Nature Biomedical Engineering最新文献

{"title":"Rapid clearance of achiral small-molecule drugs using de novo-designed proteins and their cyclic and mirror-image variants","authors":"Guilin Chen, Kai Zhao, Mengjiao Li, Yuefei Zhang, Tian Li, Jing Yuan, Lei Lu, Jesús Valdiviezo, Dan Liu, Nicholas F. Polizzi, William F. DeGrado, Bobo Dang","doi":"10.1038/s41551-025-01404-w","DOIUrl":"https://doi.org/10.1038/s41551-025-01404-w","url":null,"abstract":"<p>Small-molecule-binding proteins can neutralize toxins and cytotoxic drugs, but their development is hindered by unpredictable in vivo behaviour and the poor immunogenicity of small molecules, which limits antibody-based approaches. Here we present a strategy to engineer de novo-designed proteins for the effective clearance of Food and Drug Administration-approved drugs in healthy mice. As a proof of concept, we designed proteins that bind to the anticoagulant apixaban. Since apixaban lacks chirality, we used mirror-image synthesis and cyclization to enhance the designed protein’s in vivo stability. Both protein variants demonstrated effective activity, facilitating the rapid clearance of apixaban within 30 min. To assess the broader applicability of this approach, we extended our analysis to a de novo-designed protein targeting the anticancer drug rucaparib, further confirming its potential for small-molecule clearance. Our study shows that de novo-designed small-molecule-binding proteins can be used as antidotes in vivo, and that computational tools can be integrated with medicinal chemistry strategies for precise pharmacological interventions.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"58 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144165308","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":"A wireless device for continuous measurement of brain parenchymal resistance tracks glymphatic function in humans","authors":"Paul Dagum, Laurent Giovangrandi, Swati Rane Levendovszky, Jake J. Winebaum, Tarandeep Singh, Yeilim Cho, Robert M. Kaplan, Michael S. Jaffee, Miranda M. Lim, Carla Vandeweerd, Jeffrey J. Iliff","doi":"10.1038/s41551-025-01394-9","DOIUrl":"https://doi.org/10.1038/s41551-025-01394-9","url":null,"abstract":"<p>Glymphatic function in animal models supports the clearance of brain proteins whose mis-aggregation is implicated in neurodegenerative conditions including Alzheimer’s and Parkinson’s disease. The measurement of glymphatic function in the human brain has been elusive due to invasive, bespoke and poorly time-resolved existing technologies. Here we describe a non-invasive multimodal device for the continuous measurement of sleep-active changes in parenchymal resistance in humans using repeated electrical impedance spectroscopy measurements in two separate clinical validation studies. Device measurements successfully paralleled sleep-associated changes in extracellular volume that regulate glymphatic function and predicted glymphatic solute exchange measured by contrast-enhanced MRI. We replicate preclinical findings showing that glymphatic function is increased with increasing sleep electroencephalogram (EEG) delta power and is decreased with increasing sleep EEG beta power and heart rate. The present investigational device permits the continuous and time-resolved assessment of parenchymal resistance in naturalistic settings necessary to determine the contribution of glymphatic impairment to risk and progression of Alzheimer’s disease and to enable target-engagement studies that modulate glymphatic function in humans.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"7 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145591","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":"The cerebellum shapes motions by encoding motor frequencies with precision and cross-individual uniformity","authors":"Chia-Wei Liu, Yi-Mei Wang, Shun-Ying Chen, Liang-Yin Lu, Ting-Yu Liang, Ke-Chu Fang, Peng Chen, I-Chen Lee, Wen-Chuan Liu, Ami Kumar, Sheng-Han Kuo, Jye-Chang Lee, Chung-Chuan Lo, Shun-Chi Wu, Ming-Kai Pan","doi":"10.1038/s41551-025-01409-5","DOIUrl":"https://doi.org/10.1038/s41551-025-01409-5","url":null,"abstract":"<p>Understanding brain behaviour encoding or designing neuroprosthetics requires identifying precise, consistent neural algorithms across individuals. However, cerebral microstructures and activities are individually variable, posing challenges for identifying precise codes. Here, despite cerebral variability, we report that the cerebellum shapes motor