# CRISPRa Lipid Nanocomplex‐Mediated Mt3 Targeting Enhances Astrocytic Endocytosis of Amyloid‐β in an Alzheimer's Disease Mouse Model

## TL;DR

This study shows that using CRISPRa lipid nanocomplexes to boost Mt3 in astrocytes improves amyloid-beta clearance in a mouse model of Alzheimer's disease.

## Contribution

A novel CRISPRa lipid nanocomplex approach for targeted Mt3 upregulation in astrocytes is introduced for Alzheimer's therapy.

## Key findings

- CRISPRa lipid nanocomplexes significantly enhance astrocytic amyloid-beta uptake.
- Mt3 upregulation reduces amyloid-beta plaque accumulation in Alzheimer's mouse brains.
- The method enables precise in vivo brain delivery and gene activation.

## Abstract

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.

GeTe exhibits intrinsically high carrier concentrations that limit its thermoelectric performance. Herein, CuAgSe alloying synergistically tunes the band structure, induces band flattening and valence‐band convergence, promotes Cu‐ion delocalization, and generates multiscale hierarchical structures to suppress phonon transport. This coordinated modulation of electrical and thermal properties synergistically enhances the thermoelectric performance of GeTe‐based materials.