Paeonia lactiflora-derived extracellular vesicles ameliorate diabetic peripheral neuropathy by modulating chemokine-guided immune trafficking in peripheral nerves

AIMS: This study investigated the therapeutic potential of Paeonia lactiflora-derived extracellular vesicles (PRA-EVs) for diabetic peripheral neuropathy (DPN), with a particular focus on their immunomodulatory effects on the CC motif chemokine ligand 21 (CCL21) / CC chemokine receptor type 7 (CCR7) axis. METHODS: PRA-EVs were isolated and characterized. In vitro, their effects on high glucose (HG)-induced Schwann cell apoptosis, CCL21 expression, and CD8⁺ T-cell migration were assessed. In vivo, therapeutic efficacy was evaluated in an STZ-induced DPN mouse model using behavioral testing, histological analysis, and molecular assays. RESULTS: PRA-EVs significantly attenuated HG-induced Schwann cell apoptosis and reduced CCL21 expression. In DPN mice, PRA-EVs improved behavioral and structural abnormalities, including neuropathic pain and myelin injury, with efficacy comparable to mecobalamin. Mechanistically, PRA-EVs were associated with downregulation of CCL21/CCR7 signaling and reduced CCR7⁺CD8⁺ T-cell infiltration in sciatic nerves. In addition, PRA-EVs suppressed CD8⁺ T-cell migration to a degree comparable to the CCR7 pathway inhibitor Cosalane. To our knowledge, this is the first study to link PRA-EVs with the amelioration of DPN in association with modulation of the CCL21/CCR7 axis. CONCLUSION: PRA-EVs ameliorate DPN, at least in part, through modulation of the CCL21/CCR7 axis, thereby attenuating Schwann cell injury and neuroinflammation. These findings support PRA-EVs as a promising multi-target therapeutic strategy for DPN.