Shen Sheng,Yuanhe Li,Ryan Ray Yen Lee,Yuxuan Gao,Huize Han,Zhijun Wan,Calvent Owh,Carol-Anne Ming Yi Chua,Zhen Yu Chong,Nicholas Wee Hao Ng,Wei Tang,Chong Tian
{"title":"Programmable molecular dethreading towards tunable drug release.","authors":"Shen Sheng,Yuanhe Li,Ryan Ray Yen Lee,Yuxuan Gao,Huize Han,Zhijun Wan,Calvent Owh,Carol-Anne Ming Yi Chua,Zhen Yu Chong,Nicholas Wee Hao Ng,Wei Tang,Chong Tian","doi":"10.1038/s41467-025-64452-5","DOIUrl":"https://doi.org/10.1038/s41467-025-64452-5","url":null,"abstract":"Precise control of molecular motion is essential for artificial molecular machines. Pseudorotaxane dethreading, a key process within interlocked architectures, offers a means to regulate such motion. However, achieving predictable and programmable control over dethreading kinetics remains challenging. Here, we achieve systematic modulation of dethreading behaviour through component engineering, using a pseudorotaxane platform composed of 24-crown-8-based macrocycles and adjustable benzylic amine stoppers. Activation energies are continuously tunable across the range of 22 to 30 kcal/mol, with a resolution as fine as 0.5-1.5 kcal/mol. Crystallographic analyses and computational modeling elucidate the dethreading pathway and the structure-kinetic relationships. As a proof-of-concept, representative assemblies are functionalized with the anticancer agent camptothecin. The resulting pseudorotaxanes display a consistent trend between their dethreading rates and cytotoxic potency. This work bridges molecular-scale mechanical motion with biological effects and provides a generalizable strategy for the design of programmable drug delivery systems. The pseudorotaxane toolkit reported here lays the foundation for the development of advanced molecular machines in biomedical applications.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"130 1","pages":"9390"},"PeriodicalIF":16.6,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structural mechanisms of assembly, gating, and calmodulin modulation of human olfactory CNG channel.","authors":"Jing Xue,Ninghai Gan,Weizhong Zeng,Youxing Jiang","doi":"10.1038/s41467-025-64436-5","DOIUrl":"https://doi.org/10.1038/s41467-025-64436-5","url":null,"abstract":"Mammalian cyclic nucleotide-gated (CNG) channels play crucial roles in visual and olfactory signal transduction. In olfactory sensory neurons, the native CNG channel functions as a heterotetramer consisting of CNGA2, CNGA4, and CNGB1b subunits and is activated by cAMP. Calmodulin (CaM) modulates the activity of the olfactory CNG channel, enabling rapid adaptation to odorants. Here we present cryo-EM structures of the native human olfactory CNGA2/A4/B1b channel in both CaM-bound closed and cAMP-bound open states, elucidating the molecular basis of the 2:1:1 subunit stoichiometry in channel assembly and the asymmetrical channel gating upon cAMP activation. Combining structural and functional analyses with AlphaFold prediction, we define two distinct CaM binding sites (CaM1 and CaM2) on the N- and C-terminal regions of CNGB1b, respectively, shedding light on the molecular mechanism of Ca2+/CaM-mediated rapid inhibition of the native olfactory CNG channel.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"105 1","pages":"9380"},"PeriodicalIF":16.6,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"DNA computing function switching by programming base stacking interactions with minimal molecular architecture changes.","authors":"Yongpeng Zhang,Bozhao Li,Xuan Liu,Xuedong Zheng,Shi Liu,Guangjun Nie,Jing Yang,Yonggang Ke,Suping Li,Cheng Zhang","doi":"10.1038/s41467-025-64406-x","DOIUrl":"https://doi.org/10.1038/s41467-025-64406-x","url":null,"abstract":"In biological systems, molecular network functionalities are usually switched in a flexible, facile, and programmable manner. Mimicking this, substantial studies are directed towards developing synthetic DNA networks that exhibit similar function-switching capabilities, though often hindered by extensive molecular architecture changes and stringent condition controls, which result in a time-consuming and labor-intensive process. Here, we develop a base stacking-mediated allostery strategy to manipulate the DNA computing function switching with minimal molecular architecture changes, usually as few as 1-2 nucleotide changes. We implement up to 20 distinct logic function switching within DNAzyme networks. We also validate our function switching platform to implement totally 84 kinds of gene regulation patterns in cancer cell lines, demonstrating its utility in RNA sensing and green fluorescent protein regulation. This strategy offers a simplified alternative approach to enrich DNA regulations, with potential applications in DNA computing and bioengineering.