kinematics by encoding dynamic motor frequencies with remarkable numerical precision and cross-individual uniformity. Using in vivo electrophysiology and optogenetics in mice, we confirm that deep cerebellar neurons encode frequencies using populational tuning of neuronal firing probabilities, creating cerebellar oscillations and motions with matched frequencies. The mechanism is consistently presented in self-generated rhythmic and non-rhythmic motions triggered by a vibrational platform or skilled tongue movements of licking in all tested mice with cross-individual uniformity. The precision and uniformity allowed us to engineer complex motor kinematics with designed frequencies. We further validate the frequency-coding function of the human cerebellum using cerebellar electroencephalography recordings and alternating current stimulation during voluntary tapping tasks. Our findings reveal a cerebellar algorithm for motor kinematics with precision and uniformity, the mathematical foundation for a brain–computer interface for motor control.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"14 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145592","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":"Tension-induced directional migration of hepatic stellate cells potentially coordinates liver fibrosis progression","authors":"Lyu Zhou, Ziao Shi, Xuesi Yang, Jia’nan Zeng, Zhifeng You, Yuying Zhang, Zhiyue Zhu, Zhiqiang Liu, Yudi Niu, Hongsheng Yu, Jinliang He, Yi Long, Zhaozhao Wu, Yan Zhang, Cheng Lyu, Liping Deng, Yuan Wang, Congying Wu, Yanan Du","doi":"10.1038/s41551-025-01381-0","DOIUrl":"https://doi.org/10.1038/s41551-025-01381-0","url":null,"abstract":"<p>Liver fibrosis is an over-reacted wound healing that becomes lethal in its late stage, when hepatic stellate cells (HSCs) trigger fibrotic response, proliferation of connective tissue and build-up of directional fibrous tissue bands (septa). Current in vitro models of liver fibrosis cannot reproduce liver lobule structure and the dynamic formation of septa at the same time, and the known biochemical cues underlying the progression of liver fibrosis cannot explain directional formation of fibrotic tissue. Here we report a microfabricated in vitro model that reproduces both the hexagonal liver lobule structure and the dynamic directionality of septa formation. By using collagen and primary mouse HSCs or human HSC lines, we found that tension was necessary to coordinate the cell migration that contributes to the band-like cell distribution and that HSCs sensed directional biophysical cues through liquid–liquid phase separation. This system allows the study of the biophysical interaction of HSCs and collagen during the formation of septa structures, and could be used to deepen our understanding of liver fibrosis progression.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"97 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122796","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":"A biochemical sensor with continuous extended stability in vivo","authors":"Yihang Chen, Kaiyu X. Fu, Renee Cotton, Zihao Ou, Jean Won Kwak, Jun-Chau Chien, Vladimir Kesler, Hnin Yin Yin Nyein, Michael Eisenstein, H. Tom Soh","doi":"10.1038/s41551-025-01389-6","DOIUrl":"https://doi.org/10.1038/s41551-025-01389-6","url":null,"abstract":"<p>The development of biosensors that can detect specific analytes continuously, in vivo, in real time has proven difficult due to biofouling, probe degradation and signal drift that often occur in vivo. By drawing inspiration from intestinal mucosa that can protect host cell receptors in the presence of the gut microbiome, we develop a synthetic biosensor that can continuously detect specific target molecules in vivo. The biomimetic multicomponent sensor features the hierarchical nano-bio interface design with three-dimensional bicontinuous nanoporous structure, polymer coating and aptamer switches, balancing small-molecule sensing and surface protection in complex biological environments. Our system is stable for at least 1 month in undiluted serum in vitro or 1 week implanted within the blood vessels of free-moving rats, retaining over 50% baseline signal and reproducible calibration curves. We demonstrate that the implanted system can intravenously track pharmacokinetics in real time even after 4 days of continuous exposure to flowing blood within rat femoral vein. In this way, our work provides a generalizable design foundation for biosensors that can continuously operate in vivo for extended durations.