Ischemic stroke remains a major cause of mortality and disability worldwide, with limited treatment options. This study aimed to develop dual-targeted liposomes containing ginsenoside CK and evaluate their neuroprotective effects against cerebral ischemia-reperfusion injury.

Liposomes modified with transferrin, rabies virus glycoprotein, and ginsenoside CK were prepared and characterized. Their uptake and protective effects were assessed in neuronal and endothelial cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). A rat model of transient middle cerebral artery occlusion was used to evaluate neuroprotection in vivo. Molecular docking, surface plasmon resonance, and co-immunoprecipitation were performed to investigate the mechanism. Western blot data were analyzed by densitometric quantification.

The dual-targeted liposomes exhibited enhanced cellular uptake and brain accumulation. They protected against mitochondrial fission and PANoptosis in vitro and reduced infarct volume and neuronal death in vivo. Quantitative analysis revealed that the ginsenoside CK-containing liposomes significantly reversed OGD/R-induced changes in apoptotic, pyroptotic, and necroptotic markers. Mechanistically, ginsenoside CK bound to O-GlcNAcase with a KD = 3.89 μM and enhanced O-GlcNAcylation of RIPK1/RIPK3, disrupting PANoptosome formation.

Dual-targeted liposomes containing ginsenoside CK represent a promising therapeutic strategy for cerebral ischemia-reperfusion injury. This approach overcomes blood-brain barrier limitations through targeted delivery. Besides, ginsenoside CK as a liposome component inhibits PANoptosis via enhanced protein O-GlcNAcylation. Further optimization and safety studies are warranted to advance this strategy toward clinical application.