Platelet Membrane-Based Nanoparticles for Targeted Delivery of Deferoxamine to Alleviate Brain Injury Induced by Ischemic Stroke

 There is much earlier research on nano stuff for recovery. HAS YOUR INCOMPETENT? DOCTOR DONE NOTHING WITH THIS? So, you DON'T have a functioning stroke doctor, do you? And complete incompetence(for over a decade!) in the stroke medical world which seems to have NO idea on how to solve stroke! They are all blithering idiots straight from the pages of Monty Python. Like this:

Monty Python's Flying Circus - Upper Class Twit of the Year (1971)

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Platelet Membrane-Based Nanoparticles for Targeted Delivery of Deferoxamine to Alleviate Brain Injury Induced by Ischemic Stroke

Authors Wang P, Lv X, Tian S, Yang W , Feng M, Chang S, You L, Chang YZ

Received 8 January 2025

Accepted for publication 8 June 2025

Published 16 June 2025 Volume 2025:20 Pages 7533—7548

DOI https://doi.org/10.2147/IJN.S516316

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Jie Huang

Download Article [PDF] 

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

1</sup>Laboratory 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

Introduction

Stroke is an acute and severe cerebrovascular disease with high morbidity, mortality, and medical cost. It has been reported that ischemic stroke, which results from a lack of blood supply to the brain, accounts for approximately 84% of all stroke cases.¹ Irreversible neurological injury can be avoided only if the blocked blood vessels are reperfused within the therapeutic time window. However, ischemia/reperfusion (I/R) can immediately cause dysregulation of oxidation and antioxidation, disrupt the balance between the generation and scavenging of reactive oxygen species (ROS), eventually leading to the accumulation of ROS in the ischemic brain, which exacerbates the activation of inflammatory responses and results in secondary neurological damage.² Therefore, I/R injury is considered the main culprit and an inevitable obstacle in the therapy of ischemic stroke. Despite the development of various drugs and functional nanoparticles with ROS scavenging ability, effective treatment options for I/R injury remain disappointingly limited.

Many studies have indicated that a higher iron status is a critical risk factor associated with neuronal damage following cerebral I/R. Standard clinical analysis has repeatedly shown that elevated plasma ferritin levels are associated with poor outcomes in patients with ischemic stroke.^3,4 Iron overload exacerbates brain edema and hemorrhagic transformation in ischemic stroke patients receiving thrombolytic therapy with tissue plasminogen activator.^5,6 Mechanistically, our previous research has demonstrated that excessive iron exacerbates neuronal damage by catalyzing the Fenton reaction to convert superoxide and hydroxyl radicals into highly reactive toxic radicals or catalyzing lipid peroxidation as a cofactor of lipid oxidation enzymes.^7–9 Of note, we and others have recently described the induction of neuronal ferroptosis, a newly identified form of regulated cell death resulting from the catastrophic accumulation of iron-dependent lipid reactive oxygen species, in I/R brains.^8,10–12 Therefore, iron is a key factor that stimulates ROS generation and facilitates the subsequent activation of cell death pathways, particularly the ferroptosis pathway, in I/R injury. Iron depletion via chelator may protect neuronal cells against ferroptosis and is expected to emerge as a promising strategy for the treatment of cerebral I/R.

Among the clinically available iron chelators, deferoxamine (DFO) has long been used to remove excess iron in iron overload diseases, such as the secondary iron overload that afflicts thalassemia patients, and has been shown to be the most effective option with the most favorable toxicity profile.^13,14 Moreover, DFO has demonstrated its protective effects in animal stroke models of I/R as well as in clinical studies in which ischemic stroke patients administered DFO exhibited improved outcomes.^5,15–17 However, the poor bioavailability and the extremely short plasma half-life (20 min in humans) of DFO limits its use in stroke treatment.^18,19 More important, at the high doses needed to achieve effective concentrations, DFO can cause serious side effects, including renal and liver complications.¹³ Another limitation of DFO for use in stroke treatment is that systemic administration does not specifically target to the injured region of the I/R brain. New delivery approaches that can target deliver DFO to the injured brain region and improve the local DFO concentration are expected to provide significant improvements in stroke outcomes.

Despite advancements in stroke-targeted nanoplatforms, such as polymeric carriers, metallic nanoparticles, and carbon-based systems, current materials face persistent translational barriers, including compromised biosafety profiles, suboptimal therapeutic efficacy, and insufficient blood–brain barrier penetrability.^20,21 Recently, cell membrane-based biomimetic cloaking has emerged as a new strategy for enhancing synthetic nanoparticles delivery, leveraging retained membrane functionalities to overcome systemic biological barriers while preserving immunoevasive properties. Platelets (PLT) play a critical role in the development and progression of thrombosis. Previous studies have shown that the platelet membrane exhibits properties in binding to injured vasculature and has advantages for targeting ischemic brain regions.^22–26 Therefore, we propose a new type of PLT membrane-coated biomimetic nanodevice to deliver DFO specifically to the ischemic brain. On the basis of the properties of liposomes in carrying hydrophilic substances and crossing the leaky blood–brain barrier in cerebral I/R,²⁷ we first encapsulated DFO within traditional liposomes through hydration to improve its biocompatibility. Subsequently, the isolated PLT membranes were coated onto the DFO-liposomes by coextrusion, endowing this nanodrug with stroke lesion targeting ability (Figure 1a). This PLT membrane-cloaked, DFO-loaded nanoliposome, named Platesome-DFO, can deliver DFO to the targeted lesion, increasing intracellular drug concentrations to markedly higher levels than those achievable through systemic administration. Particularly, we confirmed the chelation of excess iron by Plateletsome-DFO, and the consequent inhibition of iron-dependent lipid peroxidation and ferroptosis in the cerebral I/R brain (Figure 1b). 2,3,5-triphenyltetrazolium chloride (TTC) staining measurement from mouse models demonstrated that the Platesome-DFO treatment effectively alleviated I/R-induced brain damage. Our Platesome-DFO formulation offers a viable strategy for specifically targeting lesions to inhibit neuronal death, demonstrating potential to improve outcomes in cerebral I/R injury.

Figure 1 Schematic illustration of Platesome-DFO structure and its proposed protective mechanism in ischemic stroke. (a) The Platesome-DFO was fabricated by coextrusion of platelet membranes and Liposome-DFO to form nanoparticles that inherit the natural characteristics of the platelet membrane, including targeting damaged blood vessels and immune escape capabilities, by the presence of specific membrane proteins, such as CD36, CD41, and CD47. (b) After intravenous injection, Platesome-DFO is delivered to the injured brain region after stroke, followed by the release of DFO, which chelates excessive iron and inhibits ferroptosis of neuronal cells.

More at link.