Synthetic Disaggregators Enhance Central‐Peripheral Amyloid‐β Clearance in Alzheimer's Disease
Abstract
ABSTRACT Pathogenic amyloid‐β (Aβ) accumulation defines Alzheimer's disease (AD), directly inflicting neuronal damage and driving chronic neuroinflammation. While both central microglia and peripheral macrophages are critical for Aβ clearance, their functional impairment in AD inexorably leads to escalating Aβ burden and disease progression. We here report an in situ engineered synthetic Aβ disaggregator (SAD) delivered to macrophages via neuroprotective DHA‐based lipid nanoparticles (DLNPs). This platform transcends current therapeutic limitations by not only potently dismantling neurotoxic Aβ aggregates but also by fundamentally reprogramming peripheral macrophages to enhance Aβ clearance. Specifically, our results demonstrate that DLNPs effectively reprogram peripheral macrophages to produce and secrete cerebral‐penetrating SAD both in vitro and in vivo. The SAD can promote cerebral Aβ disaggregation, thereby inhibiting neuroinflammatory pathology progression. Moreover, the DLNPs efficiently reprogram the peripheral macrophages to enhance phagocytosis, further facilitating drainage of Aβ and reducing cerebral Aβ accumulation in mouse models. Collectively, these findings uncover a dual‐action mechanism of SAD through the synergistic interplay of direct Aβ disaggregation and enhanced macrophage‐mediated clearance. In sum, our findings establish that the central‐peripheral targeting therapeutic strategy significantly reversed AD pathology, highlighting the therapeutic potential of mRNA‐based in situ fusion protein in AD treatment.
Article Details
Authors (24)
Chunwei Tang
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration 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
Kun Han
Xin Wen
Jing Zhang
Weiyi Sun
Xiao Yue
Lihui Shi
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics School of Pharmaceutical Sciences Department of Neurosurgery Jinan Microecological Biomedicine Shandong Laboratory NMPA Key Laboratory For Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education) Qilu Hospital Cheeloo College of Medicine Shandong University ...
Zejuan Liu
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics School of Pharmaceutical Sciences Department of Neurosurgery Jinan Microecological Biomedicine Shandong Laboratory NMPA Key Laboratory For Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education) Qilu Hospital Cheeloo College of Medicine Shandong University ...
Jianxiong Zhao
Chongzheng Yan
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics School of Pharmaceutical Sciences Department of Neurosurgery Jinan Microecological Biomedicine Shandong Laboratory NMPA Key Laboratory For Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education) Qilu Hospital Cheeloo College of Medicine Shandong University ...
Miaoyan Liu
Zichao Yao
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration 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
Zhichao Kong
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics School of Pharmaceutical Sciences Department of Neurosurgery Jinan Microecological Biomedicine Shandong Laboratory NMPA Key Laboratory For Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education) Qilu Hospital Cheeloo College of Medicine Shandong University ...
Ying Liu
Zhipeng Fu
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration 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
Xiaotian Zhao
Shenyang National Laboratory for Materials Science Institute of Metal Research Chinese Academy of Sciences
Zhenmei Yang
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration 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
Maosen Han
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration 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
Chen Chen
Zhaoquan Xing
Department of Urology Qilu Hospital of Shandong University Jinan Shandong China
Xiaoming Zhou
School of Life Sciences
Fei Yang
Yulin Zhang
Xinyi Jiang
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration 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