NeuronOct 13, 2026

A gene delivery system for studying immune cells in the brain across different species

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 14, 2026

Abstract

The optimized AAV platform achieves greater than 90% microglial specificity in multiple mouse brain regions following direct intracranial delivery.

An integrated AAV platform was developed that enhances microglial targeting through a combination of specific regulatory elements and optimized delivery methods.
The platform enables robust, long-lasting expression of transgenes specifically in microglia, including in an Alzheimer's disease model.
Doxorubicin-assisted delivery facilitates efficient and selective microglial targeting in rats, rhesus macaques, and human brain slices.
Codon optimization allows for the expression of complex functional payloads, supporting applications such as calcium imaging and genome editing.

Simplified

Targeting microglia with adeno-associated viruses (AAVs) remains challenging because of inefficient transduction, off-target expression, and inconsistent payload performance. Here, we develop an integrated, Cre-independent AAV platform that combines a compact 446-bp microglia-specific regulatory element (MSRE), a high-yield AAV2/9.m capsid, microRNA-mediated neuronal de-targeting, and a microglia-tailored codon-optimization strategy. Following direct intracranial delivery, the optimized vector achieves robust, long-lasting transgene expression with greater than 90% microglial specificity across multiple mouse brain regions, including in an Alzheimer's disease model. With doxorubicin-assisted delivery, the platform also enables efficient and selective microglial targeting in rats, rhesus macaques, and human ex vivo brain slices. Codon optimization supports the expression of otherwise challenging functional payloads, enabling calcium imaging, chemogenetic manipulation, and CRISPR-Cas9-mediated genome editing. This cross-species toolkit provides a versatile resource for investigating microglial biology and developing microglia-directed therapeutic strategies.

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A gene delivery system for studying immune cells in the brain across different species

Abstract

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