Hybrid Exosome-Liposome Nanoparticles for Dual Modulation of Neuroinflammation and Lipid Metabolism in Ischemic Stroke.

Ischemic stroke, often modeled by middle cerebral artery occlusion and reperfusion (MCAO/R), involves severe neuroinflammation and lipid metabolic dysregulation that exacerbate neuronal damage. To address these dual pathological processes, we engineered a hybrid nanoplatform (Exo-Lip) by fusing neural stem cell-derived exosomes (Exo) with liposomes loaded with Yulangsan polysaccharide (Lip). Exosomes provide blood-brain barrier (BBB) permeability and intrinsic anti-inflammatory activity, while liposomes confer antioxidant and immunoregulatory effects. The resulting Exo-Lip exhibited improved colloidal stability and synergistic therapeutic potential. In MCAO/R mice, Exo-Lip markedly attenuated neuroinflammation by decreasing TNF-α and IL-6 while upregulating IL-10 and TGF-β. It restored lipid metabolism, alleviated oxidative stress, and preserved membrane integrity. TTC staining revealed a reduced infarct volume, and behavioral testing confirmed the recovery of motor and cognitive functions. Histological analyses further demonstrated neuronal survival and structural preservation. Transcriptomic profiling revealed that Exo-Lip modulated gene networks associated with inflammation and lipid regulation, including activation of the AKT/Nrf2/HO-1 signaling pathway. Collectively, these findings suggest that Exo-Lip represents a multifunctional, biomimetic nanotherapeutic capable of targeting both inflammatory and metabolic pathways in ischemic stroke. This work highlights a precision nanomedicine strategy with translational potential for central nervous system disorders.