mTOR 介导的免疫代谢重编程纳米调节剂能够灵敏地切换能量剥夺诱导的小胶质细胞极化，从而治疗阿尔茨海默病,ACS Nano

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mTOR 介导的免疫代谢重编程纳米调节剂能够灵敏地切换能量剥夺诱导的小胶质细胞极化，从而治疗阿尔茨海默病
ACS Nano ( IF 15.8 ) Pub Date : 2023-08-11 , DOI: 10.1021/acsnano.3c03232
Fan Yang _{1,

2} , Dongju Zhao ₁ , Meng Cheng ₂ , Yining Liu ₁ , Ziyao Chen ₁ , Jin Chang ₁ , Yan Dou ₂

Affiliation

感知大脑稳态失衡的代谢重编程对于驱动有害的小胶质细胞极化是必要的，并且对该过程的特定靶向有助于灵活控制阿尔茨海默病（AD）的病理炎症反应，显示出独特的治疗益处。在此，负载免疫抑制剂盐酸芬戈莫德的谷胱甘肽功能化金纳米笼被开发为用于 AD 管理的脑靶向和小胶质细胞定位的免疫代谢重编程纳米调节剂 (GAF NP)。凭借谷胱甘肽介导的转运特性，这种纳米调节剂可以穿过血脑屏障并定位于 AD 病变中的小胶质细胞。通过阻断 Akt/mTOR/HIF-1α 信号通路，GAF NP 不仅可以促进免疫激活下主导代谢从糖酵解向氧化磷酸化的转变，还可以抑制小胶质细胞转运介导的葡萄糖过度消耗。基于实时生物能评估和¹⁸ F 标记的氟脱氧葡萄糖 (FDG) PET 的相关分析表明，GAF NP 治疗恢复的脑葡萄糖利用和代谢可以作为小胶质细胞 M1 到 M2 极化转换的敏感且有效的指标，最终减轻神经炎症及其衍生的神经变性以及改善 AD 小鼠的认知能力下降。这项工作突出了一种潜在的纳米医学，旨在修改 mTOR 介导的免疫代谢重编程，以阻止能量剥夺诱导的 AD 进展。

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mTOR-Mediated Immunometabolic Reprogramming Nanomodulators Enable Sensitive Switching of Energy Deprivation-Induced Microglial Polarization for Alzheimer’s Disease Management

Metabolic reprogramming that senses brain homeostasis imbalances is necessary to drive detrimental microglial polarization, and specific targeting of this process contributes to the flexible control of pathological inflammatory responses in Alzheimer’s disease (AD), displaying distinctive therapeutic benefits. Herein, glutathione-functionalized gold nanocages loaded with the immunosuppressant fingolimod hydrochloride are developed as brain-targeted and microglia-located immunometabolic reprogramming nanomodulators (GAF NPs) for AD management. By virtue of glutathione-mediated transport properties, this nanomodulator can cross the blood-brain barrier and localize to microglia in AD lesions. Through blocking Akt/mTOR/HIF-1α signaling pathways, GAF NPs not only promote the dominated metabolic shift from glycolysis to oxidative phosphorylation under immune activation but also inhibit transporter-mediated glucose overconsumption by microglia. Correlation analysis based on real-time bioenergetic assessment and ¹⁸F-labeled fluorodeoxyglucose (FDG) PET reveals that brain glucose utilization and metabolism restored by GAF NP treatment can serve as a sensitive and effective indicator for microglial M1 to M2 polarization switching, ultimately alleviating neuroinflammation and its derived neurodegeneration as well as ameliorating cognitive decline in AD mice. This work highlights a potential nanomedicine aimed at modifying mTOR-mediated immunometabolic reprogramming to halt energy deprivation-induced AD progression.

更新日期：2023-08-11

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