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.