Feng Qianhua, Zhang Xueli, Zhao Xiaowen, Liu Jia, Wang Qing, Yao Yuqi, Xiao Huifang, Zhu Yucui, Zhang Wenwen, Wang Lei
School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, P. R. China.
Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou, 450001, P. R. China.
Small. 2024 Dec;20(50):e2405781. doi: 10.1002/smll.202405781. Epub 2024 Oct 6.
The activated M1-like microglia induced neuroinflammation is the critical pathogenic event in Alzheimer's disease (AD). Microglial polarization from pro-inflammatory M1 toward anti-inflammatory M2 phenotype is a promising strategy. To efficiently accomplish this, amyloid-β (Aβ) aggregates as the culprit of M1 microglia activation should be uprooted. Interestingly, this study finds out that the self-reassembly of curcumin molecules into carrier-free curcumin nanoparticles (CNPs) exhibits multivalent binding with Aβ to achieve higher inhibitory effect on Aβ aggregation, compared to free curcumin with monovalent effect. Based on this, the CNPs loaded cardiolipin liposomes are developed for efficient microglial polarization. After intranasal administration, the liposomes decompose to release CNPs and cardiolipin in response to AD oxidative microenvironment. The CNPs inhibit Aβ aggregation and promote Aβ phagocytosis/clearance in microglia, removing roadblock to microglial polarization. Subsequently, CNPs are endocytosed by microglia and inhibit TLR4/NF-κB pathway for microglia polarization (M1→M2). Meanwhile, cardiolipin is identified as signaling molecule to normalize microglial dysfunction to prevent pro-inflammatory factors release. In AD transgenic mice, neuroinflammation, Aβ burden, and memory deficits are relieved after treatment. Through combined attack by extracellularly eradicating roadblock of Aβ aggregation and intracellularly inhibiting inflammation-related pathways, this nanotechnology assisted delivery system polarizes microglia efficiently, providing a reliable strategy in AD treatment.
活化的M1样小胶质细胞诱导的神经炎症是阿尔茨海默病（AD）的关键致病事件。小胶质细胞从促炎的M1表型向抗炎的M2表型极化是一种有前景的策略。为了有效实现这一点，作为M1小胶质细胞活化罪魁祸首的淀粉样β（Aβ）聚集体应该被根除。有趣的是，本研究发现姜黄素分子自组装成无载体姜黄素纳米颗粒（CNPs）与Aβ表现出多价结合，与具有单价作用的游离姜黄素相比，对Aβ聚集具有更高的抑制作用。基于此，开发了负载心磷脂脂质体的CNPs用于有效的小胶质细胞极化。经鼻给药后，脂质体响应AD氧化微环境分解以释放CNPs和心磷脂。CNPs抑制小胶质细胞中Aβ聚集并促进Aβ吞噬/清除，消除小胶质细胞极化的障碍。随后，CNPs被小胶质细胞内吞并抑制小胶质细胞极化的TLR4/NF-κB途径（M1→M2）。同时，心磷脂被确定为信号分子，可使小胶质细胞功能障碍正常化以防止促炎因子释放。在AD转基因小鼠中，治疗后神经炎症、Aβ负担和记忆缺陷得到缓解。通过在细胞外消除Aβ聚集障碍和在细胞内抑制炎症相关途径的联合攻击，这种纳米技术辅助递送系统有效地使小胶质细胞极化，为AD治疗提供了一种可靠的策略。
