Pub Date : 2025-11-03DOI: 10.1038/s41551-025-01543-0
Rohan Bhattacharya,Tarsha Ward,Titilola D Kalejaiye,Alekshyander Mishra,Sophia M Leeman,Hamidreza Arzaghi,Jonathan G Seidman,Christine E Seidman,Samira Musah
Clinical observations of patients with congenital heart disease carrying SMAD2 genetic variants revealed correlations with multi-organ impairments at the developmental and functional levels. Many patients with congenital heart disease present with glomerulosclerosis, periglomerular fibrosis and albuminuria. It remains largely unknown whether SMAD2 variants associated with congenital heart disease can directly alter kidney cell fate, tissue patterning and organ-level function. Here we investigate the role of pathogenic SMAD2 variants in podocytogenesis, nephrogenic cell lineage specification and glomerular filtration barrier function using a combination of CRISPR-based disease modelling, stem cell and microfluidic organ-on-a-chip technologies. We show that the abrogation of SMAD2 results in altered patterning of the mesoderm and intermediate mesoderm cell lineages, which give rise to nearly all kidney cell types. Following further differentiation of intermediate mesoderm cells, the mutant podocytes failed to develop arborizations and interdigitations. A reconstituted glomerulus-on-a-chip system showed substantial albumin leakage, as observed in glomerulopathies. This study implicates chronic heart disease-associated SMAD2 mutations in kidney tissue malformation that might inform targeted regenerative therapies.
{"title":"Engineered human induced pluripotent stem cell models reveal altered podocytogenesis in congenital heart disease-associated SMAD2 mutations.","authors":"Rohan Bhattacharya,Tarsha Ward,Titilola D Kalejaiye,Alekshyander Mishra,Sophia M Leeman,Hamidreza Arzaghi,Jonathan G Seidman,Christine E Seidman,Samira Musah","doi":"10.1038/s41551-025-01543-0","DOIUrl":"https://doi.org/10.1038/s41551-025-01543-0","url":null,"abstract":"Clinical observations of patients with congenital heart disease carrying SMAD2 genetic variants revealed correlations with multi-organ impairments at the developmental and functional levels. Many patients with congenital heart disease present with glomerulosclerosis, periglomerular fibrosis and albuminuria. It remains largely unknown whether SMAD2 variants associated with congenital heart disease can directly alter kidney cell fate, tissue patterning and organ-level function. Here we investigate the role of pathogenic SMAD2 variants in podocytogenesis, nephrogenic cell lineage specification and glomerular filtration barrier function using a combination of CRISPR-based disease modelling, stem cell and microfluidic organ-on-a-chip technologies. We show that the abrogation of SMAD2 results in altered patterning of the mesoderm and intermediate mesoderm cell lineages, which give rise to nearly all kidney cell types. Following further differentiation of intermediate mesoderm cells, the mutant podocytes failed to develop arborizations and interdigitations. A reconstituted glomerulus-on-a-chip system showed substantial albumin leakage, as observed in glomerulopathies. This study implicates chronic heart disease-associated SMAD2 mutations in kidney tissue malformation that might inform targeted regenerative therapies.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"4 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433771","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 : 2025-11-03DOI: 10.1038/s41551-025-01559-6
{"title":"A modified nanoparticle-mRNA complex for improved gene editing in the heart.","authors":"","doi":"10.1038/s41551-025-01559-6","DOIUrl":"https://doi.org/10.1038/s41551-025-01559-6","url":null,"abstract":"","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"35 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433772","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 : 2025-11-03DOI: 10.1038/s41551-025-01523-4
Gabriel Neiman,Mauro W Costa,Hesong Han,Sheng Zhao,Tammy K Ng,Brian Siemons,Tomohiro Nishino,Yu Huang,Shyam Lal,Kenneth Wu,Luke M Judge,Bruce R Conklin,Deepak Srivastava,Niren Murthy,Kevin E Healy
Gene transfection via lipid nanoparticle (LNP)-mRNA complexes have tremendous potential for treating cardiac diseases. However, the transfection efficiency is poor and there is a lack of in vitro screening systems that predict transfection efficacy. Here we demonstrate a method for identifying LNP-mRNA complexes that diffuse efficiently within 3D cardiac micromuscles and transfect cardiomyocytes with high efficiency, using a phenotypic cardiac microphysiological system (MPS) constructed from a human induced pluripotent stem cell cardiomyocytes Cre-reporter line. LNP formulations containing an acid-degradable PEG-lipid had enhanced diffusion and gene editing efficiency in the cardiac MPS. The in vivo delivery of LNP-mRNA complexes, including luciferase and CRE mRNA, into Ai6 mice confirmed the cardiac MPS screening outcomes. Acid-degradable PEG-LNPs achieved notably superior transfection in the heart with reduced off-target liver uptake compared with standard LNP formulations. The cardiac MPS showed strong LNP transfection in vitro and pinpointed a promising formulation for in vivo mRNA delivery to the heart.
