Yifan Ma, Shiyan Dong, Annette Wu, Seong Dong Jeong, Andrew S Lee, Wen Jiang, Betty Y S Kim
{"title":"Engineering challenges and translational opportunities in emerging gene delivery platforms.","authors":"Yifan Ma, Shiyan Dong, Annette Wu, Seong Dong Jeong, Andrew S Lee, Wen Jiang, Betty Y S Kim","doi":"10.1038/s41551-026-01643-5","DOIUrl":"https://doi.org/10.1038/s41551-026-01643-5","url":null,"abstract":"<p><p>The clinical success of gene therapy depends critically on the development of delivery platforms capable of achieving precise, efficient and tissue-specific delivery of genetic payloads in vivo. A diverse array of carriers, including viral, non-viral, synthetic and natural vectors, have been explored to address this challenge. Among them, adeno-associated viruses, lipid nanoparticles and extracellular vesicles have emerged as leading candidates, each offering distinct advantages and translational hurdles. Here we provide a comparative analysis of these delivery modalities, highlighting their respective design principles, targeting capabilities, immunogenicity profiles and clinical progress. We survey preclinical and clinically adopted delivery strategies and explore how the three delivery platforms can be tailored for gene therapeutics in different diseases. Finally, we discuss emerging strategies to overcome current limitations and outline future directions for the rational design of next-generation gene delivery platforms that combine safety, scalability and functional precision.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":" ","pages":""},"PeriodicalIF":26.8,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840489","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}
Qiongzhe Ren, Xiaofei Zhao, Lili Zhou, Ruonan Ye, Liguo Chen, Keyun Ren, Xijun Piao, Yihan Zhou, Yiming Qi, Kevin C Chan, Li Cao, Liang Du, Peng Gao, Bo Ying, Chao Deng, Fenghua Meng, Fangfang Zhou, Congcong Xu, Zhiyuan Zhong
{"title":"Polymer-mRNA complexes for monocyte-trafficked, lymph node-targeted cancer vaccination.","authors":"Qiongzhe Ren, Xiaofei Zhao, Lili Zhou, Ruonan Ye, Liguo Chen, Keyun Ren, Xijun Piao, Yihan Zhou, Yiming Qi, Kevin C Chan, Li Cao, Liang Du, Peng Gao, Bo Ying, Chao Deng, Fenghua Meng, Fangfang Zhou, Congcong Xu, Zhiyuan Zhong","doi":"10.1038/s41551-026-01672-0","DOIUrl":"https://doi.org/10.1038/s41551-026-01672-0","url":null,"abstract":"<p><p>Lymph nodes are the primary sites where adaptive immunity is initiated, yet most messenger RNA cancer vaccines reach them inefficiently and instead accumulate in organs such as the liver, limiting therapeutic potency and increasing systemic toxicity. Here we developed a transferrin receptor-associating polyplex formed by electrostatic complexation of mRNA with low-molecular-weight polyethylenimine that had been chemically modified with cyclic disulfide monomers to enhance nucleic acid binding stability, enable thiol-based transferrin receptor engagement and reduce off-target liver uptake. After subcutaneous administration, these polyplexes activated innate immunity, rapidly recruited monocytes with high transferrin receptor expression and bound these cells through cyclic disulfide-mediated interactions. Monocytes then trafficked the vaccine to draining lymph nodes, where mRNA translation and antigen presentation occurred. Delivery of ovalbumin and interleukin 12 mRNA elicited strong antigen-specific cytotoxic T cell responses and inhibited melanoma progression and metastatic disease. Studies using Survivin and human papillomavirus antigens in distinct tumour models demonstrated broad applicability. This monocyte-driven lymph node-targeting strategy enables potent and selective delivery of mRNA cancer vaccines.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":" ","pages":""},"PeriodicalIF":26.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840504","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}
Sunan He, Yuxiang Nie, Hongmei Wang, Shu Yang, Yihui Wang, Zhiyuan Cai, Zhixuan Chen, Yingxue Xu, Linshan Wu, Ngai Shing Cheng, Luyang Luo, Huiling Xiang, Xi Lin, Mingxiang Wu, Yifan Peng, George Shih, Ziyang Xu, Xian Wu, Qiong Wang, Ronald Cheong Kin Chan, Varut Vardhanabhuti, Xiaohui Duan, Winnie Chiu Wing Chu, Yefeng Zheng, Pranav Rajpurkar, Kang Zhang, Hao Chen
