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

INTRODUCTION: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Results suggest exosome-based Stattic delivery may serve as a promising therapy for SHPT.