Hybrid Exosome–LiposomeNanoparticles for DualModulation 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.