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.
{"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}
Pub Date : 2025-10-17DOI: 10.1038/s41551-025-01540-3
Diana Romero
{"title":"Next-generation anti-Aβ antibodies show promise in a mouse model of Alzheimer disease","authors":"Diana Romero","doi":"10.1038/s41551-025-01540-3","DOIUrl":"10.1038/s41551-025-01540-3","url":null,"abstract":"","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"9 10","pages":"1564-1564"},"PeriodicalIF":26.8,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311457","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/s41551-025-01551-0
We take a look at how scientific articles have evolved over time and envision possible changes to how research findings are communicated in the age of digital media and artificial intelligence.
{"title":"The ever-changing communication of scientific discovery","authors":"","doi":"10.1038/s41551-025-01551-0","DOIUrl":"10.1038/s41551-025-01551-0","url":null,"abstract":"We take a look at how scientific articles have evolved over time and envision possible changes to how research findings are communicated in the age of digital media and artificial intelligence.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"9 10","pages":"1559-1560"},"PeriodicalIF":26.8,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41551-025-01551-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-17DOI: 10.1038/s41551-025-01495-5
Jiadong Zhang,Yonghao Li,Zheren Li,Zhiming Cui,Pinxiong Li,Jun Li,Zhen Li,Yu Xie,Kannie W Y Chan,Qinrong Zhang,Zhenhui Li,Dinggang Shen
Accurate assessment of human epidermal growth factor receptor 2 (HER2) status is crucial for effective breast cancer treatment planning and improved patient outcomes. Traditional needle biopsies, limited in tissue sampling, often lead to inaccurate assessments due to intratumoural heterogeneity. Here, to address this, we introduce the deep-learning-based HER2 multimodal alignment and prediction (MAP) model, which leverages pretreatment multimodal breast cancer images for a more comprehensive reflection of tumour characteristics and provides more accurate HER2 status prediction. We develop patient response MAP models to demonstrate the HER2 prediction performance of our model compared with needle biopsies from patients receiving neoadjuvant therapy. A large-scale multimodal breast cancer dataset from 4 centres, consisting of 14,472 images from 6,991 cases, is adopted in this study, and the results consistently demonstrate the superiority of our HER2 MAP model in predicting patient response. These findings highlight the substantial advantages of our HER2 predictions. Our study provides physicians with a crucial tool for informed clinical decisions and treatment plans, aiming to improve outcomes in patients with breast cancer.
{"title":"Deep-learning-based HER2 status assessment from multimodal breast cancer data predicts neoadjuvant therapy response.","authors":"Jiadong Zhang,Yonghao Li,Zheren Li,Zhiming Cui,Pinxiong Li,Jun Li,Zhen Li,Yu Xie,Kannie W Y Chan,Qinrong Zhang,Zhenhui Li,Dinggang Shen","doi":"10.1038/s41551-025-01495-5","DOIUrl":"https://doi.org/10.1038/s41551-025-01495-5","url":null,"abstract":"Accurate assessment of human epidermal growth factor receptor 2 (HER2) status is crucial for effective breast cancer treatment planning and improved patient outcomes. Traditional needle biopsies, limited in tissue sampling, often lead to inaccurate assessments due to intratumoural heterogeneity. Here, to address this, we introduce the deep-learning-based HER2 multimodal alignment and prediction (MAP) model, which leverages pretreatment multimodal breast cancer images for a more comprehensive reflection of tumour characteristics and provides more accurate HER2 status prediction. We develop patient response MAP models to demonstrate the HER2 prediction performance of our model compared with needle biopsies from patients receiving neoadjuvant therapy. A large-scale multimodal breast cancer dataset from 4 centres, consisting of 14,472 images from 6,991 cases, is adopted in this study, and the results consistently demonstrate the superiority of our HER2 MAP model in predicting patient response. These findings highlight the substantial advantages of our HER2 predictions. Our study provides physicians with a crucial tool for informed clinical decisions and treatment plans, aiming to improve outcomes in patients with breast cancer.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"19 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311454","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 : 2025-10-16DOI: 10.1038/s41551-025-01511-8
Diana D. Kang, Adam Marks, Judit Morla-Folch, Yizhou Dong, Brian D. Brown, Abraham J. P. Teunissen
Lipid nanoparticles (LNPs) are a versatile platform with numerous experimental, diagnostic and therapeutic applications. However, the high propensity of LNPs to accumulate in hepatocytes and antigen-presenting cells has largely limited their clinical use to vaccines and the treatment of liver diseases. In this Review, we describe established and emerging techniques for monitoring the in vivo behaviour of RNA-loaded LNPs (RNA-LNPs) and strategies for improved tissue and cell targeting that expand the applications of this technology. We discuss innovations in LNP chemistry and bioengineering, and exploiting synthetic biology to tailor the cellular expression of the mRNA cargo, including the use of microRNA target sites. We also review how modifications to the encoded protein can be used to control stability and subcellular localization of the payload. Lastly, we discuss how these techniques and strategies can accelerate the clinical translation of RNA-LNP drugs and improve therapeutic outcomes. This Review explores strategies for targeting and tracking RNA-LNP drugs, monitoring their in vivo behaviour, enhancing tissue-specific delivery, and using synthetic biology to control mRNA expression and protein localization.
