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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
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DOI：10.1016/j.biomaterials.2026.124497.png)
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Abstract
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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.
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