{"title":"Towards generalizable AI in medicine via Generalist-Specialist Collaboration.","authors":"Sunan He, Yuxiang Nie, Hongmei Wang, Shu Yang, Yihui Wang, Zhiyuan Cai, Zhixuan Chen, Yingxue Xu, Linshan Wu, Ngai Shing Cheng, Luyang Luo, Huiling Xiang, Xi Lin, Mingxiang Wu, Yifan Peng, George Shih, Ziyang Xu, Xian Wu, Qiong Wang, Ronald Cheong Kin Chan, Varut Vardhanabhuti, Xiaohui Duan, Winnie Chiu Wing Chu, Yefeng Zheng, Pranav Rajpurkar, Kang Zhang, Hao Chen","doi":"10.1038/s41551-026-01653-3","DOIUrl":"https://doi.org/10.1038/s41551-026-01653-3","url":null,"abstract":"<p><p>Generalist foundation models (GFMs) are renowned for their exceptional capability and flexibility in diverse tasks. In the field of medicine, while GFMs exhibit superior generalizability, specialist models excel in precision because of their domain-specific knowledge. Here we show a cooperative framework, Generalist-Specialist Collaboration (GSCo), that synergistically combines a powerful generalist model with lightweight specialists. In this framework, specialists provide expert guidance, such as diagnostic predictions and visually similar clinical cases, as contextual information to the generalist, which then makes a final diagnosis. We developed MedDr, an open-source GFM tailored for medicine, as well as a suite of lightweight specialist models crafted for specific downstream tasks. A comprehensive evaluation on 32 datasets across diverse medical modalities shows that MedDr outperforms state-of-the-art GFMs on downstream datasets. Furthermore, GSCo exceeds GFMs and specialists in medical image diagnosis and report generation. This approach offers an effective and computationally efficient paradigm for deploying GFMs in clinical settings, enhancing scalability and enabling precise analysis across a wide range of scenarios.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":" ","pages":""},"PeriodicalIF":26.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817951","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}
Sen Fang, Na Tang, Yiyun Li, Shuyu Guo, Yangcan Chen, Xin Wang, Xueke Li, Yanping Hu, Jiawei Hao, Jun Wu, Qi Zhou, Haoyi Wang, Chenxin Wang, Wei Li
{"title":"Non-viral targeted integration of large DNA in primary human T cells independent of double-stranded DNA breaks.","authors":"Sen Fang, Na Tang, Yiyun Li, Shuyu Guo, Yangcan Chen, Xin Wang, Xueke Li, Yanping Hu, Jiawei Hao, Jun Wu, Qi Zhou, Haoyi Wang, Chenxin Wang, Wei Li","doi":"10.1038/s41551-026-01671-1","DOIUrl":"https://doi.org/10.1038/s41551-026-01671-1","url":null,"abstract":"<p><p>Non-viral targeted integration of large DNA cargoes into human primary T cells typically requires the induction of genomic double-strand breaks (DSBs), a process associated with cytotoxicity and potential tumorigenic chromosomal abnormalities. Here we report PRIME-In, a novel genome-editing platform that uses a prime editing-engineered donor template coupled with either single (PRIME-In 1.0) or paired (PRIME-In 2.0) genomic nicks to enable precise integration of substantial DNA payloads into human cells without reliance on DSB repair pathways. Compared with traditional DSB-dependent methods, PRIME-In demonstrates markedly enhanced editing efficiency and specificity while eliminating detectable on-target and off-target chromosomal aberrations. Subsequent refinement of reagent composition and delivery protocols enabled PRIME-In-mediated engineering of primary human T cells with minimal toxicity, achieving up to 50% integration efficiency for a 3-kb CAR construct. These advances establish PRIME-In as a transformative platform for streamlining the non-viral production of genome-edited T cells, offering substantial potential for T cell-based immunotherapies.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":" ","pages":""},"PeriodicalIF":26.8,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817997","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}
Albert Blanch-Asensio, Deon S Ploessl, Benjamin B Johnson, Sara Cascione, Myrthe R M Berndsen, Nathan B Wang, Valeria V Orlova, Anna Alemany, Christine L Mummery, Kate E Galloway, Richard P Davis
{"title":"STRAIGHT-IN Dual: a platform for dual single-copy integrations of DNA payloads and gene circuits into human induced pluripotent stem cells.","authors":"Albert Blanch-Asensio, Deon S Ploessl, Benjamin B Johnson, Sara Cascione, Myrthe R M Berndsen, Nathan B Wang, Valeria V Orlova, Anna Alemany, Christine L Mummery, Kate E Galloway, Richard P Davis","doi":"10.1038/s41551-026-01677-9","DOIUrl":"10.1038/s41551-026-01677-9","url":null,"abstract":"<p><p>Targeting DNA payloads into human induced pluripotent stem cells (hiPSCs) typically requires multiple inefficient steps, slowing the testing of gene circuits and cell-fate programmes. Here we show that STRAIGHT-IN Dual enables simultaneous, allele-specific, single-copy integration