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

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.