Peina Wang,1,2,* Xin Lv,1,* Siyu Tian,1 Wen Yang,2 Mudi Feng,1 Shiyang Chang,2 Linhao You,1 Yan-Zhong Chang1 

1Laboratory of Molecular Iron Metabolism, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Ministry of Education Key Laboratory of Molecular and Cellular Biology, Department of Physiology, College of Life Science, Hebei Normal University, Shijiazhuang, Hebei Province, 050024, People’s Republic of China; 2Department of Histology and Embryology, College of Basic Medical Sciences, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yan-Zhong Chang; Peina Wang, Email chang7676@163.com; 19301641@hebmu.edu.cn

Background: Timely thrombolysis serves as the primary therapeutic approach for ischemic stroke, one of the most serious global public health problems, although reperfusion can cause severe ischemia reperfusion (I/R) injury. Oxidative stress and activation of cell death pathways are the main mechanisms of I/R injury. Our previous studies have demonstrated that iron overload stimulates the generation of reactive oxygen species and facilitates the activation of iron-dependent ferroptosis in the pathogenesis of I/R injury. Removal of excess free iron by deferoxamine (DFO), an iron chelator, may inhibit iron toxicity and reverse I/R-induced neurological deficits. Despite its therapeutic potential, DFO’s clinical translation for I/R injury is hampered by rapid systemic clearance, suboptimal bioavailability, and a lack of ischemic lesion-targeting ability. Nanoscale delivery platforms enabling targeted DFO release in stroke lesions may overcome these pharmacokinetic barriers and enhance clinical outcomes.
Methods: On the basis of the properties of liposomes in carrying hydrophilic substances and crossing the leaky blood–brain barrier in cerebral I/R, we first encapsulated DFO within traditional liposomes to improve its biocompatibility. Subsequently, inspired by the natural homing properties of platelets to damaged blood vessels during I/R injury, the isolated platelet membranes were coated onto the DFO-liposomes, thus endowing the nanodrug with the ability to target stroke lesion.
Results: Our results demonstrate that Platesome-DFO exhibits accurate lesion-targeting ability and significantly decreases lesion iron content, thereby preventing neuronal ferroptosis and ultimately reversing neurological deficits in I/R mice.
Conclusion: Platesome-DFO provides a novel therapeutic approach for cerebral I/R injury by regulating brain iron status and iron-dependent pathways, highlighting its promising application in the clinical treatment of cerebral I/R injury.

Keywords: ischemic stroke, iron, ferroptosis, deferoxamine, platelet membrane, nanomedicine