Stattic engineering M2 macrophage-derived exosomes mediate autophagy and immune reprogramming for secondary hyperparathyroidism

Stattic engineering M2 macrophage-derived exosomes (M2-E@St) release stattic promote SHPT primary cells autophagy and apoptosis. The carrier M2-E reprogramed macrophage from M1 to M2 phenotype. • STAT3 overexpressed suppressing autophagy promotes secondary hyperparathyroidism. • Stattic blocks STAT3 phosphorylation, restoring autophagy in parathyroid cells. • Macrophage pro-inflammatory shifting promotes secondary hyperparathyroidism. • M2 macrophage-derived exosomes alleviate parathyroid inflammation. • M2-Exo deliver Stattic dual-target alleviate secondary hyperparathyroidism. Secondary hyperparathyroidism (SHPT) remains a major complication of chronic kidney disease (CKD), characterized by parathyroid hyperplasia, inflammation, and parathyroid hormone (PTH) excessive secretion, affecting millions of patients worldwide. Current treatments can temporarily restore calcium–phosphate balance while failing to provide lasting relief due to unchecked parathyroid cell proliferation, which mechanisms remained unknown. Signal transducer and activator of transcription 3 (STAT3) has been implicated in the autophagic process and diverse cellular processes, including cell growth and apoptosis. Present study seeks to uncover roles of STAT3 pathway-regulated autophagy and macrophage-mediated inflammation in SHPT progression. Building upon sequencing and pathology results, we propose a potential therapeutic approach for SHPT utilizing macrophage-derived exosomes loaded with a STAT3 inhibitor. RNA-seq and tissue-molecular examination were applied to identify the role of STAT3 and macrophage in SHPT. This study fabricates engineered M2 macrophage-derived exosomes loading with STAT3 inhibitor Stattic (M2-E@St) by a dual physics encapsulation. Suppressing STAT3 phosphorylation through inhibitor, Stattic (St), SHPT primary cell autophagy blockage relieved shown as p62 and p53 reduced, LC3B II v.s. I elevated with cell proliferation suppression. Based on dual SHPT drivers, an M2 macrophage-derived exosomes-camouflaged nanomedicine, M2-E@St, was developed that can reprogram macrophages anti-inflammation and alleviate STAT3-mediated autophagy inhibition, reducing parathyroid cell proliferation in the parathyroid gland. M2-E@St efficacy on SHPT was evaluated at a comprehensive level, including in vitro SHPT primary cells and macrophages co-culture system, SHPT mouse model, human SHPT primary cells, and macrophage organoids. Once uptake by parathyroid cells and macrophages, M2-E@St blocks STAT3/mTOR signaling pathway and promotes downstream autophagy, while M2-E induces macrophage M2 polarization. Results show M2-E@St significantly reduced STAT3 phosphorylation, resumed autophagy, curbed cell proliferation, alleviated inflammation, and lowered PTH secretion in vitro and in vivo . Results suggest exosome-based Stattic delivery may serve as a promising therapy for SHPT.