Synergistic neuroprotection against ischemic stroke: A biomimetic nanoplatform simultaneously targeting calcium Dyshomeostasis and ferroptosis

Abstract

In ischemic stroke, calcium overload and ferroptosis-inducing ROS production are two critically interlinked drivers. These elements engage in a vicious, self-reinforcing cycle, which in turn propagates a destructive cascade that triggers both apoptotic and necrotic cell death pathways. We developed a ROS-responsive liposome that efficiently encapsulates the hydrophobic prodrug BAPTA-AM and is camouflaged with a macrophage-membrane coating co-loaded with Salvianolic acid B (SAB). The macrophage membrane confers blood–brain barrier penetration and ischemia-targeting specificity. Upon reaching the ischemic lesion, ROS-responsive bonds cleave, triggering controlled release of BAPTA-AM. The membrane-permeable prodrug is then hydrolyzed by intracellular esterases to active BAPTA, which rapidly chelates Ca 2+ to relieve calcium overload. Meanwhile, SAB exerts dual effects by (1) activating the Nrf2/HO-1 pathway to counter oxidative stress and (2) modulating the Bcl-2-associated X protein/B-cell lymphoma 2 balance to inhibit neuronal apoptosis. This coordinated, multi-target strategy reduces intracellular Ca 2+ , mitigates oxidative damage, and attenuates neuroinflammation, collectively addressing the complex pathophysiology of ischemic stroke.