Magnetic biomimetic nanoparticles delivering astragaloside IV alleviate ischemic stroke via ferroptosis modulation

• Magnetic biomimetic nanoparticles (MM@FeMA) enable targeted drug delivery across the blood–brain barrier for ischemic stroke therapy. • MM@FeMA enhances brain accumulation and shows superior penetration at ischemic sites under magnetic guidance. • The formulation effectively inhibits neuronal ferroptosis by regulating HIF-1α/GPX4 and ACSL4/lipid peroxidation pathways. • MM@FeMA significantly reduces infarct volume and improves neurobehavioral outcomes in MCAO/R model mice. Ischemic stroke (IS) remains a leading cause of mortality and long-term disability worldwide, while effective treatment is still hindered by the blood–brain barrier (BBB), insufficient drug accumulation, and severe ischemia reperfusion–induced neuronal damage. Brain-targeted strategies based on nanobiotechnology have shown great promise in the treatment of IS. Herein, we engineered a magnetic biomimetic nanoplatform (MM@FeMA) by integrating mesoporous silica (MSN) based drug loading, Fe 3 O 4 -enabled magnetic responsiveness, and macrophage membrane (MM) mediated inflammation targeting into a unified system for the delivery of astragaloside IV (AS). MM@FeMA nanoparticles exhibited high drug loading efficiency and excellent biocompatibility. MM coating preserved key surface proteins, enabling immune evasion and enhanced accumulation at ischemic lesions, while Fe 3 O 4 incorporation allowed magnetic field-guided targeting and improved BBB penetration. In vitro and in vivo results demonstrated that MM@FeMA effectively alleviated oxidative stress, suppressed neuroinflammation, and inhibited ferroptosis, thereby significantly reducing infarct volume and improving neurological outcomes. Mechanistic studies revealed that these protective effects are primarily associated with the activation of the HIF-1α mediated pathway and subsequent inhibition of ACSL4 dependent lipid peroxidation. This work presents a multifunctional biomimetic nanoplatform that integrates targeting, controlled delivery, and microenvironment modulation, providing a promising therapeutic strategy for IS therapy.