Brain targeted lipid nanoparticles with Hv1 inhibitors alleviate neuroinflammation post-ischemic stroke

作者：Zeyu Yang, Lei Jin, Longxiang Li, Yu Na Wu, Wenchao Liu, Xin Feng, Liyan Li, Fa Jin, Yiming Bi, Ran Li, Shenquan Guo, Yanan Wang, Boyang Wei, Yanchao Liu, Xifeng Li, Chuanzhi Duan · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03540-6 · 被引用次数：11 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Inflammasome and immune disorders、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

BACKGROUND: Ischemic stroke (IS) represents a significant global health burden. Current therapeutic options face problems such as window narrowing and reperfusion injury risk. Moreover, with increasing aging and risk factors, novel treatment strategies are urgently needed. NADPH oxidase (NOX)-mediated oxidative stress in microglia is a critical mechanism driving neuroinflammation and cell death. Hv1, a voltage-gated proton channel highly expressed in microglia, synergizes with NOX to generate reactive oxygen species (ROS), exacerbating brain damage. YHV984, a potent Hv1 inhibitor, alleviates post-IS neuroinflammation but faces clinical limitations due to potential toxic side effects and solubility issues. To improve the physicochemical and pharmacokinetic properties of YHV984 for specific Hv1 inhibition in the brain, the multifunctional nanoparticles consisting of a T7-targeting peptide and lipid nanoparticles (LNP) were developed to deliver YHV984 (T7-LNP@YHV984). RESULTS: The results demonstrated that T7-LNP@YHV984 exhibited good stability and brain targeting capability, effectively crossing the blood-brain barrier (BBB) and accumulating within microglia. This targeted delivery significantly suppressed Hv1 expression and activation of the NLRP3 inflammasome pathway in the damaged brain. Furthermore, it promoted the polarization of microglia towards the M2 phenotype, enhancing the release of anti-inflammatory factors, alleviating neuroinflammation and improved neuronal survi...