Neuroprotective effects of intranasal mPEG-PLA modified nanoliposomes loaded with Gleditsiae Fructus Abnormalis volatile on cerebral ischemia-reperfusion injury <i>via</i> the HIF-1α/VEGF signaling pathway

Sustained release of neuroprotective agents from polymeric nanocarriers offers a promising approach for ischemic stroke treatment. This study investigates the neuroprotective effects of methoxy poly(ethylene glycol)-poly(lactic acid) (mPEG-PLA) modified nanoliposomes (mLP) loaded with Gleditsiae Fructus Abnormalis volatile oil (VOGFA) on cerebral ischemia-reperfusion injury (CIRI) in rats. Five active components—paeonol, eugenol, methyl eugenol, linalool, and anethole—were identified and screened for their potential to mitigate ischemic damage. The five active components of VOGFA of mPEG-PLA modified nanoliposomes (FVOGFA-mLP) system was prepared using an optimized ethanol injection method and characterized using transmission electron microscopy (TEM) and laser granulometry to evaluate particle size distribution and encapsulation efficiency. In vitro studies on PC12 cells subjected to oxygen-glucose deprivation/reperfusion (OGD/R) demonstrated that FVOGFA-mLP significantly enhanced cell survival and migration. In vivo experiments further confirmed the improved brain targeting capability and bioavailability of FVOGFA-mLP, which significantly reduced inflammatory cytokine levels [tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β)] and upregulated VEGF expression in cortical regions of CIRI rats. Behavioral assessments and histological analysis showed that medium and high doses of FVOGFA-mLP notably improved neurological function and reduced infarct volume, outperforming nimodipine. This study highlights the therapeutic potential of FVOGFA-mLP for ischemic stroke, demonstrating enhanced brain targeting and neuroprotection through the regulation of hypoxia-inducible factor 1-alpha (HIF-α) and vascular endothelial growth factor (VEGF) signaling pathways.