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"1 1","pages":"9369"},"PeriodicalIF":16.6,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Flexible InGaAs/InAlAs avalanche photodiodes for short-wave infrared detection.","authors":"Jishen Zhang,Rui Shao,Haiwen Xu,Kian Hua Tan,Satrio Wicaksono,Qiwen Kong,Gong Zhang,Chen Sun,Yue Chen,Aaron Danner,Soon-Fatt Yoon,Xiao Gong","doi":"10.1038/s41467-025-64401-2","DOIUrl":"https://doi.org/10.1038/s41467-025-64401-2","url":null,"abstract":"Flexible detectors have gained growing research interest due to their promising applications in optical sensing and imaging systems with a broad field-of-view. However, most research have focused on conventional photodiodes of which the responsivity are limited at short-wave infrared due to the absence of internal multiplication gain. Here we have realized and demonstrated flexible thin-film InGaAs/InAlAs avalanche photodiodes on a mica substrate for short-wave infrared detection. This achievement was made possible by the development and implementation of a low-temperature bonding and well-optimized fabrication process. Our devices exhibit promising characteristics, including low dark current, good responsivity, and high multiplication gain. Even when subjected to bending conditions, the avalanche photodiodes maintain their general performance. The advent of such flexible InGaAs avalanche photodiodes with reliable and promising performance enables a significantly broader range of potential applications.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"45 1","pages":"9367"},"PeriodicalIF":16.6,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A cortex-wide multimodal microscope for simultaneous Ca2+ and hemodynamic imaging in awake mice.","authors":"Wei Qin,Tingting Li,Linyang Li,Tian Jin,Baochen Li,Weizhi Qi,Yifan Chen,Haoyang Li,Shijie Ruan,Heng Guo,Xiao Liang,Lei Xi","doi":"10.1038/s41467-025-64393-z","DOIUrl":"https://doi.org/10.1038/s41467-025-64393-z","url":null,"abstract":"Developments in optical imaging techniques have advanced the study of neurovascular coupling across the whole cortex. Unfortunately, each cortex-wide optical imaging modality is specialized in revealing limited neural or hemodynamic actions. Here, we develop a cortex-wide multimodal microscope (multiScope) integrating widefield Ca2+ fluorescence microscopy, optical resolution photoacoustic microscopy, and laser speckle contrast imaging to simultaneously observe neuron firing, total hemoglobin and blood flow velocity with endogenous biomarkers. The multiScope features a cortex-wide field-of-view of Ø 8.6 mm, a maximum imaging speed of 4 Hz, and the average spatial resolutions of 10.7 ± 3.1 μm and 7.1 ± 0.8 μm respectively for widefield imaging and photoacoustic microscopy after model-based restoration. We demonstrate the multi-parametric imaging capability of the multiScope using animal models, observe fast neural and hemodynamic activities across the entire cortex, and carry out both global and local neural vascular coupling analyses for different brain stimulations.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"140 1","pages":"9364"},"PeriodicalIF":16.6,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Organocatalytic enantioselective [2π + 2σ] cycloaddition reactions of bicyclo[1.1.0]butanes with α,β-unsaturated aldehydes.","authors":"Yi-Xiang Geng,Teng-Fei Xiao,Dong Xie,Ming-Ming Li,Pan-Pan Zhou,Guo-Qiang Xu,Peng-Fei Xu","doi":"10.1038/s41467-025-64399-7","DOIUrl":"https://doi.org/10.1038/s41467-025-64399-7","url":null,"abstract":"Bicyclo[2.1.1]hexanes (BCHs), three-dimensional benzene bioisosteres characterized by high sp3-carbon content, hold great promise for diverse applications in medicinal chemistry. Although significant advances have been made in the synthesis of racemic BCHs, highly enantioselective approaches remain comparatively rare. Here we report a mild, secondary amine-catalyzed asymmetric [2π + 2σ] cycloaddition of