A Nanoformulation-Mediated Multifunctional Stem Cell Therapy with Improved Beta-Amyloid Clearance and Neural Regeneration for Alzheimer's Disease
A Nanoformulation-Mediated Multifunctional Stem Cell Therapy with Improved Beta-Amyloid Clearance and Neural Regeneration for Alzheimer's Disease
复制标题
纳米制剂介导的多功能干细胞疗法可改善阿尔茨海默病的β-淀粉样蛋白清除和神经再生
DOI：
10.1002/adma.202006357
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发表时间：
2021-02-24
影响因子：
29.4
通讯作者：
Wang, Qiangbin
中科院分区：
文献类型：
--
作者：
Huang, Dehua;Cao, Yuheng;Wang, Qiangbin
阿尔茨海默病（AD）是一种常见的痴呆症，目前无法治愈。现有的治疗只能适度缓解AD的症状，以减缓其进展。如何实现有效的神经再生以改善认知障碍是当前AD治疗的主要挑战。在此，在鼠模型中研究了能够同时进行A β清除和神经再生的纳米制剂介导的神经干细胞（NSC）疗法的治疗潜力。开发了能够稳定和连续表达脑啡肽酶（NEP）的基因工程化NSC以增强脑中的A β降解和NSC存活。合成具有高基因/药物递送能力的PBAE-PLGA-Ag 2S-RA-siSOX 9（PPAR-siSOX 9）纳米制剂以克服AD微环境相关的不良作用并促进表达NEP的NSC的神经元分化。为了实现精确的立体定向移植，基于Ag 2 S量子点的荧光成像用于真实的实时指导NSC移植。这种策略显示出许多好处，包括有效和持久的A β降解，改善神经再生和准确的细胞移植。结果表明，单次给予该疗法在记忆逆转和改善学习缺陷方面实现了长期疗效（6个月）。
Alzheimer's disease (AD) is a common dementia that is currently incurable. The existing treatments can only moderately relieve the symptoms of AD to slow down its progress. How to achieve effective neural regeneration to ameliorate cognitive impairments is a major challenge for current AD treatment. Here, the therapeutic potential of a nanoformulation-mediated neural stem cell (NSC) therapy capable of simultaneous A beta clearance and neural regeneration is investigated in a murine model. Genetically engineered NSCs capable of stably and continuously expressing neprilysin (NEP) are developed to enhance A beta degradation and NSC survival in the brain. A PBAE-PLGA-Ag2S-RA-siSOX9 (PPAR-siSOX9) nanoformulation with high gene/drug deliverability is synthesized to overcome AD microenvironment-associated adverse effects and to promote neuronal differentiation of the NEP-expressing NSCs. For achieving accurate stereotactic transplantation, Ag2S quantum-dot-based fluorescence imaging is used to guide NSC transplantation in real time. This strategy shows numerous benefits, including efficient and long-lasting A beta degradation, improved neural regeneration, and accurate cell transplantation. It is shown that a single administration of this therapy achieves long-term efficacy (6 months) with respect to memory reversal and improvement of learning deficits.