{"title":"gpx1驱动的硒纳米平台重编程mam介导的细胞器串扰,以逆转甲状腺眼病中的炎症性脂肪扩张。","authors":"Yao Tan, Feng Zhang, Jiamin Cao, Lemeng Feng, Bingyu Xie, Limo Gao, Xiangdong Chen, Zuyun Yan, Wei Xiong","doi":"10.7150/thno.117582","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background:</b> Thyroid eye disease (TED) is a multifactorial autoimmune disorder with limited therapeutic options due to the complexity of its oxidative, metabolic, and inflammatory networks. This study aims to develop a selenium-based nanoplatform that targets mitochondria-ER interactions to reverse inflammatory adipose expansion in TED. <b>Methods:</b> We designed a dual-responsive selenium nanoparticle (Se@LNT) modified with lentinan, capable of ROS/pH-triggered release. Human primary orbital fibroblasts, bioinformatic analysis of public datasets, and TED mouse models were used to investigate the therapeutic mechanism. <b>Results:</b> Se@LNT undergoes intracellular metabolic conversion into selenocysteine, which enhances GPX1 activity and promotes redox balance. It exerts triple regulatory effects by stabilizing mitochondrial membranes to reduce mtDNA leakage, downregulating GRP75 to normalize MAMs contact and calcium flux, and suppressing PERK-eIF2α-ATF4 signaling to relieve ER stress. Transcriptomic profiling reveals multi-target modulation of immune-stromal interactions. <i>In vivo</i>, Se@LNT achieves orbital targeting, rapid hepatic-renal clearance, and significant reduction of adipose expansion with immune remodeling. <b>Conclusions:</b> Se@LNT offers the first MAMs-targeted nanotherapy for TED by reprogramming organelle crosstalk, restoring metabolic-immune homeostasis, and modifying disease progression at the subcellular level.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9601-9622"},"PeriodicalIF":13.3000,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486268/pdf/","citationCount":"0","resultStr":"{\"title\":\"GPX1-driven selenium nanoplatform reprograms MAMs-mediated organelle crosstalk to reverse inflammatory adipose expansion in thyroid eye disease.\",\"authors\":\"Yao Tan, Feng Zhang, Jiamin Cao, Lemeng Feng, Bingyu Xie, Limo Gao, Xiangdong Chen, Zuyun Yan, Wei Xiong\",\"doi\":\"10.7150/thno.117582\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Background:</b> Thyroid eye disease (TED) is a multifactorial autoimmune disorder with limited therapeutic options due to the complexity of its oxidative, metabolic, and inflammatory networks. This study aims to develop a selenium-based nanoplatform that targets mitochondria-ER interactions to reverse inflammatory adipose expansion in TED. <b>Methods:</b> We designed a dual-responsive selenium nanoparticle (Se@LNT) modified with lentinan, capable of ROS/pH-triggered release. Human primary orbital fibroblasts, bioinformatic analysis of public datasets, and TED mouse models were used to investigate the therapeutic mechanism. <b>Results:</b> Se@LNT undergoes intracellular metabolic conversion into selenocysteine, which enhances GPX1 activity and promotes redox balance. It exerts triple regulatory effects by stabilizing mitochondrial membranes to reduce mtDNA leakage, downregulating GRP75 to normalize MAMs contact and calcium flux, and suppressing PERK-eIF2α-ATF4 signaling to relieve ER stress. Transcriptomic profiling reveals multi-target modulation of immune-stromal interactions. <i>In vivo</i>, Se@LNT achieves orbital targeting, rapid hepatic-renal clearance, and significant reduction of adipose expansion with immune remodeling. <b>Conclusions:</b> Se@LNT offers the first MAMs-targeted nanotherapy for TED by reprogramming organelle crosstalk, restoring metabolic-immune homeostasis, and modifying disease progression at the subcellular level.</p>\",\"PeriodicalId\":22932,\"journal\":{\"name\":\"Theranostics\",\"volume\":\"15 18\",\"pages\":\"9601-9622\"},\"PeriodicalIF\":13.3000,\"publicationDate\":\"2025-08-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486268/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Theranostics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/thno.117582\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.117582","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
GPX1-driven selenium nanoplatform reprograms MAMs-mediated organelle crosstalk to reverse inflammatory adipose expansion in thyroid eye disease.
Background: Thyroid eye disease (TED) is a multifactorial autoimmune disorder with limited therapeutic options due to the complexity of its oxidative, metabolic, and inflammatory networks. This study aims to develop a selenium-based nanoplatform that targets mitochondria-ER interactions to reverse inflammatory adipose expansion in TED. Methods: We designed a dual-responsive selenium nanoparticle (Se@LNT) modified with lentinan, capable of ROS/pH-triggered release. Human primary orbital fibroblasts, bioinformatic analysis of public datasets, and TED mouse models were used to investigate the therapeutic mechanism. Results: Se@LNT undergoes intracellular metabolic conversion into selenocysteine, which enhances GPX1 activity and promotes redox balance. It exerts triple regulatory effects by stabilizing mitochondrial membranes to reduce mtDNA leakage, downregulating GRP75 to normalize MAMs contact and calcium flux, and suppressing PERK-eIF2α-ATF4 signaling to relieve ER stress. Transcriptomic profiling reveals multi-target modulation of immune-stromal interactions. In vivo, Se@LNT achieves orbital targeting, rapid hepatic-renal clearance, and significant reduction of adipose expansion with immune remodeling. Conclusions: Se@LNT offers the first MAMs-targeted nanotherapy for TED by reprogramming organelle crosstalk, restoring metabolic-immune homeostasis, and modifying disease progression at the subcellular level.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.