bicyclo[1.1.0]butanes (BCBs) with α,β-unsaturated aldehydes, which overcomes key limitations of existing metal-catalyzed and photochemical methods. The protocol operates under ambient air and tolerates a wide range of BCB and aldehyde substrates bearing diverse functional groups, affording BCH scaffolds in yields of up to 84% under Supramolecular Iminium Catalysis with excellent enantioselectivity (up to 99% ee) and high diastereoselectivity (>20:1 dr). The mild conditions and operational simplicity underscore the potential of this transformation for stereoselective manufacturing of BCHs at scale. Mechanistic experiments and DFT studies support an acid-promoted dual activation of both substrates, followed by an enamine-iminium tandem catalytic process that delivers the enantioenriched products.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"43 1","pages":"9361"},"PeriodicalIF":16.6,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeted degradation of endogenous YAP by nanobody bioPROTAC inhibits tumor progression.","authors":"Runhua Zhou,Huifang Wang,Gui-Ming Zhang,Yawei Liu,Xiao-Lian Liu,Zhifen Li,Guangwei Shi,Junling Yuan,Chengming Qu,Yang Li,Liang Chen,Jingnan Huang,Hongchao Zhou,Lingyun Dai,Chongzhi Bai,Jigang Wang,Le Yu,Zhijie Li,Yi-Lei Li","doi":"10.1038/s41467-025-64426-7","DOIUrl":"https://doi.org/10.1038/s41467-025-64426-7","url":null,"abstract":"Yes-associated protein (YAP), a key effector of the Hippo pathway, regulates gene expression and promotes tumorigenesis. YAP is conventionally considered \"undruggable\", however, targeted protein degradation offers a promising approach to address the challenges associated with targeting this oncogenic protein. In this study, through naïve nanobody phage library screening, we identify multiple nanobodies against human YAP with high affinity and specificity. The YAP nanobody is then fused to the RING domain of RNF4, creating a bio-Proteolysis-Targeting Chimera (bioPROTAC) molecule capable of selectively targeting endogenous YAP for ubiquitin-mediated degradation. Notably, the constructed YAP bioPROTAC demonstrates significant YAP degradation and anticancer efficacy in various YAP-dependent cancers both in vitro and in vivo. Nanoparticles and adeno-associated virus (AAV) can effectively deliver the encoding gene of YAP bioPROTAC, achieving YAP degradation in tumors. Collectively, our study provides a proof-of-concept that the YAP nanobody-bioPROTAC approach can effectively degrade endogenous YAP via the ubiquitin-proteasome system, highlighting a feasible strategy for \"undruggable\" YAP-dependent cancers.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"12 1","pages":"9374"},"PeriodicalIF":16.6,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correlative voltage imaging and cryo-electron tomography bridge neuronal activity and molecular structure.","authors":"Mingyu Jung,Gwanho Ko,Dongsung Lim,Seonghoon Kim,Sojeong Kim,Young-Joon Kim,Myunghwan Choi,Soung-Hun Roh","doi":"10.1038/s41467-025-64431-w","DOIUrl":"https://doi.org/10.1038/s41467-025-64431-w","url":null,"abstract":"Neurons exhibit varying electrophysiological properties due to dynamic changes in spatiotemporal molecular networks. In situ cryo-electron tomography (cryo-ET) provides advantages for high-resolution visualization of macromolecular complexes within their cellular context. Although correlation with fluorescent labeling allows cryo-ET to target specific cellular regions, it does not adequately reflect the electrophysiological properties of heterogeneous neurons. To bridge high-resolution molecular imaging with electrophysiological properties of individual neurons, we develop a Correlative Voltage Imaging and cryo-ET (CoVET) technique. The nondestructive nature of voltage imaging is compatible with cryo-ET, enabling a direct correlation between neuronal electrophysiology and molecular structures. Neurons are clustered based on their electrophysiological properties, allowing for single-cell-guided structural analysis using cryo-ET. We analyze the translational landscapes of individual neurons and find distinct structural characteristics and spatial networks among ribosomes from different electrophysiological clusters. Our results highlight the importance of the correlation between the electrophysiological properties and molecular structures.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"23 1","pages":"9378"},"PeriodicalIF":16.6,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Moritz Wachsmuth-Melm,Sarah Peterl,Aidan O'Riain,Jana Makroczyová,Konstantin Fischer,Tim Krischuns,Sílvia Vale-Costa,Maria João Amorim,Petr Chlanda
