{"title":"Single-molecule sensing inside stereo- and regio-defined hetero-nanopores","authors":"Wei Liu, Qiang Zhu, Chao-Nan Yang, Ying-Huan Fu, Ji-Chang Zhang, Meng-Yin Li, Zhong-Lin Yang, Kai-Li Xin, Jing Ma, Mathias Winterhalter, Yi-Lun Ying, Yi-Tao Long","doi":"10.1038/s41565-024-01721-2","DOIUrl":"10.1038/s41565-024-01721-2","url":null,"abstract":"Heteromeric pore-forming proteins often contain recognition patterns or stereospecific selection filters. However, the construction of heteromeric pore-forming proteins for single-molecule sensing is challenging due to the uncontrollability of producing position isomers and difficulties in purification of regio-defined products. To overcome these preparation obstacles, we present an in situ strategy involving single-molecule chemical modification of a heptameric pore-forming protein to build a stereo- and regio-specific heteromeric nanopore (hetero-nanopore) with a subunit stoichiometric ratio of 3:4. The steric hindrance inherent in the homo-nanopore of K238C aerolysin directs the stereo- and regio-selective modification of maleimide derivatives. Our method utilizes real-time ionic current recording to facilitate controlled voltage manipulation for stoichiometric modification and position-based side-isomer removal. Single-molecule experiments and all-atom molecular dynamics simulations revealed that the hetero-nanopore features an asymmetric stereo- and regio-defined residue structure. The hetero-nanopore produced was characterized by mass spectrometry and single-particle cryogenic electron microscopy. In a proof-of-concept single-molecule sensing experiment, the hetero-nanopore exhibited 95% accuracy for label-free discrimination of four peptide stereoisomers with single-amino-acid structural and chiral differences in the mixtures. The customized hetero-nanopores could advance single-molecule sensing. This Article presents a single-molecule ‘synthesis by sensing’ approach that enables in situ stepwise generation of stereo- and regio-defined heteromeric nanopores to resolve structural and chiral differences of amino-acids in single peptide stereoisomers.","PeriodicalId":18915,"journal":{"name":"Nature nanotechnology","volume":"19 11","pages":"1693-1701"},"PeriodicalIF":38.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xingliang Liu, Shi Chen, Jing Huang, Yibo Du, Zhi Luo, Yue Zhang, Lixin Liu, Yongming Chen
{"title":"Synthetic polypeptides inhibit nucleic acid-induced inflammation in autoimmune diseases by disrupting multivalent TLR9 binding to LL37-DNA bundles","authors":"Xingliang Liu, Shi Chen, Jing Huang, Yibo Du, Zhi Luo, Yue Zhang, Lixin Liu, Yongming Chen","doi":"10.1038/s41565-024-01759-2","DOIUrl":"10.1038/s41565-024-01759-2","url":null,"abstract":"Complexes of extracellular nucleic acids (NAs) with endogenous proteins or peptides, such as LL37, break immune balance and cause autoimmune diseases, whereas NAs with arginine-enriched peptides do not. Inspired by this, we synthesize a polyarginine nanoparticle PEG-TK-NPArg, which effectively inhibits Toll-like receptor-9 (TLR9) activation, in contrast to LL37. To explore the discrepancy effect of PEG-TK-NPArg and LL37, we evaluate the periodic structure of PEG-TK-NPArg-NA and LL37-NA complexes using small-angle X-ray scattering. LL37-NA complexes have a larger inter-NA spacing that accommodates TLR9, while the inter-NA spacing in PEG-TK-NPArg-NA complexes mismatches with the cavity of TLR9, thus inhibiting an interaction with multiple TLR9s, limiting their clustering and damping immune induction. Subsequently, the inhibitory inflammation effect of PEG-TK-NPArg is proved in an animal model of rheumatoid arthritis. This work on how the scavenger-NA complexes inhibit the immune response may facilitate proof-of-concept research translating to clinical application. This study shows how amino acid composition and topology in synthetic polypeptides affect anti-inflammatory effects and how scavenging debris nucleic acids inhibits inflammation and relieves symptoms of autoimmune diseases.","PeriodicalId":18915,"journal":{"name":"Nature nanotechnology","volume":"19 11","pages":"1745-1756"},"PeriodicalIF":38.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142002804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Nanomedicine pioneers awarded the Kavli Prize","authors":"","doi":"10.1038/s41565-024-01777-0","DOIUrl":"10.1038/s41565-024-01777-0","url":null,"abstract":"The 2024 Kavli Prize in Nanoscience is awarded to three nanomedicine pioneers who laid the foundation of controlled release, biomedical imaging and diagnostics.","PeriodicalId":18915,"journal":{"name":"Nature nanotechnology","volume":"19 8","pages":"1073-1073"},"PeriodicalIF":38.1,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41565-024-01777-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yung-Chien Chou, Chih-Yuan Lin, Alice Castan, Joshua Chen, Rachael Keneipp, Parisa Yasini, Dimitri Monos, Marija Drndić
