The journal of gene medicineMay 10, 2026

Designing and Improving CRISPR-Cas9 Delivery Methods for Precise Gene Editing

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated May 11, 2026

Abstract

Viral vectors, such as adeno-associated viruses (AAVs) and lentiviruses (LVs), show high transduction efficiency and blood-brain barrier permeability for gene editing in Alzheimer's disease.

CRISPR-Cas9 may offer a potential therapeutic strategy for genetic disorders, including neurodegenerative diseases like Alzheimer's disease.
The blood-brain barrier poses challenges to the delivery of gene editing components in the brain.
Adeno-associated viruses (AAVs) are favored due to their low immunogenicity and ability to provide sustained gene expression without integration risks.
Lentiviruses (LVs) can carry larger genetic material but raise concerns about genomic integration and potential cancer risk.
Nonviral vectors and physical delivery methods require further optimization for effective use in living organisms.
Preclinical studies indicate that these delivery systems may successfully edit genes and offer therapeutic benefits, though challenges such as off-target effects remain.

Simplified

The CRISPR-Cas9 genome-editing technique offers a promising therapeutic strategy for genetic disorders, including neurodegenerative diseases like Alzheimer's disease (AD), characterised by inherited susceptibility and progressive cognitive decline, as well as other hallmarks such as amyloid beta (Aβ) plaques and neurofibril tangles (NFTs). However, the blood-brain barrier (BBB) poses a significant challenge to the effectiveness of gene editing components in the affected brain region and impedes clinical translation. This comprehensive review compares various CRISPR-Cas9 delivery vectors, viral, nonviral and physical, with a focus on their efficacy in neurological diseases such as AD. Viral vectors viz., adeno-associated viruses (AAVs) and lentiviruses (LVs) demonstrate high transduction efficiency and BBB permeability. AAVs are preferred for their low immunogenicity, minimal toxicity, high neuronal tropism and episomal persistence, enabling sustained expression without insertional mutagenesis. LVs offer larger genetic payloads but raise concerns about genomic integration and potential oncogenesis, though integration-defective variants mitigate these risks. Nonviral vectors, including peptide and polymer-based nanoparticles, lipid nanoparticles (LNPs) and Inorganic carriers such as gold and silver nanoparticles, are less immunogenic and easier to handle but require further optimisation for in vivo BBB crossing and endosomal escape. Physical methods such as electroporation and microinjection are suitable for in vitro/ex vivo use, while novel CNS-targeted strategies, such as RVG-tagged particles, TfR-directed LNPs and engineered AAV variants, enhance brain penetration via receptor-mediated transcytosis. These preclinical studies show that these technologies can successfully edit genes and provide therapeutic benefits, including amyloid reduction and cognitive improvement in AD models. Yet off-target effects, immune responses and regulatory hurdles persist. Overall, continuous innovation in delivery vector design and safety profile-targeting strategies is crucial for advancing CRISPR-Cas9 towards clinical therapies for AD-based therapies and related neurological disorders. 1-42

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Designing and Improving CRISPR-Cas9 Delivery Methods for Precise Gene Editing

Abstract

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