Nature communicationsAug 13, 2026

Cellular factors that influence how well nonviral genome editing works, found using a large-scale CRISPR screen

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Aug 15, 2026

Abstract

Depletion of certain genes can increase genome editing efficiency by up to six-fold.

A genome-wide CRISPR screening platform was developed to link 19,114 gene perturbations to genome editing outcomes in human cells.
Six negative regulators of delivery were identified, which when depleted, enhance editing efficiency across various contexts.
Specific gene knockdowns, particularly of GJB2 and BET1L, significantly improved base-editing outcomes in different human models.
In a model of retinal channelopathy, knocking down either gene increased lipid nanoparticle base editing efficiency by over 3.5-fold.
These findings suggest that targeting cellular factors may represent a viable strategy to improve the effectiveness of genetic therapies.

Simplified

To systematically map cellular factors constraining nonviral genome editing, influencing uptake and intracellular trafficking, we develop a genome-wide CRISPR screening platform linking perturbation of 19,114 genes to editing outcomes in human cells. We identify six negative regulators of delivery whose depletion increases editing efficiency by up to six-fold across diverse payloads, loci, and cell types. We test the top two factors, GJB2 and BET1L, in two distinct human models: correction of a pathogenic adenine base mutation in KCNJ13 and introduction of a cytosine base mutation in the GABA_A receptor gene. Depletion of either improves base-editing outcomes by 6-fold, potentially through effects on delivery. In a patient-derived model of retinal channelopathy, knockdown of either gene improves lipid nanoparticle base editing efficiency by over 3.5-fold. This enables functional restoration of Kir7.1 ion channels in a subset of edited cells, highlighting cellular barriers as actionable targets to enhance the potency of genetic therapies.

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Cellular factors that influence how well nonviral genome editing works, found using a large-scale CRISPR screen

Abstract

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