Shao Lijuan, Zhang Yi, Yang Zhenmei, Shi Chongdeng, Yue Xiao, Li Caiping, Liu Ying, Fu Zhipeng, Tang Chunwei, Zhao Xiaotian, Han Maosen, Zhang Jing, Sun Weiyi, Yao Zichao, Xi Kaiyan, Fang Zezheng, Wang Zixu, Feng Fan, Ma Chunhong, Zhao Kun, Zhang Yulin, Ni Shilei, Jiang Xinyi, Chen Chen
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Cultural West Road, Shandong Province, China.
The Model Animal Research Center, Shandong University, Wenhua Xi Road, Jinan, Shandong, China.
Sci Adv. 2025 Jul 11;11(28):eads6613. doi: 10.1126/sciadv.ads6613. Epub 2025 Jul 9.
Monoclonal antibody immunotherapy targeting the clearance of amyloid-β (Aβ) has shown promise in Alzheimer's disease (AD). However, current antibody treatments trigger Fc receptors and induce proinflammatory responses, in turn exacerbating neuronal damage. Here, we report a synthetic efferocytic receptor (SER) integrating Aβ-targeting scFv, efferocytosis receptor backbone based on TIM4 and downstream signal for microglia (MG) reprogramming, which enabled selective elimination of Aβ without inducing an inflammatory response. Specifically, our in-house-customized MG-editing mRNA lipid nanoparticles (MERLINs) efficiently introduced SER mRNA into MG to generate Aβ-specific SER-MG in situ. SER-MG exhibited robust Aβ-specific phagocytosis and stimulated anti-inflammatory efferocytosis typical signaling in vitro. In a mouse model of AD, SER expression in the MG markedly increased the clearance of Aβ and dampened inflammation, resulting in improved behavioral outcomes along with substantially reduced synapse elimination. Our findings establish that AD-associated aberrant MG can be in situ reprogrammed with SER for Aβ clearance in an anti-inflammatory manner, with broad application in other inflammation-related diseases.
靶向清除淀粉样β蛋白（Aβ）的单克隆抗体免疫疗法在阿尔茨海默病（AD）治疗中显示出前景。然而，目前的抗体治疗会触发Fc受体并诱导促炎反应，进而加剧神经元损伤。在此，我们报告了一种合成的胞葬作用受体（SER），它整合了靶向Aβ的单链抗体片段（scFv）、基于TIM4的胞葬作用受体骨架以及用于小胶质细胞（MG）重编程的下游信号，能够选择性清除Aβ而不诱导炎症反应。具体而言，我们内部定制的MG编辑mRNA脂质纳米颗粒（MERLINs）有效地将SER mRNA导入MG，以原位生成Aβ特异性的SER-MG。SER-MG在体外表现出强大的Aβ特异性吞噬作用，并刺激典型的抗炎胞葬作用信号。在AD小鼠模型中，MG中SER的表达显著增加了Aβ的清除并减轻了炎症，导致行为结果改善，同时突触消除也大幅减少。我们的研究结果表明，与AD相关的异常MG可以通过SER进行原位重编程，以抗炎方式清除Aβ，在其他炎症相关疾病中具有广泛应用。