{"title":"Coupled nanopores for single-molecule detection","authors":"Yung-Chien Chou, Chih-Yuan Lin, Alice Castan, Joshua Chen, Rachael Keneipp, Parisa Yasini, Dimitri Monos, Marija Drndić","doi":"10.1038/s41565-024-01746-7","DOIUrl":"10.1038/s41565-024-01746-7","url":null,"abstract":"Rapid sensing of molecules is increasingly important in many studies and applications, such as DNA sequencing and protein identification. Here, beyond atomically thin 2D nanopores, we conceptualize, simulate and experimentally demonstrate coupled, guiding and reusable bilayer nanopore platforms, enabling advanced ultrafast detection of unmodified molecules. The bottom layer can collimate and decelerate the molecule before it enters the sensing zone, and the top 2D pore (~2 nm) enables position sensing. We varied the number of pores in the bottom layer from one to nine while fixing one 2D pore in the top layer. When the number of pores in the bottom layer is reduced to one, sensing is performed by both layers, and distinct T- and W-shaped translocation signals indicate the precise position of molecules and are sensitive to fragment lengths. This is uniquely enabled by microsecond resolution capabilities and precision nanofabrication. Coupled nanopores represent configurable multifunctional systems with inter- and intralayer structures for improved electromechanical control and prolonged dwell times in a 2D sensing zone. In this study, the authors present the design and fabrication of reusable, atomically thin, coupled bilayer solid-state nanopores that enable the slowing down and positional tracking of molecules for label-free, single-molecule sensing.","PeriodicalId":18915,"journal":{"name":"Nature nanotechnology","volume":"19 11","pages":"1686-1692"},"PeriodicalIF":38.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141980964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tingbiao Guo, Zhi Zhang, Zijian Lin, Jiahan Tian, Yi Jin, Julian Evans, Yinghe Xu, Sailing He
{"title":"Durable and programmable ultrafast nanophotonic matrix of spectral pixels","authors":"Tingbiao Guo, Zhi Zhang, Zijian Lin, Jiahan Tian, Yi Jin, Julian Evans, Yinghe Xu, Sailing He","doi":"10.1038/s41565-024-01756-5","DOIUrl":"10.1038/s41565-024-01756-5","url":null,"abstract":"Locally addressable nanophotonic devices are essential for modern applications such as light detection, optical imaging, beam steering and displays. Despite recent advances, a versatile solution with a high-speed tuning rate, long-life durability and programmability across multiple pixels remains elusive. Here we introduce a programmable nanophotonic matrix consisting of vanadium dioxide (VO2) cavities on pixelated microheaters that meets all these requirements. The indirect Joule heating of these VO2 cavities can result in pronounced spectral modulation with colour changes and ensures exceptional endurance even after a million switching cycles. Precise control over the thermal dissipation power through a SiO2 layer of an optimized thickness on Si facilitates an ultrafast modulation rate exceeding 70 kHz. We demonstrated a video-rate nanophotonic colour display by electrically addressing a matrix of 12 × 12 pixels. Furthermore, inspired by the unique pixel-level programmability with multiple intermediate states of the spectral pixels, a spatiotemporal modulation concept is introduced for spectrum detection. Electrically addressable VO2 elements show large resonance shifts during phase transitions, producing a brilliant colour change at a modulation rate of 70 kHz.","PeriodicalId":18915,"journal":{"name":"Nature nanotechnology","volume":"19 11","pages":"1635-1643"},"PeriodicalIF":38.1,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41565-024-01756-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Engineering modular enzymes using DNA