Super-small zwitterionic nitric oxide-donor micelles efficiently scavenge ROS and alleviate inflammation for combined ischemic stroke therapy

Ischemic stroke has severely threatened the health of human beings, attributed to blood-brain barrier (BBB) damage, excess reactive oxygen species (ROS), and inflammation effect, which trigger neuronal death and impairment of neurological function. Herein, atorvastatin (ATO)-encapsulated super-small nitric oxide (NO)-donor micelles (M-NO@A) based on hyper-branched polyzwitterion are developed to reverse brain injury status and reduce infarct size. M-NO@A upon super-small volume can significantly accumulate in the ischemic region, thereby inhibiting the adhesion of inflammatory cells' to BBB by NO decreasing the expression of intracellular cell adhesion molecule-1 (ICAM-1) on BBB. Additionally, the introduction of NO is adequate to suppress inflammation amplification, in a combination with ATO-mediated oxidative stress reduction to maintain the brain's health synergistically. Meanwhile, significant reduction in cerebral infarct area and marked improvement in neurological function are clearly visualized in transient middle cerebral artery occlusion/reperfusion (tMCAO/R) models treated with M-NO@A. Consequently, these micelles provide a multifaceted strategy for drug delivery to damaged brains, thereby achieving efficient treatment of brain diseases. STATEMENT OF SIGNIFICANCE: The designed atorvastatin (ATO)-encapsulated super-small nitric oxide (NO)-donor micelles (M-NO@A) utilize their ultra-small size and carboxybetaine (CB) functionalization to facilitate efficient blood-brain barrier (BBB) penetration and subsequent brain accumulation. This formulation effectively inhibits inflammatory cell adhesion to the BBB through nitric oxide (NO)-mediated downregulation of intercellular adhesion molecule-1 (ICAM-1) expression. Furthermore, the incorporated NO effectively suppresses inflammatory amplification, while ATO-mediated oxidative stress reduction synergistically preserves brain homeostasis. In transient middle cerebral artery occlusion/reperfusion (tMCAO/R) models, M-NO@A treatment demonstrated significant reductions in cerebral infarct volume and substantial improvements in neurological function. Collectively, these nanomicelles represent a multifaceted therapeutic strategy for targeted drug delivery to the injured brain, offering an effective approach for treating cerebrovascular disorders.