Nature biotechnologyMay 21, 2026

AI-driven improvements to lab-evolved enzymes boost prime editing

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

Updated Jun 28, 2026

Abstract

Essence

AI-guided redesign of prime editor reverse transcriptases improved stability, expression, and prime editing efficiency across ex vivo systems and in mice.

Evidence

Protein-engineering and preclinical genome-editing study redesigning reverse transcriptase domains with structure-informed AI, then testing edited constructs in human primary cells, multiple delivery modalities, and mice.

Caveat

This is platform and preclinical evidence, so stronger editing performance does not by itself establish therapeutic safety or effectiveness in humans.

Simplified

Although protein engineering and laboratory evolution have been used to optimize prime editors, we show that previous changes that improve prime editor efficiency also compromise protein stability and expression level, limiting performance. To address these limitations, we apply structure-informed artificial intelligence-guided methods such as the inverse-folding network ProteinMPNN to redesign the reverse transcriptase (RT) domains of engineered and evolved prime editors while preserving regions essential for catalysis. Redesigned RTs are extensively mutated, with 30-163 amino acid substitutions, and exhibit enhanced folding stability and soluble expression and up to twofold higher intracellular prime editor protein levels following mRNA delivery. Redesigned PE8 prime editors demonstrate enhanced editing efficiencies across multiple ex vivo contexts, including in several human primary cell types and via several delivery modalities. In mice, editing efficiency is up to 2.9-fold higher than that of state-of-the-art PE6, PE7 and PEmax prime editors. These findings demonstrate a generalizable approach for augmenting laboratory evolution to improve genome editing agents.

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CRISPR Gene EditingIssue #38

AI-redesigned gene editors boost efficiency 2.9-fold in mice

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AI-driven improvements to lab-evolved enzymes boost prime editing

Abstract

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