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Adipose-derived mesenchymal stem cell-derived exosomal miR-22-3p alleviates depression-like behaviors in a rat model via the FURIN/HMGB1 axis

Year: 2026

Type: article

Abstract: Background: Major depressive disorder (MDD) is characterized by neuroinflammation and neuronal apoptosis, yet effective brain-targeted delivery strategies remain limited. Exosomes represent promising carriers capable of crossing the blood-brain barrier. This study investigated whether engineered exosomes delivering miR-22-3p by modulating the FURIN/HMGB1 axis. Methods: Serum microRNA expression was assessed in patients with MDD. A rat model of depression was established using chronic unpredictable mild stress (CUMS). miR-22-3p-engineered adipose-derived mesenchymal stem cell exosomes were administered intranasally. Behavioral tests (SPT, OFT, FST), RT-qPCR, ELISA, HE staining, and TUNEL assays were performed to evaluate neurobehavioral and molecular changes. Results: miR-22-3p was significantly downregulated in both MDD patients and CUMS rats (P < 0.01). Intranasal administration of engineered exosomes increased brain miR-22-3p levels and significantly improved depressive-like behaviors (P < 0.05 or P < 0.01). Mechanistically, treatment suppressed FURIN and HMGB1 expression, reduced proinflammatory cytokines (IL-1β, IL-6, TNF-α), and attenuated hippocampal neuronal apoptosis (P < 0.05 or P < 0.01). These effects were more pronounced than those of native exosomes. Conclusions: miR-22-3p-engineered exosomes exert antidepressant effects by inhibiting the FURIN/HMGB1-mediated neuroinflammatory and apoptotic pathways. This study highlights a novel intranasal exosome-based microRNA delivery strategy for MDD.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1924891