Biomimetic propofol liposomes alleviate ischemic stroke by targeting ferroptosis via EGFR/Nrf2 pathway activation

Ischemic stroke remains a leading cause of death and long-term disability worldwide, with therapeutic efficacy limited by narrow treatment windows and severe ischemia–reperfusion injury. Excessive oxidative stress and neuroinflammation drive progressive neuronal injury after ischemia–reperfusion, with ferroptosis emerging as a key downstream form of regulated cell death, thereby underscoring the need for lesion-specific and sustained neuroprotective interventions. Propofol exhibits intrinsic antioxidant, mitochondrial-protective, and anti-ferroptotic activities beyond its anesthetic effects. However, its therapeutic application in ischemic stroke is constrained by insufficient accumulation at ischemic lesion sites and rapid systemic clearance, resulting in unstable neuroprotective efficacy. In this study, we developed a macrophage membrane–coated lipid nanoparticle loaded with propofol (MCM@LNP@Propofol), integrating efficient liposomal encapsulation, membrane-biomimetic inflammation targeting, and environmentally responsive drug release within a single modular platform. The nanoparticles exhibit high encapsulation efficiency, uniform size distribution and colloidal stability. The macrophage membrane coating preserves key immune-evading and inflammation-homing features, markedly enhancing propofol accumulation in ischemic brain lesions compared with non-biomimetic liposomes. Furthermore, incorporation of an ROS-sensitive thioketal–PEG linker endows the system with dual pH/ROS responsiveness, enabling spatially controlled drug release within the ischemia–reperfusion microenvironment. In vitro and in vivo studies demonstrate that MCM@LNP@Propofol effectively suppresses ferroptosis, restores mitochondrial homeostasis, and significantly improves neurological function. Mechanistic investigations further reveal that these protective effects are mediated predominantly through activation of the EGFR/NRF2 signaling axis. Overall, this work presents a multifunctional, inflammation-targeted nanotherapeutic platform that stabilizes and enhances the therapeutic performance of propofol, offering a safe and translatable materials-based strategy for ischemic stroke treatment.