Neutrophil membrane fusogenic nanoliposomal leonurine for targeted ischemic stroke therapy via remodeling cerebral niche and restoring blood-brain barrier integrity

Ischemic stroke (IS) constitutes the leading cause of global morbidity and mortality. Neuroprotectants are essential to ameliorate the clinical prognosis, but their therapeutic outcomes are tremendously compromised by insufficient delivery to the ischemic lesion and intricate pathogenesis associated with neuronal damage, oxidative stress, inflammation responses, blood-brain barrier (BBB) dysfunction, etc. Herein, a biomimetic nanosystem (Leo@NM-Lipo) composed of neutrophil membrane-fused nanoliposomal leonurine (Leo) is constructed, which can not only efficiently penetrate and repair the disrupted BBB but also robustly remodel the harsh cerebral microenvironment to reverse ischemia-reperfusion (I/R) injury. More specifically, the neutrophil membrane inherits the BBB penetrating, infarct core targeting, inflammation neutralization, and immune evasion properties of neutrophils, while Leo, a naturally occurring neuroprotectant, exerts pleiotropic effects to attenuate brain damage. Remarkably, comprehensive investigations disclose the critical factors influencing the targetability and therapeutic performances of biomimetic nanosystems. Leo@NM-Lipo with a low membrane protein-to-lipid ratio of 1:10 efficiently targets the ischemic lesion and rescues the injured brain by alleviating neuronal apoptosis, oxidative stress, neuroinflammation, and restoring BBB integrity in transient middle cerebral artery occlusion (tMCAO) rats. Taken together, our study provides a neutrophil-mimetic nanoplatform for targeted IS therapy and sheds light on the rational design of biomimetic nanosystems favoring wide medical applications.