Zhuo, Y., Lu, Y., Zhu, Y., Wen, N., Zou, G., Lu, H., Pei, X., Zhang, Y., Zhang, Q., Wang, X. and Zhang, W., 2025. Targeted clearance of extracellular Tau using aptamer-armed monocytes alleviates neuroinflammation in mice with Alzheimer’s disease. Nature Biomedical Engineering, pp.1-15.

Targeted clearance of extracellular Tau using aptamer-armed monocytes alleviates neuroinflammation in mice with Alzheimer’s disease

Abstract
Extracellular Tau determines the progression of Alzheimer’s disease, yet therapeutic strategies targeting it are hindered by poor brain delivery and limited clearance. Here we developed a Tau-clearing cell therapy based on monocytes functionalized with a high-affinity Tau-specific aptamer. The aptamer was covalently conjugated to the surface of monocytes (derived from bone marrow leucocytes and cultured under monocyte-inducing conditions) via bioorthogonal chemistry without affecting their viability or function. Upon intravenous administration in mice expressing mutant and disease-relevant human Tau, the engineered monocytes actively crossed the blood–brain barrier and accumulated in Tau-rich brain regions such as the hippocampus and striatum. They efficiently phagocytosed extracellular Tau, leading to a significant reduction in Tau burden. As a result, glial activation was suppressed, neuroinflammation was alleviated, and neuronal and mitochondrial integrity was preserved. Long-term treatment improved memory and spatial learning, without inducing toxicity or behavioural side effects. These results demonstrate that aptamer-guided monocytes can achieve targeted delivery, effective clearance and sustained neuroprotection, offering a promising strategy for therapeutic intervention in Alzheimer’s disease.

摘要
细胞外 tau 蛋白（Tau）是阿尔茨海默病进展的决定性因素，然而针对该蛋白的治疗策略却因脑部递送效率低、清除能力有限而受阻。本研究基于单核细胞开发了一种 tau 蛋白清除细胞疗法，该疗法通过高亲和力 tau 蛋白特异性适配体（aptamer）对单核细胞进行功能化修饰。
研究人员采用生物正交化学技术，将适配体共价偶联至单核细胞（来源于骨髓白细胞，在单核细胞诱导条件下培养获得）表面，且该修饰过程不会影响单核细胞的活性或功能。在表达突变型、且与疾病相关的人 tau 蛋白的小鼠中进行静脉注射后，经工程化改造的单核细胞可主动穿过血脑屏障，并在海马体、纹状体等 tau 蛋白富集的脑区聚集。
这些工程化单核细胞能高效吞噬细胞外 tau 蛋白，显著降低 tau 蛋白负荷。其结果表现为：胶质细胞活化受到抑制，神经炎症得到缓解，神经元及线粒体完整性得以维持。长期治疗可改善小鼠的记忆能力与空间学习能力，且未引发毒性反应或行为学副作用。
上述研究结果表明，适配体引导的单核细胞能够实现靶向递送、高效清除（tau 蛋白）及持续性神经保护，为阿尔茨海默病的治疗干预提供了一种具有潜力的新策略。

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