Exosomes derived from umbilical cord mesenchymal stem cells ameliorate ischemic brain injury in mice by regulating AAK1 via miR-664a-5p

To identify the molecular targets of mesenchymal stem cell (MSC)-derived exosomes in treating cerebral ischemia and elucidate their therapeutic mechanisms. We utilized a mouse model of middle cerebral artery occlusion and treated mice with umbilical cord mesenchymal stem cells derived exosomes. Proteomic analysis identified AAK1(AP2 associated kinase 1) as a key target protein. Functional studies confirmed that AAK1 modulates the NF-κB signaling pathway in ischemic stroke. MicroRNA profiling, bioinformatic prediction and cell experiments identified miR-664a-5p as the specific microRNA regulating AAK1 expression. Finally, we validated the therapeutic effects of umbilical cord mesenchymal stem cell-derived exosomes using engineered miR-664a-5p-deficient exosomes. Our findings demonstrate that umbilical cord mesenchymal stem cells-derived exosomes exert neuroprotective effects in ischemic stroke by modulating the AAK1/NF-κB axis via miR-664a-5p. This study provides novel insights into the therapeutic mechanism of mesenchymal stem cell-derived exosomes in ischemic stroke, highlighting their potential for developing exosome-based therapies.