Metabolic and immunomodulatory control of type 2 diabetes via generating cellular itaconate reservoirs by inflammatory-targeting gene-therapy nanovesicles.

Type 2 diabetes (T2D) is characterized by persistent and unresolved tissue inflammation caused by the infiltration and dysregulation of immune cells. Current therapeutics targeting inflammatory immune cells for T2D remain limited. In this study, we analyzed single cell RNA from metabolic organs in T2D, revealing increased macrophage accumulation and a pathogenic macrophage subpopulation defined as NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3)⁺ inflammatory and metabolically activated macrophages. To target these inflammatory cells, we developed nanovesicles encapsulating mitochondrial metabolic enzyme-related gene segments [immune-responsive gene 1 (IRG1)-overexpression plasmids] with cell membrane decoration. The nanovesicles functioned as cellular itaconate producers that elegantly circumvented the drug utilization barriers of a classic NLRP3 inhibitor and, as a mitochondria-reprograming system, mitigated fatty acid (FA)-associated metabolic dysfunction. The nanovesicles reversed inflammation, restored metabolic functions, and ameliorated obesity. Therefore, the metabolic and immunomodulatory functions of nanovesicles may offer translational opportunities for the prevention and treatment of T2D.