{"title":"A microphysiological system for screening lipid nanoparticle-mRNA complexes predicts in vivo heart transfection efficacy.","authors":"Gabriel Neiman,Mauro W Costa,Hesong Han,Sheng Zhao,Tammy K Ng,Brian Siemons,Tomohiro Nishino,Yu Huang,Shyam Lal,Kenneth Wu,Luke M Judge,Bruce R Conklin,Deepak Srivastava,Niren Murthy,Kevin E Healy","doi":"10.1038/s41551-025-01523-4","DOIUrl":"https://doi.org/10.1038/s41551-025-01523-4","url":null,"abstract":"Gene transfection via lipid nanoparticle (LNP)-mRNA complexes have tremendous potential for treating cardiac diseases. However, the transfection efficiency is poor and there is a lack of in vitro screening systems that predict transfection efficacy. Here we demonstrate a method for identifying LNP-mRNA complexes that diffuse efficiently within 3D cardiac micromuscles and transfect cardiomyocytes with high efficiency, using a phenotypic cardiac microphysiological system (MPS) constructed from a human induced pluripotent stem cell cardiomyocytes Cre-reporter line. LNP formulations containing an acid-degradable PEG-lipid had enhanced diffusion and gene editing efficiency in the cardiac MPS. The in vivo delivery of LNP-mRNA complexes, including luciferase and CRE mRNA, into Ai6 mice confirmed the cardiac MPS screening outcomes. Acid-degradable PEG-LNPs achieved notably superior transfection in the heart with reduced off-target liver uptake compared with standard LNP formulations. The cardiac MPS showed strong LNP transfection in vitro and pinpointed a promising formulation for in vivo mRNA delivery to the heart.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"130 4 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433773","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}
Tissue engineering-based vascular reconstruction represents a promising therapeutic strategy for ischaemic stroke. However, in the confined stroke cavity, conventional implants are unable to simultaneously provide swelling-resistant support and growth-permissive internal space, which are crucial for effective revascularization. To address this limitation, we develop a bioinspired, non-expansive biodegradable matrix (NEBM) through covalent-non-covalent assembly of commercially available, clinical-grade natural polymers. We show that NEBM recapitulates key features of brain extracellular matrix-including porous microstructure and tissue-matched stiffness-to deliver structural stability. Moreover, its progressively degradable structure establishes a dynamic remodelling niche that directs cellular behaviour towards promoting angiogenesis. Compared with commercial Matrigel-based matrix, NEBM fosters blood vessel organoid development with higher vascular density, larger vessel diameters and more distinct arterial features. In both subcutaneous and stroke transplantation models, we find that NEBM facilitates the integration of blood vessel organoids with the host vasculature. Strikingly, this revascularization in stroke cavity stimulates neurogenesis, contributing to significant functional recovery. As such, our study provides valuable guidance to design clinically translatable matrices for organ repair and regeneration in confined environments.
{"title":"Nonexpansive biodegradable matrix promotes blood vessel organoid development for neurovascular repair and functional recovery in ischaemic stroke.","authors":"Dongling Xiao,Yue Sun,Guanyuan Yang,Weixi Yan,Meilin Jiang,Zhongliang Qin,Zijun Wang,Yawei Gu,Jingting Zhou,Ju Tan,Gang Li,Yinghao Li,Chuhong Zhu","doi":"10.1038/s41551-025-01550-1","DOIUrl":"https://doi.org/10.1038/s41551-025-01550-1","url":null,"abstract":"Tissue engineering-based vascular reconstruction represents a promising therapeutic strategy for ischaemic stroke. However, in the confined stroke cavity, conventional implants are unable to simultaneously provide swelling-resistant support and growth-permissive internal space, which are crucial for effective revascularization. To address this limitation, we develop a bioinspired, non-expansive biodegradable matrix (NEBM) through covalent-non-covalent assembly of commercially available, clinical-grade natural polymers. We show that NEBM recapitulates key features of brain extracellular matrix-including porous microstructure and tissue-matched stiffness-to deliver structural stability. Moreover, its progressively degradable structure establishes a dynamic remodelling niche that directs cellular behaviour towards promoting angiogenesis. Compared with commercial Matrigel-based matrix, NEBM fosters blood vessel organoid development with higher vascular density, larger vessel diameters and more distinct arterial features. In both subcutaneous and stroke transplantation models, we find that NEBM facilitates the integration of blood vessel organoids with the host vasculature. Strikingly, this revascularization in stroke cavity stimulates neurogenesis, contributing to significant functional recovery. As such, our study provides valuable guidance to design clinically translatable matrices for organ repair and regeneration in confined environments.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"27 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433775","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 : 2025-10-31DOI: 10.1038/s41551-025-01534-1
