Extracellular vesicles at the immune–metabolic crossroads of Hashimoto’s thyroiditis and diabetes mellitus

Abstract

Hashimoto’s thyroiditis (HT) and diabetes mellitus are highly prevalent chronic immune-mediated disorders that frequently co-occur and share genetic susceptibility, T-helper (Th) 1/Th17 skewing, and regulatory T-cell (Treg) dysfunction. Among individuals with type 1 diabetes mellitus (T1DM), autoimmune thyroiditis is the most common comorbid autoimmune disease. Extracellular vesicles (EVs) have emerged as important mediators linking autoimmune and metabolic inflammation. This review compares how EVs remodel the immune microenvironment in HT, type 2 diabetes mellitus (T2DM), and related disease contexts, with attention to donor cells, cargo, recipient pathways, biomarkers, and therapeutic implications. In HT and T1DM, EVs can deliver organ-specific autoantigens, whereas in classical T2DM current evidence more strongly supports EVs as carriers of stress signals, chemokines, and immunoregulatory miRNAs that shape islet inflammation and insulin resistance rather than autoantigen presentation; latent autoimmune diabetes in adults is considered separately. Across these diseases, recurrent EV-miRNA programs and DAMP/NLRP3 signaling converge on Treg/Th17 imbalance and M1/M2 macrophage polarization. We also emphasize the marked asymmetry of evidence maturity, with substantially stronger in-vivo and clinical support on the T2DM side than on the HT side. This asymmetry is treated as an explicit interpretive boundary throughout the review. We assess circulating and urinary EV cargoes as liquid-biopsy candidates and discuss EV-based drug delivery, engineered immunomodulatory EVs, and modulation of EV biogenesis. Translational claims remain limited by heterogeneity, manufacturing, and safety challenges, particularly in organ-specific autoimmune disease. In this review, the term “immune–metabolic crossroads” refers to shared mechanisms, shared biomarker opportunities, and partially overlapping therapeutic entry points.