{"title":"Visualizing influenza A virus assembly by in situ cryo-electron tomography.","authors":"Moritz Wachsmuth-Melm,Sarah Peterl,Aidan O'Riain,Jana Makroczyová,Konstantin Fischer,Tim Krischuns,Sílvia Vale-Costa,Maria João Amorim,Petr Chlanda","doi":"10.1038/s41467-025-65117-z","DOIUrl":"https://doi.org/10.1038/s41467-025-65117-z","url":null,"abstract":"Influenza A virus (IAV) forms pleomorphic particles that package eight ribonucleoprotein complexes (vRNPs), each carrying a distinct RNA genome segment. vRNPs assemble in the nucleus and undergo selective sorting during Rab11a-mediated trafficking to the plasma membrane. Virion assembly is orchestrated by matrix protein 1 (M1), which forms a layer beneath the viral envelope containing hemagglutinin (HA) and neuraminidase (NA). However, molecular details of vRNP distribution, cytosolic trafficking, and coordination of IAV assembly remains unclear. Using in situ cryo-ET, we reveal that HA-containing membranes provide Rab11a-dependent platforms for membrane-assisted vRNP clustering, reducing inter-vRNP distances. In the absence of HA, vRNPs cluster on NA-containing membranes and virus assembly remains intact, indicating that vRNP clustering and trafficking is membrane-assisted but HA independent. The characteristic 7 + 1 vRNP bundle forms concomitantly with budding and is orchestrated by M1 layer assembly that precedes plasma membrane attachment. We further reveal that intracellular M1 forms multilayered helical assemblies of antiparallel dimers, structurally distinct from the M1 layer in virions. These assemblies are compact in the nucleus but partially dissociate in the cytoplasm, likely serving as a reservoir for budding. Together, our findings uncover membrane-assisted vRNP clustering and molecular details of M1 coordinated influenza virus assembly.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"26 1","pages":"9394"},"PeriodicalIF":16.6,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nghi C D Truong,Chandan Ganesh Bangalore Yogananda,Benjamin C Wagner,James M Holcomb,Divya D Reddy,Niloufar Saadat,Jason Bowerman,Kimmo J Hatanpaa,Toral R Patel,Baowei Fei,Matthew D Lee,Rajan Jain,Richard J Bruce,Ananth J Madhuranthakam,Marco C Pinho,Joseph A Maldjian
{"title":"Categorical and phenotypic image synthetic learning as an alternative to federated learning.","authors":"Nghi C D Truong,Chandan Ganesh Bangalore Yogananda,Benjamin C Wagner,James M Holcomb,Divya D Reddy,Niloufar Saadat,Jason Bowerman,Kimmo J Hatanpaa,Toral R Patel,Baowei Fei,Matthew D Lee,Rajan Jain,Richard J Bruce,Ananth J Madhuranthakam,Marco C Pinho,Joseph A Maldjian","doi":"10.1038/s41467-025-64385-z","DOIUrl":"https://doi.org/10.1038/s41467-025-64385-z","url":null,"abstract":"Multi-center collaborations are crucial in developing robust and generalizable machine learning models in medical imaging. Traditional methods, such as centralized data sharing or federated learning (FL), face challenges, including privacy issues, communication burdens, and synchronization complexities. We present CATegorical and PHenotypic Image SyntHetic learnING (CATphishing), an alternative to FL using Latent Diffusion Models (LDM) to generate synthetic multi-contrast three-dimensional magnetic resonance imaging data for downstream tasks, eliminating the need for raw data sharing or iterative inter-site communication. Each institution trains an LDM to capture site-specific data distributions, producing synthetic samples aggregated at a central server. We evaluate CATphishing using data from 2491 patients across seven institutions for isocitrate dehydrogenase mutation classification and three-class tumor-type classification. CATphishing achieves accuracy comparable to centralized training and FL, with synthetic data exhibiting high fidelity. This method addresses privacy, scalability, and communication challenges, offering a promising alternative for collaborative artificial intelligence development in medical imaging.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"105 1","pages":"9384"},"PeriodicalIF":16.6,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}