Junjie Li,Kazuko Toh,Panyue Wen,Xueying Liu,Anjaneyulu Dirisala,Haochen Guo,Joachim F R Van Guyse,Saed Abbasi,Yasutaka Anraku,Yuki Mochida,Hiroaki Kinoh,Horacio Cabral,Masaru Tanaka,Kazunori Kataoka
The high interfacial energy of nanomaterials limits their certain biomedical applications that require stealthiness to minimize non-specific interaction with biological components. While steric repulsion-based entropic stabilization-such as PEGylation-has long been the dominant strategy for designing stealth nanomaterials, its inherent softness and susceptibility to dynamic deformation and external forces often result in only moderate stealth performance. Here we report a distinct approach to achieving stealthiness by harnessing an ion-pair network, rather than maximizing steric repulsion. Using model polyion complex nanoparticles composed of equimolar charge ratios of polycations and polyanions, we demonstrate that increasing crosslinks between the constituent polyions beyond a critical threshold effectively reduces protein adsorption and macrophage uptake, enabling prolonged circulation with a half-life exceeding 100 hours. Building on this, we develop an asparaginase-loaded vesicular nanoreactor enveloped by a semi-permeable ion-pair network sheath for asparagine starvation therapy. The extended circulation of these nanoreactors enables sustained depletion of asparagine, leading to improved therapeutic outcomes for metastatic breast and pancreatic cancers. Our findings open an avenue for improving the pharmacokinetics of nanomaterials for therapeutic delivery through delicately engineering stable intermolecular structures with holistic cooperativity.
{"title":"Steric stabilization-independent stealth cloak enables nanoreactors-mediated starvation therapy against refractory cancer.","authors":"Junjie Li,Kazuko Toh,Panyue Wen,Xueying Liu,Anjaneyulu Dirisala,Haochen Guo,Joachim F R Van Guyse,Saed Abbasi,Yasutaka Anraku,Yuki Mochida,Hiroaki Kinoh,Horacio Cabral,Masaru Tanaka,Kazunori Kataoka","doi":"10.1038/s41551-025-01534-1","DOIUrl":"https://doi.org/10.1038/s41551-025-01534-1","url":null,"abstract":"The high interfacial energy of nanomaterials limits their certain biomedical applications that require stealthiness to minimize non-specific interaction with biological components. While steric repulsion-based entropic stabilization-such as PEGylation-has long been the dominant strategy for designing stealth nanomaterials, its inherent softness and susceptibility to dynamic deformation and external forces often result in only moderate stealth performance. Here we report a distinct approach to achieving stealthiness by harnessing an ion-pair network, rather than maximizing steric repulsion. Using model polyion complex nanoparticles composed of equimolar charge ratios of polycations and polyanions, we demonstrate that increasing crosslinks between the constituent polyions beyond a critical threshold effectively reduces protein adsorption and macrophage uptake, enabling prolonged circulation with a half-life exceeding 100 hours. Building on this, we develop an asparaginase-loaded vesicular nanoreactor enveloped by a semi-permeable ion-pair network sheath for asparagine starvation therapy. The extended circulation of these nanoreactors enables sustained depletion of asparagine, leading to improved therapeutic outcomes for metastatic breast and pancreatic cancers. Our findings open an avenue for improving the pharmacokinetics of nanomaterials for therapeutic delivery through delicately engineering stable intermolecular structures with holistic cooperativity.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"46 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145411638","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 : 2025-10-31DOI: 10.1038/s41551-025-01558-7
Rohit Reddy, Perry J. Pickhardt, Arjun Manrai, Ronald M. Summers, David Kim, Pranav Rajpurkar
NotifAI-OS (notification artificial intelligence for opportunistic screening) is a conceptual deep learning-based framework that performs automated multi-target analysis of computed tomography examinations through quantitative tissue density and volumetric measurements to enable comprehensive disease screening during routine computed tomography examinations.
