Reactive Oxygen Species-Responsive Chitosan–Bilirubin Nanoparticles Loaded with Statin for Treatment of Cerebral Ischemia

Cerebral ischemia impairs blood circulation, leading to elevated reactive oxygen species (ROS) production. A ROS-responsive delivery of drugs can enhance the therapeutic efficacy and minimize the side effects. There is insufficient evidence on the impact of ROS-responsive nanoparticles on ischemic stroke. We developed ROS-responsive chitosan–bilirubin (ChiBil) nanoparticles to target acute ischemic lesions and investigated the effect of atorvastatin-loaded ROS-responsive ChiBil. We randomly assigned rats with transient middle cerebral artery occlusion (MCAO) to 4 groups: saline, Statin, ChiBil, and ChiBil-Statin. These groups were treated daily via the tail vein for 7 d. Behavioral assessment, magnetic resonance (MR) imaging, evaluation of neuroinflammation, blood–brain barrier (BBB) integrity, apoptosis, and neurogenesis after stroke were conducted. In vitro, results showed nanoparticle uptake and reduced intracellular ROS, lipid peroxidation, and inflammatory cytokines (IL-6 and TNF-α). In vivo, results showed improved motor deficits and decreased infarct volumes on MR images in the ChiBil-Statin group compared with the Control group on day 7 ( P < 0.05). Furthermore, the expression of inflammatory cytokines such as IL-1β and IL-6 was reduced in the ChiBil-Statin group compared with the Control group ( P < 0.05). Improvements in BBB integrity, apoptosis, and neurogenesis were observed in the ChiBil-Statin group. The findings demonstrated that intravenous ROS-responsive multifunctional ChiBil-Statin could effectively deliver drugs to the ischemic brain, exerting marked synergistic pleiotropic neuroprotective effects. Therefore, ChiBil-Statin holds promise as a targeted therapy for ischemic vascular diseases characterized by increased ROS production, leading to new avenues for future research and potential clinical applications.