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"31 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122797","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":"High-throughput single-cell density measurements enable dynamic profiling of immune cell and drug response from patient samples","authors":"Weida Wu, Sarah H. Ishamuddin, Thomas W. Quinn, Smitha Yerrum, Ye Zhang, Lydie L. Debaize, Pei-Lun Kao, Sarah Marie Duquette, Mark A. Murakami, Morvarid Mohseni, Kin-Hoe Chow, Teemu P. Miettinen, Keith L. Ligon, Scott R. Manalis","doi":"10.1038/s41551-025-01408-6","DOIUrl":"https://doi.org/10.1038/s41551-025-01408-6","url":null,"abstract":"<p>Cell density, the ratio of cell mass to volume, is an indicator of molecular crowding and a fundamental determinant of cell state and function. However, existing density measurements lack the precision or throughput to quantify subtle differences in cell states, particularly in primary samples. Here we present an approach for measuring the density of 30,000 single cells per hour by integrating fluorescence exclusion microscopy with a suspended microchannel resonator. This approach achieves a precision of 0.03% (0.0003 g ml⁻¹) for cells larger than 12 μm in diameter. In human lymphocytes, we discover that cell density and its variation decrease as cells transition from quiescence to a proliferative state, suggesting that the level of molecular crowding decreases and becomes more regulated upon entry into the cell cycle. Using a pancreatic cancer patient-derived xenograft model, we find that the ex vivo density response of primary tumour cells to drug treatment can predict the in vivo tumour growth response. Our method reveals unexpected behaviour in molecular crowding during cell state transitions and suggests density as a biomarker for functional precision medicine.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"32 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144096862","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":"Treatment of a metabolic liver disease in mice with a transient prime editing approach","authors":"Tanja Rothgangl, András Tálas, Eleonora I. Ioannidi, Yanik Weber, Desirée Böck, Mai Matsushita, Elina Andrea Villiger, Lukas Schmidheini, Woohyun J. Moon, Paulo J. C. Lin, Steven H. Y. Fan, Kim F. Marquart, Cornelia Schwerdel, Nicole Rimann, Erica Faccin, Lukas Villiger, Hiromi Muramatsu, Máté Vadovics, Alessio Cremonesi, Péter István Kulcsár, Beat Thöny, Manfred Kopf, Johannes Häberle, Norbert Pardi, Ying K. Tam, Gerald Schwank","doi":"10.1038/s41551-025-01399-4","DOIUrl":"https://doi.org/10.1038/s41551-025-01399-4","url":null,"abstract":"<p>Prime editing is a versatile genome editing technology that circumvents the need for DNA double-strand break formation and homology-directed repair, making it particularly suitable for in vivo correction of pathogenic mutations. Here we developed liver-specific prime editing approaches with temporally restricted prime editor (PE) expression. We first established a dual-delivery approach where the prime editor guide RNA is continuously expressed from adeno-associated viral vectors and only the PE is transiently delivered as nucleoside-modified mRNA encapsulated in lipid nanoparticles (LNP). This strategy achieved 26.2% editing with PEmax and 47.4% editing with PE7 at the <i>Dnmt1</i> locus using a single 2 mg kg⁻¹ dose of mRNA–LNP. When targeting the pathogenic <i>Pah</i>^<i>enu2</i> mutation in a phenylketonuria mouse model, gene correction rates reached 4.3% with PEmax and 20.7% with PE7 after three doses of 2 mg kg⁻¹ mRNA–LNP, effectively reducing blood <span>l</span>-phenylalanine levels from over 1,500 µmol l⁻¹ to below the therapeutic threshold of 360 µmol l⁻¹. Encouraged by the high efficiency of PE7, we next explored a simplified approach where PE7 mRNA was co-delivered with synthetic prime editor guide RNAs encapsulated in LNP. This strategy yielded 35.9% editing after two doses of RNA–LNP at the <i>Dnmt1</i> locus and 8.0% editing after three doses of RNA–LNP at the <i>Pah</i>^<i>enu2</i> locus, again reducing <span>l</span>-phenylalanine levels below 360 µmol l⁻¹. These findings highlight the therapeutic potential of mRNA–LNP-based prime editing for treating phenylketonuria and other genetic liver diseases, offering a scalable and efficient platform for future clinical translation.