GPX1-driven selenium nanoplatform reprograms MAMs-mediated organelle crosstalk to reverse inflammatory adipose...

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.