{"title":"NotifAI-OS: an AI framework for automated CT-based opportunistic screening in post-acute value-based care","authors":"Rohit Reddy, Perry J. Pickhardt, Arjun Manrai, Ronald M. Summers, David Kim, Pranav Rajpurkar","doi":"10.1038/s41551-025-01558-7","DOIUrl":"10.1038/s41551-025-01558-7","url":null,"abstract":"NotifAI-OS (notification artificial intelligence for opportunistic screening) is a conceptual deep learning-based framework that performs automated multi-target analysis of computed tomography examinations through quantitative tissue density and volumetric measurements to enable comprehensive disease screening during routine computed tomography examinations.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"9 11","pages":"1791-1796"},"PeriodicalIF":26.8,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145411639","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 : 2025-10-31DOI: 10.1038/s41551-025-01542-1
Elena Garreta,Daniel Moya-Rull,Alberto Centeno,Andrés Marco,Asier Ullate-Agote,Gaia Amato,Carlos J Aranda,Roger Oria,Daniel Lozano-Ojalvo,Merel B F Pool,Tim L Hamelink,Idoia Lucía Selfa,Federico González,Carolina Tarantino,Alejandro Montero Salinas,Patricia López San Martín,Priyanka Koshy,Aleix Gavaldà-Navarro,Amaia Vilas-Zornoza,Juan R Rodríguez-Madoz,Antón Fernández García,Inmaculada Marquez-Leiva,Henri G D Leuvenink,Cristobal Belda-Iniesta,Maarten Naesens,Beatriz Dominguez-Gil,Marcelino González-Martín,Javier Rodríguez-Rivera,Jordi Ochando,Felipe Prosper,Cyril Moers,Nuria Montserrat
Organoids derived from human pluripotent stem (hPS) cells hold promise for therapeutic purposes. However, technological advances to overcome their massive production while ensuring differentiation fidelity are still lacking. Here we report a procedure sustaining the derivation of kidney organoids from hPS cells (hPSC-kidney organoids) using a scalable, reproducible and affordable approach that allows hPSC-kidney organoid differentiation into different renal cell types. Using single-cell RNA sequencing, confocal image analysis, metabolic assays and CRISPR-Cas9 engineering for generation of fluorescent reporters, we show that hPSC-kidney organoids exhibit transcriptional variety and cellular composition following cell-to-cell contact. We infuse human kidney organoids into ex vivo porcine kidneys using normothermic machine perfusion, and demonstrate in vivo engraftment of hPSC-kidney organoids. We further evaluate the immune response, confirming the feasibility and viability of the procedure. We identify cells of human origin after normothermic machine perfusion and in vivo transplantation by means of in situ hybridization, immunohistochemistry, confocal microscopy, image analysis and quantification, in vivo imaging, and flow cytometry. This work provides a foundation for using hPSC-kidney organoids for ex vivo cell-based therapies in clinical trials.
{"title":"Systematic production of human kidney organoids for transplantation in porcine kidneys during ex vivo machine perfusion.","authors":"Elena Garreta,Daniel Moya-Rull,Alberto Centeno,Andrés Marco,Asier Ullate-Agote,Gaia Amato,Carlos J Aranda,Roger Oria,Daniel Lozano-Ojalvo,Merel B F Pool,Tim L Hamelink,Idoia Lucía Selfa,Federico González,Carolina Tarantino,Alejandro Montero Salinas,Patricia López San Martín,Priyanka Koshy,Aleix Gavaldà-Navarro,Amaia Vilas-Zornoza,Juan R Rodríguez-Madoz,Antón Fernández García,Inmaculada Marquez-Leiva,Henri G D Leuvenink,Cristobal Belda-Iniesta,Maarten Naesens,Beatriz Dominguez-Gil,Marcelino González-Martín,Javier Rodríguez-Rivera,Jordi Ochando,Felipe Prosper,Cyril Moers,Nuria Montserrat","doi":"10.1038/s41551-025-01542-1","DOIUrl":"https://doi.org/10.1038/s41551-025-01542-1","url":null,"abstract":"Organoids derived from human pluripotent stem (hPS) cells hold promise for therapeutic purposes. However, technological advances to overcome their massive production while ensuring differentiation fidelity are still lacking. Here we report a procedure sustaining the derivation of kidney organoids from hPS cells (hPSC-kidney organoids) using a scalable, reproducible and affordable approach that allows hPSC-kidney organoid differentiation into different renal cell types. Using single-cell RNA sequencing, confocal image analysis, metabolic assays and CRISPR-Cas9 engineering for generation of fluorescent reporters, we show that hPSC-kidney organoids exhibit transcriptional variety and cellular composition following cell-to-cell contact. We infuse human kidney organoids into ex vivo porcine kidneys using normothermic machine perfusion, and demonstrate in vivo engraftment of hPSC-kidney organoids. We further evaluate the immune response, confirming the feasibility and viability of the procedure. We identify cells of human origin after normothermic machine perfusion and in vivo transplantation by means of in situ hybridization, immunohistochemistry, confocal microscopy, image analysis and quantification, in vivo imaging, and flow cytometry. This work provides a foundation for using hPSC-kidney organoids for ex vivo cell-based therapies in clinical trials.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"12 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145411645","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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