NIR-II-Responsive Biomimetic Nanoplatform for Precise Inhibition of Ischemic Stroke via Dual Modulation of Ion Channels and Microglia

Ischemic stroke, a predominant cause of global mortality and disability, is characterized by a complex pathological cascade, following cerebral ischemia. Despite some progress in current conventional therapies and light-responsive nanosystems, there remains a lack of precise treatment strategies. Notably, the function of ion channels has attracted considerable attention due to its close association with the pathogenesis of ischemic stroke. Consequently, developing near-infrared (NIR)-responsive nanoplatforms for the targeted modulation of ion channels allows for a more precise treatment of ischemic stroke. Herein, a second NIR window (NIR-II) photothermal responsiveness nanoplatform (MNPs@Mi), camouflaged with a 4T1 cell membrane (CM) for targeted delivery, is designed to synergistically modulate microglial polarization and ion channel activity in the ischemic region. In a mouse model of distal middle cerebral artery occlusion (dMCAO), this integrated nanoplatform significantly shifts microglial polarization from the pro-inflammatory M1 to anti-inflammatory M2 phenotype, enhances neuronal survival, restores blood-brain barrier (BBB) integrity, and improves motor functional recovery. Quantitative analyses reveal a 2.3-fold increase in NeuN-positive cells and a 51.1% reduction in intracerebral IgG extravasation compared to those in the injury model group. Overall, this biomimetic NIR-II-responsive nanoplatform provides a noninvasive, spatiotemporally precise strategy for the treatment of ischemic stroke via the coordinated regulation of ion channels and microglial polarization.