Mitochondrial dysfunction and impaired mitophagy-a key event in diabetic hyperglycemia-aggravated ischemic injury - lead to accumulation of dysfunctional mitochondria and neuronal apoptosis, which are vital processes involved in diabetic cerebral infarction (DCI). Herein, we developed SRT1720-loaded exosome-mimetic nanovesicles (SRT1720@M) to leverage the potential of SIRT1/PARKIN pathway activation to inhibit these processes and counteract DCI. The lipid fusion approach was used to fabricate exosome-loaded SRT1720@M. The properties of SRT1720@M were established by employing UV-Vis, transmission electron microscopy (TEM), dynamic light scattering, and Fourier-transform infrared (FTIR) spectroscopy. Oxygen-glucose deprivation/reperfusion (OGD/R) and high-glucose (HG)-treated primary hippocampal neurons were used as an in vitro DCI model treated with SRT1720@M. qPCR, Western blotting and immunofluorescence were used for expression analyses, whereas cell viability, phagocytosis, inflammation, and ATP/L-LA levels were assessed by CCK-8, ELISA and TEM. A rat model of DCI was obtained by establishing middle cerebral artery occlusion (MCAO), from which infarct volume, neurological deficits, histopathology, behavioral indexes, and molecular markers were detected. SRT1720@M average size was ∼68 nm, with an encapsulation efficiency of 78.19%, loading capacity of 8.52%, and zeta potential of -54 mV. In vitro, SRT1720@M markedly improved cell viability (P < 0.01), decreased IL-1β, TNF-α, and L-LA, but increased ATP levels, and promoted mitophagy and suppressed inflammatory responses compared with the DCI group. In the DCI model, SRT1720@M improved neurological deficits, reduced infarct volume, and alleviated behavioral disorders by inhibiting apoptosis and inflammation and promoting mitophagy and mitochondrial function through activation of the SIRT1/PARKIN pathway. SRT1720@M alleviates DCI by activating the SIRT1/PARKIN pathway and promoting mitophagy, highlighting its potential as a promising preclinical therapeutic strategy.