{"title":"Targeting and tracking mRNA lipid nanoparticles at the particle, transcript and protein level","authors":"Diana D. Kang, Adam Marks, Judit Morla-Folch, Yizhou Dong, Brian D. Brown, Abraham J. P. Teunissen","doi":"10.1038/s41551-025-01511-8","DOIUrl":"10.1038/s41551-025-01511-8","url":null,"abstract":"Lipid nanoparticles (LNPs) are a versatile platform with numerous experimental, diagnostic and therapeutic applications. However, the high propensity of LNPs to accumulate in hepatocytes and antigen-presenting cells has largely limited their clinical use to vaccines and the treatment of liver diseases. In this Review, we describe established and emerging techniques for monitoring the in vivo behaviour of RNA-loaded LNPs (RNA-LNPs) and strategies for improved tissue and cell targeting that expand the applications of this technology. We discuss innovations in LNP chemistry and bioengineering, and exploiting synthetic biology to tailor the cellular expression of the mRNA cargo, including the use of microRNA target sites. We also review how modifications to the encoded protein can be used to control stability and subcellular localization of the payload. Lastly, we discuss how these techniques and strategies can accelerate the clinical translation of RNA-LNP drugs and improve therapeutic outcomes. This Review explores strategies for targeting and tracking RNA-LNP drugs, monitoring their in vivo behaviour, enhancing tissue-specific delivery, and using synthetic biology to control mRNA expression and protein localization.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"9 10","pages":"1591-1609"},"PeriodicalIF":26.8,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305587","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}
Naive T cells are maintained under a quiescent state, and their exit from quiescence is a hallmark of antigen stimulation. Here we identify the RNA binding protein La-related protein 4 (LARP4) as an important checkpoint regulator of quiescence exit in naive CD4+ T cells. Conditional knockout of LARP4 in naive CD4+ T cells leads to an enhanced quiescence state and/or dampened quiescence exit due to altered stability of several messenger RNAs important for T-cell activation. The differentiation of naive CD4+ T cells into helper T-cell subsets is also impaired after conditional knockout, leading to ameliorated autoimmune and allergic responses. Lastly, we design a peptide inhibitor of LARP4 (LIPEP), and treatment with LIPEP could perfectly mimic LARP4 deficiency and alleviate the severity of autoimmune and allergic diseases in the corresponding mouse models. Our study reveals a link between RNA stability and CD4+ T-cell homeostasis/adaptive activation, highlighting the potential of LARP4 as a preventative and therapeutic target for autoimmune and allergic diseases although at quite high doses.