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"1 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144096863","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":"Long-term engraftment of human stem and progenitor cells for large-scale production of functional immune cells in engineered pigs","authors":"Zheng Hu, Jun Zou, Zhengzhu Wang, Kai Xu, Tang Hai, Sheng Zhang, Peipei An, Cong Fu, Shuai Dong, Yanan Lv, Jilong Ren, Zhiqiang Han, Chongyang Li, Jing Wang, Qingwei Wang, Renren Sun, Long Su, Hanjing Zuo, Qinghao Ding, Huimin Tian, Xinlan An, Yanhui Zhai, Dawei Yu, Chang Shu, Jin He, Liguang Sun, Tianmeng Sun, Xiangpeng Dai, Ziyi Li, Wei Li, Qi Zhou, Yong-Guang Yang","doi":"10.1038/s41551-025-01397-6","DOIUrl":"https://doi.org/10.1038/s41551-025-01397-6","url":null,"abstract":"<p>Existing immunodeficient pig models have demonstrated limited success in supporting robust human haematopoietic engraftment and multilineage differentiation. Here we hypothesize that the targeted deletion of integrin-associated protein (Cd47) in severe combined immunodeficient pigs, with deletions in the X-linked interleukin-2 receptor gamma chain and recombination activating gene 1, would enable long-term haematopoietic engraftment following transplantation with human haematopoietic stem/progenitor cells. In Cd47-deficient pigs, we observed high levels of human haematopoietic chimerism in the blood and spleen, with functional T and B lymphocytes, natural killer and myeloid cells, as well as robust thymopoiesis. Our findings suggest that severe combined immunodeficient pigs with Cd47 deletion represent an improved preclinical model for studying human haematopoiesis, disease mechanisms and therapies, and offer potential as a bioreactor for large-scale production of human immune cells.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"38 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144096866","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":"siRNA conjugate with high albumin affinity and degradation resistance for delivery and treatment of arthritis in mice and guinea pigs","authors":"Juan M. Colazo, Megan C. Keech, Veeraj Shah, Ella N. Hoogenboezem, Justin H. Lo, Nora Francini, Nina T. Cassidy, Fang Yu, Alexander G. Sorets, Joshua T. McCune, Carlisle R. DeJulius, Hongsik Cho, Danielle L. Michell, Tristan Maerz, Kacey C. Vickers, Katherine N. Gibson-Corley, Karen A. Hasty, Leslie J. Crofford, Rebecca S. Cook, Craig L. Duvall","doi":"10.1038/s41551-025-01376-x","DOIUrl":"https://doi.org/10.1038/s41551-025-01376-x","url":null,"abstract":"<p>Osteoarthritis and rheumatoid arthritis are debilitating joint diseases marked by pain, inflammation and cartilage destruction. Current osteoarthritis treatments only relieve symptoms, while rheumatoid arthritis therapies can cause immune suppression and provide variable efficacy. Here we developed an optimized small interfering RNA targeting matrix metalloproteinase 13 for preferential delivery to arthritic joints. Chemical modifications in a stabilizing ‘zipper’ pattern improved RNA resistance to degradation, and two independent linkers with 18 ethylene glycol repeats connecting to tandem C18 lipids enhanced albumin binding and targeted delivery to inflamed joints following intravenous administration. In preclinical models of post-traumatic osteoarthritis and rheumatoid arthritis, a single intravenous injection of the albumin-binding small interfering RNA achieved long-term joint retention, sustained gene silencing and reduced matrix metalloproteinase 13 activity over 30 days, resulting in decreased cartilage erosion and improved clinical outcomes, including reduced joint swelling and pressure sensitivity. This approach demonstrated superior efficacy over corticosteroids and small-molecule MMP inhibitors, highlighting the therapeutic promise of albumin ‘hitchhiking’ for targeted, systemic delivery of gene-silencing therapeutics to treat osteoarthritis and rheumatoid arthritis.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"41 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066269","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":"Activating membrane receptors with ultrasound","authors":"Yi-Xian Qin, Elias Georgas","doi":"10.1038/s41551-025-01395-8","DOIUrl":"https://doi.org/10.1038/s41551-025-01395-8","url":null,"abstract":"Non-invasive ultrasonic activation of RET increases colonic cell proliferation primarily through acoustic pressure.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"25 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065973","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}