of two DNA constructs efficiently within 1 week. STRAIGHT-IN Dual leverages the STRAIGHT-IN platform for near-scarless payload integration, facilitating the recycling of components for further modifications. Using STRAIGHT-IN Dual, we investigate how promoter choice and gene syntax influence transgene silencing and how these design features affect reporter expression and forward programming of hiPSCs into neurons, motor neurons and endothelial cells. We also incorporate a grazoprevir-inducible synthetic gene switch that complements tetracycline-inducible control, providing tunable and temporally controlled expression of different transcription factors within the same cell. STRAIGHT-IN Dual generates homogeneous engineered hiPSC populations, accelerating synthetic biology design-build-test cycles in stem cells and enabling controlled comparisons of circuit performances.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":" ","pages":""},"PeriodicalIF":26.8,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817988","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}
Song Wang (王淞), Kexin Lou (楼可心), Chen Wei (魏晨), Zhiyuan Sheng (盛致远), Jiahao Tang (唐家豪), Kaining Peng (彭恺宁), Xinke Shen (沈新科), Shuhao Mei (梅殊豪), Liang Chen (陈亮), Dongfeng Gu (顾东风), Quanying Liu (刘泉影)
{"title":"A geometry aware framework enhances noninvasive mapping of whole human brain dynamics","authors":"Song Wang \u0000 (王淞), Kexin Lou \u0000 (楼可心), Chen Wei \u0000 (魏晨), Zhiyuan Sheng \u0000 (盛致远), Jiahao Tang \u0000 (唐家豪), Kaining Peng \u0000 (彭恺宁), Xinke Shen \u0000 (沈新科), Shuhao Mei \u0000 (梅殊豪), Liang Chen \u0000 (陈亮), Dongfeng Gu \u0000 (顾东风), Quanying Liu \u0000 (刘泉影)","doi":"10.1038/s41551-026-01664-0","DOIUrl":"https://doi.org/10.1038/s41551-026-01664-0","url":null,"abstract":"Non-invasive electrophysiology lacks methods that accurately reconstruct whole-brain spatiotemporal dynamics while incorporating individual cortical geometry, leaving current electroencephalography and magnetoencephalography source imaging limited by simplistic or biologically implausible priors. Here we show that embedding patient-specific geometric basis function (GBF), eigenmodes derived from each individual’s cortical surface, provides a powerful anatomic constraint that resolves the inverse problem and improves reconstruction fidelity. The method allows reconstruction of the sources as linear combinations of geometric organization of neural dynamics. We validate GBF across a meta-source benchmark, task-evoked data, resting-state networks, intracranial stimulation and epilepsy data. Results demonstrate that GBF yields high localization accuracy and captures fast spatiotemporal dynamics consistent with anatomical pathways. These findings suggest that both spontaneous and evoked whole-brain activity can be described by hundreds of geometric modes, providing a compact yet accurate representation of neural sources. By linking cortical geometry to electrophysiological dynamics, GBF offers a versatile source imaging tool for both scientific and clinical applications.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"11 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751837","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":"DeepDrugDiscovery identifies blood-brain barrier permeable autophagy enhancers for Alzheimer's disease.","authors":"Yu Dong,Xianglu Xiao,Xu-Xu Zhuang,Wenfan Wu,Zi-Ying Wang,Shuang Zhang,Jin-Tao Li,Ke Zhang,Wen-Yu Fu,Jun-Ming Chen,Shi Hang Xiong,Shenglong Deng,Krinos Li,Chao Ma,Wangzhen Jin,Xurui Jin,Qiwei Cai,Han-Ming Shen,Min Li,Huanxing Su,Jian-Bo Wan,Hua Yu,Defang Ouyang,Keqiang Ye,Evandro F Fang,Chris Soon Heng Tan,Guang Yang,Zhangming Niu,Jia-Hong Lu","doi":"10.1038/s41551-026-01667-x","DOIUrl":"https://doi.org/10.1038/s41551-026-01667-x","url":null,"abstract":"Dysfunctional autophagy, a key cellular cleaning process, is a key driver of brain ageing and neurodegenerative diseases such as Alzheimer's disease (AD). However, developing effective treatments by enhancing autophagy has been challenging, as most known compounds act through the broad mTOR pathway, risking side effects, and few can effectively penetrate the brain. To address this, we developed DeepDrugDiscovery-a mechanism-aware, AI-powered screening platform incorporating ADMET and blood-brain barrier penetrability predictions. Here we show that this platform successfully identified novel, mTOR-independent autophagy enhancers, with two lead compounds demonstrating an ability to cross the blood-brain barrier, clear AD-related protein aggregates and restore memory function in worm and mouse AD models. By releasing DeepDrugDiscovery as an open-source, modular tool, we offer a user-friendly AI platform that enables customized therapeutic screening. Our work establishes a scalable, AI-driven pipeline that integrates cross-species validation to rapidly discover mechanism-based therapeutics for diseases with high unmet medical need.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"22 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147738956","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}
