A polymerized probucol nanoformulation with neutrophil extracellular vesicle camouflage for cerebral ischemia-reperfusion injury therapy

Mengjie Jia; Wenjun Miao; Yiliang Li; Yajie Guo; Jieying Zeng; Yan Gao; Xinting Li; Yufan Wang; Zhenghuan Zhao; Zichen Xu; Nancy Wang; Fang Yang; Jing Zhao; Yi Wang; Guixue Wang

doi:10.1016/j.xinn.2024.100761

A polymerized probucol nanoformulation with neutrophil extracellular vesicle camouflage for cerebral ischemia-reperfusion injury therapy

Innovation (Camb). 2024 Dec 27;6(4):100761. doi: 10.1016/j.xinn.2024.100761. eCollection 2025 Apr 7.

Authors

Mengjie Jia¹, Wenjun Miao¹, Yiliang Li², Yajie Guo¹, Jieying Zeng¹, Yan Gao¹, Xinting Li¹, Yufan Wang¹, Zhenghuan Zhao¹, Zichen Xu³, Nancy Wang⁴, Fang Yang⁵, Jing Zhao¹, Yi Wang^{1

3}, Guixue Wang^{3

6}

Affiliations

¹ School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
² The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, China.
³ Jinfeng Laboratory, Chongqing 401329, China.
⁴ School of Clinical Medicine, The University of Cambridge, CB2 0SP Cambridge, UK.
⁵ Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210009, China.
⁶ Key Laboratory for Biorheological Science and Technology of Ministry of Education, National Local Joint Engineering Lab for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing 400044, China.

Abstract

This study leverages the unique advantages of polyprodrug systems and biomimetic technology to develop a novel biomimetic nanoformulation, in which neutrophil extracellular vesicles (NEVs) are coated onto reactive oxygen species (ROS)-sensitive probucol-based polyprodrug nanoparticles (NPPBNPs). This NEV-camouflaged biomimetic nanoformulation holds significant potential for the effective treatment of cerebral ischemia-reperfusion injury (CIRI), offering multifaceted therapeutic effects, such as ROS elimination, inhibition of oxidative stress-induced neuronal apoptosis, attenuation of glial hyperactivation, and suppression of pro-inflammatory mediator secretion. In a murine CIRI model, NPPBNPs markedly enhanced neuronal viability, ameliorated the ischemic penumbra, restored behavioral functions, and exhibited an acceptable safety profile. The therapeutic mechanism of NPPBNPs involves NEV-mediated camouflage, which enables selective targeting of the pathological endothelium, thereby reducing peripheral neutrophil recruitment and facilitating blood-brain barrier (BBB) transport. Upon internalization by neurons, astrocytes, and microglia within ischemic regions, NPPBNPs respond to elevated intracellular ROS levels by releasing probucol in a controlled manner, which synergistically mitigates oxidative stress and inflammatory responses in CIRI-affected areas. Collectively, this multifunctional biomimetic nanoformulation represents a promising and practical strategy for the safe and effective treatment of CIRI.