Mechanistic interplay between extracellular vesicles and neutrophil extracellular traps: unveiling the "sterile inflammation" cascade in obesity-induced diabetes progression.

Obesity-driven type 2 diabetes mellitus is sustained by chronic low-grade sterile inflammation. The intercellular mechanisms underlying this self-amplifying state remain incompletely defined. Extracellular vesicles and neutrophil extracellular traps have each been independently implicated in metabolic inflammation. Whether they form a coordinated pathological axis in the obesity/type 2 diabetes microenvironment has not been systematically synthesized. This narrative review integrates current mechanistic evidence in three areas: vesicle biogenesis and cargo remodeling in obesity; trap formation in the hyperglycemic and hyperlipidemic milieu; and molecular cross-talk between the two systems. We attend explicitly to the level of clinical evidence supporting each step. Our central argument is the following. Adipocyte- and macrophage-derived vesicles enriched in pro-inflammatory microRNAs activate neutrophils to undergo NETosis. The resulting traps release damage-associated molecules. These molecules stimulate further vesicle secretion. A self-reinforcing positive feedback circuit emerges. It operates through Toll-like receptor signaling, the NLRP3 inflammasome, peptidylarginine deiminase 4, and the cyclic GMP-AMP synthase-stimulator of interferon genes axis. The vesicle pool in obesity is not uniformly pathogenic. Insulin-sensitizing populations also exist. Hepatocyte exosomes from early-onset obese mice are enriched in microRNA-3075 and improve insulin sensitivity. Small vesicles from rosiglitazone-treated adipose tissue macrophages are enriched in microRNA-690 and exert similar effects. Any therapeutic strategy must preserve these protective populations. The pathogenic arm propagates local adipose inflammation systemically. This drives insulin resistance, pancreatic β-cell injury, hepatic inflammation, and the vascular, renal, and ocular complications of diabetes. Preclinical interruption of the circuit shows multi-organ benefit. Candidate strategies include peptidylarginine deiminase 4 inhibition, DNase I, NLRP3 blockade, and engineered therapeutic vesicles. Among clinically deployed agents, metformin and sodium-glucose cotransporter 2 inhibitors already show anti-trap and anti-inflammasome activity. The framework is mechanistically compelling. The evidence base, however, remains predominantly preclinical. No completed randomized controlled trial in obesity-related type 2 diabetes has yet validated it. Translation requires multidisciplinary collaboration, methodological standardization, sex-stratified design, and adequately powered prospective human studies.