Yun Chang,Kunming Shao,Huiyang Li,Gyuhyung Jin,R Timothy Bentley,Robyn R McCain,Christa J Crain,Jingqiao Shen,Yan Tan,Po-Yu Liang,Haley A Harper,Sandra Torregrosa-Allen,Bennett D Elzey,Isabelle F Vanhaezebrouck,Aaron A Cohen-Gadol,Cheng Dong,Yu Zhu,Yuewei Wang,Jie Luo,Xiaojun Lance Lian,Xiaoping Bao
{"title":"CAR-neutrophils produced in vivo to treat glioma.","authors":"Yun Chang,Kunming Shao,Huiyang Li,Gyuhyung Jin,R Timothy Bentley,Robyn R McCain,Christa J Crain,Jingqiao Shen,Yan Tan,Po-Yu Liang,Haley A Harper,Sandra Torregrosa-Allen,Bennett D Elzey,Isabelle F Vanhaezebrouck,Aaron A Cohen-Gadol,Cheng Dong,Yu Zhu,Yuewei Wang,Jie Luo,Xiaojun Lance Lian,Xiaoping Bao","doi":"10.1038/s41551-026-01656-0","DOIUrl":"https://doi.org/10.1038/s41551-026-01656-0","url":null,"abstract":"Despite their notable abundance in circulation and biological significance in the tumour microenvironment, direct genetic programming of neutrophils has been challenging. Here we develop a neutrophil-specific modified RNA translation platform, termed NeuSMRT, that enables the expression of chimeric antigen receptors (CARs) in primary neutrophils. NeuSMRT combines engineered extracellular vesicles or lipid nanoparticles for modified RNA delivery with a microRNA-responsive L7Ae:k-turn switch to restrict protein translation to neutrophils. In a syngeneic glioma model, CAR-neutrophils produced in vivo significantly inhibit tumour growth and prolong survival, accompanied by enhanced T cell recruitment and activation, and reduced immunosuppression of myeloid cells in the tumour microenvironment. CAR-neutrophils further enhance the efficacy of chemotherapy and CAR-T therapy. Furthermore, CAR-neutrophils display antitumour activities in a humanized glioblastoma mouse model. The feasibility and safety of NeuSMRT are also demonstrated in experimental dogs. These findings establish a programmable neutrophil platform for cancer immunotherapy.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"4 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147738954","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}
David C. Garrett, Jinhua Xu, Donghyeon Oh, Yousuf Aborahama, Geng Ku, Konstantin Maslov, William W. Tseng, Lihong V. Wang
{"title":"Whole cross-sectional human ultrasound tomography","authors":"David C. Garrett, Jinhua Xu, Donghyeon Oh, Yousuf Aborahama, Geng Ku, Konstantin Maslov, William W. Tseng, Lihong V. Wang","doi":"10.1038/s41551-026-01660-4","DOIUrl":"https://doi.org/10.1038/s41551-026-01660-4","url":null,"abstract":"Ultrasonography is a vital component of modern clinical care, with handheld probes routinely used for diagnostic imaging and procedural guidance. However, handheld ultrasound imaging is limited by factors such as the partial cross-sectional field of view, operator dependency, contact-induced distortion and lack of transmission contrast. Here we demonstrate a new system that enables whole cross-sectional ultrasound tomography of humans in both reflection and transmission modes. We generate two-dimensional images of the entire in vivo human cross-section in the abdomen and thighs with uniform in-plane resolution using a custom 512-element circular ultrasound receiver array and a rotating transmitter. Sequential scans with our system show strong agreement with clinical magnetic resonance imaging counterparts. To address unmet clinical needs, we explore two key applications. First, we observe abdominal adipose distributions in our images, enabling adipose thickness assessment without ionising radiation or mechanical deformation. Second, we demonstrate an approach for video-rate biopsy needle localization with respect to internal tissue features. These capabilities make whole cross-sectional ultrasound tomography a potential practical tool for clinical needs currently unmet by other modalities.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"27 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751838","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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