携带Hv1抑制剂的脑靶向脂质纳米颗粒可减轻缺血性中风后的神经炎症。
Brain targeted lipid nanoparticles with Hv1 inhibitors alleviate neuroinflammation post-ischemic stroke.
作者信息
Yang Zeyu, Jin Lei, Li Longxiang, Wu Yu, Liu Wenchao, Feng Xin, Li Liyan, Jin Fa, Bi Yiming, Li Ran, Guo Shenquan, Wang Yanan, Wei Boyang, Liu Yanchao, Li Xifeng, Duan Chuanzhi
机构信息
Neurosurgery Center, Department of Cerebrovascular Surgery, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, The National Key Clinical Specialty, Southern Medical University, Guangzhou, 510282, China.
School of Materials Science and Engineering, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou, 510275, China.
出版信息
J Nanobiotechnology. 2025 Jul 1;23(1):464. doi: 10.1186/s12951-025-03540-6.
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 survival. Additionally, T7-LNP@YHV984 improved survival and facilitated neurological recovery in post-IS mice.
CONCLUSIONS
T7-LNP@YHV984 multifunctional nanoparticles with long-term stability emerged as a potent strategy to alleviate reperfusion injury and inhibit neuroinflammation post-IS. By precisely targeting Hv1 in microglia, the nanoparticles effectively suppressed microglia-induced neuroinflammation, minimizing off-target effects. This innovation offers novel insights into stroke treatment and neuroprotective strategies.
背景
缺血性中风（IS）是一项重大的全球健康负担。当前的治疗选择面临诸如治疗窗变窄和再灌注损伤风险等问题。此外，随着老龄化加剧和风险因素增多，迫切需要新的治疗策略。小胶质细胞中烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（NOX）介导的氧化应激是驱动神经炎症和细胞死亡的关键机制。Hv1是一种在小胶质细胞中高度表达的电压门控质子通道，与NOX协同产生活性氧（ROS），加剧脑损伤。YHV984是一种有效的Hv1抑制剂，可减轻缺血性中风后的神经炎症，但由于潜在的毒副作用和溶解性问题而面临临床局限性。为改善YHV984的理化性质和药代动力学特性，以特异性抑制大脑中的Hv1，研发了由T7靶向肽和脂质纳米颗粒（LNP）组成的多功能纳米颗粒来递送YHV984（T7-LNP@YHV984）。
结果
结果表明，T7-LNP@YHV984具有良好的稳定性和脑靶向能力，能有效穿过血脑屏障（BBB）并在小胶质细胞内蓄积。这种靶向递送显著抑制了受损大脑中Hv1的表达以及NLRP3炎性小体途径的激活。此外，它促进小胶质细胞向M2表型极化，增强抗炎因子的释放，减轻神经炎症并改善神经元存活。另外，T7-LNP@YHV984提高了缺血性中风后小鼠的存活率并促进神经功能恢复。
结论
具有长期稳定性的T7-LNP@YHV984多功能纳米颗粒成为减轻缺血性中风后再灌注损伤和抑制神经炎症的有效策略。通过精确靶向小胶质细胞中的Hv1，纳米颗粒有效抑制了小胶质细胞诱导的神经炎症，将脱靶效应降至最低。这一创新为中风治疗和神经保护策略提供了新的见解。
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