Xingliang Liu, Shi Chen, Jing Huang, Yibo Du, Zhi Luo, Yue Zhang, Lixin Liu, Yongming Chen
{"title":"合成多肽通过破坏多价 TLR9 与 LL37-DNA 束的结合,抑制核酸诱导的自身免疫性疾病炎症","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":null,"url":null,"abstract":"<p>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-<i>TK</i>-NP<sub>Arg</sub>, which effectively inhibits Toll-like receptor-9 (TLR9) activation, in contrast to LL37. To explore the discrepancy effect of PEG-<i>TK</i>-NP<sub>Arg</sub> and LL37, we evaluate the periodic structure of PEG-<i>TK</i>-NP<sub>Arg</sub>-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-<i>TK</i>-NP<sub>Arg</sub>-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-<i>TK</i>-NP<sub>Arg</sub> 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.</p>","PeriodicalId":18915,"journal":{"name":"Nature nanotechnology","volume":null,"pages":null},"PeriodicalIF":38.1000,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"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\":null,\"url\":null,\"abstract\":\"<p>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-<i>TK</i>-NP<sub>Arg</sub>, which effectively inhibits Toll-like receptor-9 (TLR9) activation, in contrast to LL37. To explore the discrepancy effect of PEG-<i>TK</i>-NP<sub>Arg</sub> and LL37, we evaluate the periodic structure of PEG-<i>TK</i>-NP<sub>Arg</sub>-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-<i>TK</i>-NP<sub>Arg</sub>-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-<i>TK</i>-NP<sub>Arg</sub> 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.</p>\",\"PeriodicalId\":18915,\"journal\":{\"name\":\"Nature nanotechnology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":38.1000,\"publicationDate\":\"2024-08-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature nanotechnology\",\"FirstCategoryId\":\"88\",\"ListUrlMain\":\"https://doi.org/10.1038/s41565-024-01759-2\",\"RegionNum\":1,\"RegionCategory\":\"材料科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MATERIALS SCIENCE, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature nanotechnology","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1038/s41565-024-01759-2","RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MATERIALS SCIENCE, MULTIDISCIPLINARY","Score":null,"Total":0}
Synthetic polypeptides inhibit nucleic acid-induced inflammation in autoimmune diseases by disrupting multivalent TLR9 binding to LL37-DNA bundles
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.
期刊介绍:
Nature Nanotechnology is a prestigious journal that publishes high-quality papers in various areas of nanoscience and nanotechnology. The journal focuses on the design, characterization, and production of structures, devices, and systems that manipulate and control materials at atomic, molecular, and macromolecular scales. It encompasses both bottom-up and top-down approaches, as well as their combinations.
Furthermore, Nature Nanotechnology fosters the exchange of ideas among researchers from diverse disciplines such as chemistry, physics, material science, biomedical research, engineering, and more. It promotes collaboration at the forefront of this multidisciplinary field. The journal covers a wide range of topics, from fundamental research in physics, chemistry, and biology, including computational work and simulations, to the development of innovative devices and technologies for various industrial sectors such as information technology, medicine, manufacturing, high-performance materials, energy, and environmental technologies. It includes coverage of organic, inorganic, and hybrid materials.