College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China.
Department of Health Products Technical Research and Development Center, Yunnanbaiyao Group Co. Ltd., Kunming, 650500, China.
Adv Mater. 2024 Jan;36(3):e2308393. doi: 10.1002/adma.202308393. Epub 2023 Dec 6.
The abnormal amyloid-β accumulation is essential and obbligato in Alzheimer's disease pathogenesis and natural polyphenols exhibit great potential as amyloid aggregation inhibitors. However, the poor metabolic stability, low bioavailability, and weak blood-brain barrier crossing ability of natural polyphenol molecules fail to meet clinical needs. Here, a universal protocol to prepare natural polyphenolic nanodots is developed by heating in aqueous solution without unacceptable additives. The nanodots are able to not only inhibit amyloid-β fibrillization and trigger the fibril disaggregation, but mitigate the amyloid-β-plaque-induced cascade impairments including normalizing oxidative microenvironment, altering microglial polarization, and rescuing neuronal death and synaptic loss, which results in significant improvements in recognition and cognition deficits in transgenic mice. More importantly, natural polyphenolic nanodots possess stronger antiamyloidogenic performance compared with small molecule, as well as penetrate the blood-brain barrier. The excellent biocompatibility further guarantees the potential of natural polyphenolic nanodots for clinical applications. It is expected that natural polyphenolic nanodots provide an attractive paradigm to support the development of the therapeutics for Alzheimer's disease.
异常淀粉样蛋白-β的积累是阿尔茨海默病发病机制的必要条件和关键因素，天然多酚表现出作为淀粉样蛋白聚集抑制剂的巨大潜力。然而，天然多酚分子的代谢稳定性差、生物利用度低、血脑屏障穿透能力弱，无法满足临床需求。在这里，开发了一种在水溶液中加热而无需使用不可接受的添加剂来制备天然多酚纳米点的通用方案。这些纳米点不仅能够抑制淀粉样蛋白-β的纤维化并引发纤维的解聚，还能够减轻淀粉样蛋白-β斑块诱导的级联损伤，包括使氧化微环境正常化、改变小胶质细胞极化以及挽救神经元死亡和突触丢失，从而导致转基因小鼠的识别和认知缺陷得到显著改善。更重要的是，与小分子相比，天然多酚纳米点具有更强的抗淀粉样蛋白形成性能，并且能够穿透血脑屏障。优异的生物相容性进一步保证了天然多酚纳米点在临床应用中的潜力。预计天然多酚纳米点为阿尔茨海默病治疗药物的开发提供了一个有吸引力的范例。
