2. Academic Validation
  3. Anti-CLEC7A nanobody in situ engineering promotes amyloid-β oligomers clearance by CAR-microglia to alleviate Alzheimer's disease pathology in mice

Anti-CLEC7A nanobody in situ engineering promotes amyloid-β oligomers clearance by CAR-microglia to alleviate Alzheimer's disease pathology in mice

  • J Control Release. 2026 Apr 10:392:114710. doi: 10.1016/j.jconrel.2026.114710.
Chongzheng Yan 1,  Zhichao Kong 2,  Yuxue Pan 1,  Zhipeng Fu 2,  Kun Han 2,  Xiaotian Zhao 2,  Jing Zhang 2,  Longyu Bo 2,  Weiyi Sun 2,  Jinxin Gao 2,  Xianghui Dong 2,  Zuolin Zheng 2,  Xiao Yue 2,  Peng Sun 3,  Xinyi Jiang 4,  Chen Chen 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China.
  • 2 Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, 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 250012, China.
  • 3 School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China. Electronic address: [email protected].
  • 4 School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China; Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, 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 250012, China. Electronic address: [email protected].
  • 5 Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, 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 250012, China. Electronic address: [email protected].
PMID: 41702507 DOI: 10.1016/j.jconrel.2026.114710
Abstract

Chimeric antigen receptor microglia (CAR-M)-mediated Amyloid-β oligomers (AβO) phagocytosis shows great promise in Alzheimer's disease (AD) treatment, however, the limited AβO degradation of CAR-M compromises their anti-AβO potency. This work here reports an in situ engineered agonistic anti-C-type lectin domain containing 7 A (CLEC7A) nanobody to accelerate AβO degradation of CAR-M, augmenting their anti-AβO efficacy. Specifically, with the intranasal-delivered microglia-targeting lipid nanoparticles (LNP), this work generates an AβO-specific degradation-potentiated CAR-M by introducing dual mRNAs encoding AβO-specific CAR and anti-CLEC7A nanobody into the cerebral microglia. These data show that these engineered CAR-M exhibited superior phagocytic function and promoted intracellular AβO degradation via activating CLEC7A-spleen tyrosine kinase (Syk) signaling pathway through the local secretion of anti-CLEC7A nanobody. In the APP/PS1 mouse model of AD, these in situ reprogrammed CAR-M significantly reduced cerebral Aβ levels, suppressed neuroinflammation, and restored cognitive function. In sum, these findings demonstrate that potentiating AβO degradation within CAR-M effectively alleviates AD pathology, providing a promising therapeutic strategy for AD with broad application in Other neurodegenerative diseases.

Keywords

Alzheimer's disease; Amyloid-β oligomers; Anti-CLEC7A nanobody; Chimeric antigen receptor microglia; Lipid nanoparticle.

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