Extracellular vesicle-mediated restraint of hepatic CD74-NF-κB repairs diabetic neuropathy

Diabetic peripheral neuropathy (DPN) affects up to half of people with diabetes and lacks disease-modifying therapy. Here, we profiled MSC-EV biodistribution and multiomic programs across diabetic models, with key nerve repair established in db/db mice and corroborated in high-fat diet/streptozotocin- and methionine-choline-deficient mice. Systemically administered EVs predominantly accumulated in the liver and improved peripheral nerve structure and function, with benefits supported by glycemia-controlled or glycemia-adjusted analyses rather than being fully explained by systemic glycemic changes. EV treatment was associated with reduced circulating injury markers, attenuated spinal inflammatory responses, and improved endothelial junction integrity. Mechanistically, EV-encapsulated miR-24-3p repressed hepatic CD74, coinciding with reduced MHC II/NF-κB activity in macrophages. Hepatic CD74 overexpression promoted systemic inflammation and peripheral nerve injury, whereas pharmacologic NF-κB inhibition recapitulated EV-associated benefits. Together, these data define a liver-to-nerve causal axis and support EV-mediated restraint of hepatic CD74-NF-κB signaling as a cross-organ strategy for DPN repair.