origami","authors":"","doi":"10.1038/s41565-024-01739-6","DOIUrl":"10.1038/s41565-024-01739-6","url":null,"abstract":"A DNA origami nanocompartment is designed to trap an unfoldase machine in a unidirectional orientation. This trapping provides a gateway mechanism for substrate recruitment and translocation to a downstream compartment that hosts a protease. Kinetics and proteomics data demonstrate that the physical connection of the DNA-based modules improves the global performance of the chimera and reduces off-target reactions.","PeriodicalId":18915,"journal":{"name":"Nature nanotechnology","volume":"19 10","pages":"1440-1441"},"PeriodicalIF":38.1,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An artificial metabzyme for tumour-cell-specific metabolic therapy","authors":"Xi Hu, Bo Zhang, Miao Zhang, Wenshi Liang, Bangzhen Hong, Zhiyuan Ma, Jianpeng Sheng, Tianqi Liu, Shengfei Yang, Zeyu Liang, Jichao Zhang, Chunhai Fan, Fangyuan Li, Daishun Ling","doi":"10.1038/s41565-024-01733-y","DOIUrl":"10.1038/s41565-024-01733-y","url":null,"abstract":"Metabolic dysregulation constitutes a pivotal feature of cancer progression. Enzymes with multiple metal active sites play a major role in this process. Here we report the first metabolic-enzyme-like FeMoO4 nanocatalyst, dubbed ‘artificial metabzyme’. It showcases dual active centres, namely, Fe2+ and tetrahedral Mo4+, that mirror the characteristic architecture of the archetypal metabolic enzyme xanthine oxidoreductase. Employing spatially dynamic metabolomics in conjunction with the assessments of tumour-associated metabolites, we demonstrate that FeMoO4 metabzyme catalyses the metabolic conversion of tumour-abundant xanthine into uric acid. Subsequent metabolic adjustments orchestrate crosstalk with immune cells, suggesting a potential therapeutic pathway for cancer. Our study introduces an innovative paradigm in cancer therapy, where tumour cells are metabolically reprogrammed to autonomously modulate and directly interface with immune cells through the intervention of an artificial metabzyme, for tumour-cell-specific metabolic therapy. A metabolic-enzyme-like nanocatalyst is reported, dubbed ‘artificial metabzyme’. Tumour cells can be metabolically reprogrammed to autonomously modulate and interact with immune cells, facilitating tumour-cell-specific metabolic therapy.","PeriodicalId":18915,"journal":{"name":"Nature nanotechnology","volume":"19 11","pages":"1712-1722"},"PeriodicalIF":38.1,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuesong Hu, Jhordan Rogers, Yuxin Duan, Arventh Velusamy, Steven Narum, Sarah Al Abdullatif, Khalid Salaita
{"title":"Quantifying T cell receptor mechanics at membrane junctions using DNA origami tension sensors","authors":"Yuesong Hu, Jhordan Rogers, Yuxin Duan, Arventh Velusamy, Steven Narum, Sarah Al Abdullatif, Khalid Salaita","doi":"10.1038/s41565-024-01723-0","DOIUrl":"10.1038/s41565-024-01723-0","url":null,"abstract":"The T cell receptor (TCR) is thought to be a mechanosensor, meaning that it transmits mechanical force to its antigen and leverages the force to amplify the specificity and magnitude of TCR signalling. Although a variety of molecular probes have been proposed to quantify TCR mechanics, these probes are immobilized on hard substrates, and thus fail to reveal fluid TCR–antigen interactions in the physiological context of cell membranes. Here we developed DNA origami tension sensors (DOTS) which bear force sensors on a DNA origami breadboard and allow mapping of TCR mechanotransduction at dynamic intermembrane junctions. We quantified the mechanical forces at fluid TCR–antigen bonds and observed their dependence on cell state, antigen mobility, antigen potency, antigen height and F-actin activity. The programmability of DOTS allows us to tether these to microparticles to mechanically screen antigens in high throughput using flow cytometry. Additionally, DOTS were anchored onto live B cells, allowing quantification of TCR mechanics at immune cell–cell junctions. The authors present nanoscale DNA origami tension sensors tethered to lipid membranes and reveal the magnitude, dynamics and driving mechanisms of molecular forces experienced by immunoreceptors at fluid membrane junctions.","PeriodicalId":18915,"journal":{"name":"Nature nanotechnology","volume":"19 11","pages":"1674-1685"},"PeriodicalIF":38.1,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}