Song Xiaolei, Wang Chenchen, Ding Qin, Li Peng, Sun Shihao, Wei Wei, Zhang Juan, Sun Rongli, Yin Lihong, Liu Songqin, Pu Yuepu
Key Laboratory of Environmental Medicine Engineering of Ministry of Education, State Key Laboratory of Bioelectronics, Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, School of Public Health, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210009, PR China.
Beijing Life Science Academy, Beijing 102200, PR China.
J Control Release. 2025 Feb 10;378:735-749. doi: 10.1016/j.jconrel.2024.12.060. Epub 2024 Dec 28.
Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. The vicious circle between amyloid-β peptide (Aβ) overgeneration and microglial dysfunction is an important pathological event that promotes AD progression. However, therapeutic strategies toward only Aβ or microglial modulation still have many problems. Herein, inspired by the Aβ transportation, an Aβ-derived peptide (CKLVFFAED) engineered biomimetic nanodelivery system (MK@PC-R NPs) is reported for realizing BBB penetration and reprogram neuron and microglia in AD lesion sites. This hollow mesoporous Prussian blue-based MK@PC-R NPs carrying curcumin and miRNA-124 can down-regulate β secretase expression, thereby inhibiting Aβ production and reducing Aβ-induced neurotoxicity. Meanwhile, MK@PC-R NPs with excellent antioxidant and anti-inflammatory properties could normalize the microglial phenotype and promote Aβ degradation, providing neuroprotection. As expected, after treatment with MK@PC-R NPs, the Aβ burdens, neuron damages, neuroinflammation, and memory deficits of transgenic AD mice (APP/PS1 mice) are significantly attenuated. Overall, this biomimetic nanodelivery system with anti-Aβ and anti-inflammatory properties provides a promising strategy for the multi-target therapy of early AD.
阿尔茨海默病（AD）是一种不可逆的进行性神经退行性疾病。淀粉样β肽（Aβ）过度生成与小胶质细胞功能障碍之间的恶性循环是促进AD进展的重要病理事件。然而，仅针对Aβ或小胶质细胞调节的治疗策略仍存在许多问题。在此，受Aβ转运的启发，报道了一种Aβ衍生肽（CKLVFFAED）工程化仿生纳米递送系统（MK@PC-R NPs），用于实现血脑屏障穿透以及对AD病变部位的神经元和小胶质细胞进行重编程。这种负载姜黄素和miRNA-124的基于中空介孔普鲁士蓝的MK@PC-R NPs可以下调β分泌酶的表达，从而抑制Aβ的产生并降低Aβ诱导的神经毒性。同时，具有优异抗氧化和抗炎特性的MK@PC-R NPs可以使小胶质细胞表型正常化并促进Aβ降解，提供神经保护作用。正如预期的那样，用MK@PC-R NPs治疗后，转基因AD小鼠（APP/PS1小鼠）的Aβ负担、神经元损伤、神经炎症和记忆缺陷均得到显著减轻。总体而言，这种具有抗Aβ和抗炎特性的仿生纳米递送系统为早期AD的多靶点治疗提供了一种有前景的策略。
