CRISPRa Lipid Nanocomplex‐Mediated Mt3 Targeting Enhances Astrocytic Endocytosis of Amyloid‐β in an Alzheimer's Disease Mouse Model
Metallothionein 3 (Mt3) is crucial for cellular homeostasis and neuroprotection, with accumulating evidence linking it to amyloid-beta (Aβ) clearance by astrocytes. This study developed a CRISPR activator (CRISPRa) system using lipid nanoparticles to selectively upregulate Mt3 in astrocytes, aiming to enhance Aβ endocytosis in an Alzheimer's disease (AD) mouse model. To directly assess the therapeutic potential of Mt3 activation in a specific brain region, stereotaxic injection is utilized to deliver the CRISPRa lipid nanocomplexes. This approach enabled precise in vivo brain delivery and Mt3 activation. The findings reveal that CRISPRa lipid nanocomplex-mediated Mt3 upregulation significantly boosts Aβ uptake by astrocytes, leading to a marked reduction in Aβ plaque accumulation in AD mouse brains. These results highlight CRISPRa lipid nanocomplex-mediated Mt3 targeting as a promising strategy to enhance endogenous Aβ clearance, presenting a novel therapeutic avenue for AD.
Authors
- Jin Tae Hong (ORCID: https://orcid.org/0000-0002-6534-9575)
- Jung-Eun Park (ORCID: https://orcid.org/0000-0002-0423-6147)
- Moonsu Park
- Seok‐Beom Yong (ORCID: https://orcid.org/0000-0003-1783-3802)
- Chun‐Woong Park (ORCID: https://orcid.org/0000-0001-5329-8443)
- B.-G. Kim (ORCID: https://orcid.org/0009-0001-6479-3105)
- H. Ryu (ORCID: https://orcid.org/0009-0005-5111-4918)
- Sang‐Bae Han (ORCID: https://orcid.org/0000-0001-6656-6523)
- Hyerin Yu (ORCID: https://orcid.org/0000-0001-7222-5004)
- Key‐Hwan Lim (ORCID: https://orcid.org/0000-0002-3636-379X)
- Megan V. Ha (ORCID: https://orcid.org/0000-0001-6948-2667)
- Hanseul Park (ORCID: https://orcid.org/0000-0002-8182-8963)
- Yoon‐Seok Roh
- Sung Soo Park (ORCID: https://orcid.org/0000-0002-1779-8683)
Institutions
- Chungbuk National University (KR)
- Korea Research Institute of Bioscience and Biotechnology (KR)
- Jeonbuk National University (KR)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-12-12
- DOI
- https://doi.org/10.1002/advs.202503725
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Research Foundation
- Chungbuk National University
- National Research Foundation of Korea
- Ministry of Science and ICT, South Korea