A thiol-alkyne click chemistry-driven lipoic acid precise delivery platform for targeted therapy of cerebral ischemic stroke via redox homeostasis restoration and neuroinflammatory cascade suppression.

Redox homeostasis imbalance, an early triggering event in cerebral ischemic stroke (CIS), precipitates neuronal death and neuroinflammatory response. The endogenous redox pair α-lipoic acid (LA) and dihydrolipoic acid (DHLA) serve as potent antioxidants and possess enormous potential for treating ischemia/reperfusion-induced organ injury. However, their application is constrained by a short half-life and DHLA's susceptibility to metal ion complexes in the bloodstream. Herein, a borneol (Bo)-mediated brain-targeted, ROS-responsive release of DHLA hyperbranched polymer nanomedicine (Bo-HBP(LA) NPs) was prepared via an efficient one-pot 'thiol-alkyne' click chemistry strategy employing diethynyl lipoic acid and dihydrolipoic acid. Following intravenous administration in MCAO mice, the nanoformulation (LA: 20 mg kg-1) efficiently traversed the blood-brain barrier (BBB), resulting in enhanced brain accumulation levels of 13.7%, 14.8%, 11.2% ID/g of the total administered dose at 1, 3, and 6 h post-administration, respectively. Under elevated-ROS pathological conditions, the release of DHLA and its conversion into LA can effectively restore redox homeostasis by scavenging ROS (a 92.2% reduction) and upregulating the Nrf2-NQO1/HO-1 pathway. Additionally, it positively modulated the intracellular TCA cycle, corrected energy metabolism imbalance, and inhibited the Cleaved Caspase-3/9/12 apoptosis pathway, resulting in a 93.9% reduction in neuronal apoptosis. It also remodelled the neuroinflammatory microenvironment by suppressing the activation of astrocytes and microglia and downregulating TNF-α and IL-6. Consequently, this nano-formulation intervention repaired the damaged neurons, reduced the cerebral infarction area from 44% to 1.4%, preserved BBB integrity, prevented brain edema, and restored neurological function, presenting a feasible approach to tackle the existing clinical challenges in CIS treatment.