Yang Zhang,Ling Zhong,Kaiyao Hu,Wendan Pu,Gaoxing Luo,Jianxiang Zhang
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.
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