Reactive oxygen species-responsive nanotherapy for the prevention and treatment of cerebral ischemia–reperfusion injury

Vascular recanalization intervention is the primary recommended approach for the treatment of ischemic stroke. However, the damage caused by cerebral ischemia-reperfusion (I/R) poses a significant challenge for effective treatment. The aim of this study was to address this challenge by developing multifunctional nanoparticles (NPs). Cu_4.6O NP was encapsulated by zein-Se-Se-DHA (Dz), the diselenide bond-conjugated zein and docosahexaenoic acid (DHA), and then coated by platelet membrane (PLTM) to form Cu_4.6O@Dz@PLTM (MDzCu) NP. MDzCu with the PLTM coating showed strong targeting ability to the cerebral ischemic lesions in the rat model of cerebral I/R injury. Furthermore, in the reactive oxygen species (ROS)-rich brain microenvironment, both Cu_4.6O and DHA are released from MDzCu, exerting ROS scavenging, promoting microglia polarization, and providing neuroprotective effects, ultimately alleviating cerebral I/R injury. This study presents several novel findings, such as the use of Cu⁰/Cu⁺ NPs for brain-related diseases, ROS scavenger-assisted DHA therapy for the central nervous system (CNS), and the application of stimuli-responsive NPs with diselenides to treat I/R injuries. This study provides insights into the development of stimuli-responsive nanomedicines with cell membrane coatings for the targeted treatment of brain diseases.