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 Aβ 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 Aβ 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 Aβ 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.

中文翻译：

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一种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

阿尔茨海默病 (AD) 是一种常见的痴呆症，目前无法治愈。现有的治疗方法只能适度缓解 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治疗的一大挑战。在这里，在小鼠模型中研究了能够同时清除 Aβ 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。开发出能够稳定和持续表达脑啡肽酶 (NEP) 的基因工程 NSC，以增强大脑中的 Aβ 降解和 NSC 存活。PBAE-PLGA-Ag ₂合成具有高基因/药物递送能力的 S-RA-siSOX9 (PPAR-siSOX9) 纳米制剂，以克服 AD 微环境相关的不利影响并促进表达 NEP 的神经干细胞的神经元分化。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实时指导NSC移植。该策略显示出许多好处，包括高效且持久的 Aβ 降解、改善神经再生和准确的细胞移植。结果表明，单次给药该疗法可在记忆逆转和改善学习缺陷方面取得长期疗效（6 个月）。