{"title":"Inhibition of LARP4-mediated quiescence exit of naive CD4+ T cells ameliorates autoimmune and allergic diseases.","authors":"Jian Zhou,Di Yang,Chao Han,Hui Dong,Shufeng Wang,Xiang Li,Jun Hu,Cui Wang,Jie Luo,Zhiyuan Wei,Taiping Liu,Shuai Xu,Chen Xu,Yiwei Zhang,Xian Wang,Yuanyu Deng,Baiqing Li,Ruihan Mao,Mingyang Zhang,Yi Sun,Xinyuan Zhou,Lilin Ye,Bing Ni,Jun Zhu,Juan Li,Jingbo Zhang,Tingting Zhao,Xiangmei Chen,Rong Lin,Yi Zhang,Yuzhang Wu,Yi Tian","doi":"10.1038/s41551-025-01514-5","DOIUrl":"https://doi.org/10.1038/s41551-025-01514-5","url":null,"abstract":"Naive T cells are maintained under a quiescent state, and their exit from quiescence is a hallmark of antigen stimulation. Here we identify the RNA binding protein La-related protein 4 (LARP4) as an important checkpoint regulator of quiescence exit in naive CD4+ T cells. Conditional knockout of LARP4 in naive CD4+ T cells leads to an enhanced quiescence state and/or dampened quiescence exit due to altered stability of several messenger RNAs important for T-cell activation. The differentiation of naive CD4+ T cells into helper T-cell subsets is also impaired after conditional knockout, leading to ameliorated autoimmune and allergic responses. Lastly, we design a peptide inhibitor of LARP4 (LIPEP), and treatment with LIPEP could perfectly mimic LARP4 deficiency and alleviate the severity of autoimmune and allergic diseases in the corresponding mouse models. Our study reveals a link between RNA stability and CD4+ T-cell homeostasis/adaptive activation, highlighting the potential of LARP4 as a preventative and therapeutic target for autoimmune and allergic diseases although at quite high doses.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"20 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305586","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}
Gene-silencing mechanisms using RNA interference (RNAi) and antisense oligomers have drawn attention to nucleic acid medicines. However, several challenges remain such as low in vivo stability and inadequate target selectivity. Here we report a versatile and highly selective method for suppressing gene expression with a short oligonucleotide. The oligonucleotide, a Staple oligomer, hybridizes specifically to a target mRNA and artificially induces a higher-order structure, an RNA G-quadruplex (rG4), on the mRNA. This results in the rG4 effectively suppressing the target protein's translation. The method is validated by successfully regulating translation of TPM3, MYD88 and TRPC6 mRNAs in a cell-free system and in living mammalian cells. Unlike RNAi and antisense technologies, the present technology does not require cooperation with bioprocesses, permitting the quick and easy development of fully non-natural nucleic acid-based Staple oligomers without compromising their effectiveness. In vivo application of the technology to TRPC6 mRNA helps prevent cardiac hypertrophy in thoracic aortic constriction-treated mice without detectable off-target effects. This technology provides new insights into gene therapy after RNAi and antisense technologies.
利用RNA干扰（RNAi）和反义寡聚物的基因沉默机制引起了核酸药物的关注。然而，仍存在一些挑战，如体内稳定性低和靶标选择性不足。在这里，我们报告了一种多功能和高选择性的方法来抑制基因表达短寡核苷酸。寡核苷酸是一种短链寡聚物，它与目标mRNA特异性杂交，并在mRNA上人工诱导高阶结构，即RNA g -四重体（rG4）。这导致rG4有效抑制靶蛋白的翻译。通过在无细胞系统和活的哺乳动物细胞中成功调节TPM3、MYD88和TRPC6 mrna的翻译，验证了该方法。与RNAi和反义技术不同，目前的技术不需要与生物过程合作，允许快速和容易地开发完全非天然的核酸基短链低聚物，而不会影响其有效性。在体内将该技术应用于TRPC6 mRNA有助于防止胸主动脉收缩治疗小鼠的心脏肥厚，而无明显的脱靶效应。该技术为继RNAi和反义技术之后的基因治疗提供了新的见解。
{"title":"Staple oligomers induce a stable RNA G-quadruplex structure for protein translation inhibition in therapeutics.","authors":"Yousuke Katsuda,Takuto Kamura,Tomoki Kida,Rinka Ohno,Shuhei Shiroto,Yua Hasegawa,Kaito Utsumi,Yuki Sakamoto,Shinichiro Nakamura,Taishi Nakamura,Kenichi Tsujita,Yusuke Kitamura,Yukiko Kamiya,Hiroyuki Asanuma,Toshihiro Ihara,Masaki Hagihara,Shin-Ichi Sato","doi":"10.1038/s41551-025-01515-4","DOIUrl":"https://doi.org/10.1038/s41551-025-01515-4","url":null,"abstract":"Gene-silencing mechanisms using RNA interference (RNAi) and antisense oligomers have drawn attention to nucleic acid medicines. However, several challenges remain such as low in vivo stability and inadequate target selectivity. Here we report a versatile and highly selective method for suppressing gene expression with a short oligonucleotide. The oligonucleotide, a Staple oligomer, hybridizes specifically to a target mRNA and artificially induces a higher-order structure, an RNA G-quadruplex (rG4), on the mRNA. This results in the rG4 effectively suppressing the target protein's translation. The method is validated by successfully regulating translation of TPM3, MYD88 and TRPC6 mRNAs in a cell-free system and in living mammalian cells. Unlike RNAi and antisense technologies, the present technology does not require cooperation with bioprocesses, permitting the quick and easy development of fully non-natural nucleic acid-based Staple oligomers without compromising their effectiveness. In vivo application of the technology to TRPC6 mRNA helps prevent cardiac hypertrophy in thoracic aortic constriction-treated mice without detectable off-target effects. This technology provides new insights into gene therapy after RNAi and antisense technologies.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"25 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296132","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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