Protein-nucleic acid language model-assisted design of precise and compact adenine base editor

Dec 13, 2025Nature communications

Using a protein-DNA language model to design precise and small adenine base editors

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Abstract

The smallest engineered adenine base editor, PNLM-pcABE, shows a 27% size reduction while achieving high editing precision.

  • PNLM-pcABE has a precise 3-nucleotide editing window and reduced off-target events, approaching background levels in HEK293T cells.
  • Compared to the standard ABE8e, PNLM-pcABE demonstrates up to 133.5-fold improvement in precision for correcting pathogenic mutations.
  • In an albino mouse model, nearly 100% of zygotes with the desired base mutation were successfully obtained using PNLM-pcABE.
  • In vivo delivery of PNLM-pcABE with lipid nanoparticles resulted in a substantial decrease in PCSK9 expression in mice.

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Key numbers

133.5×
Precision Improvement
Precision improvement of -pcABE compared to ABE8e.
27%
Size Reduction
Size reduction of -pcABE compared to ABE8e.
100%
Mutation Success Rate
Success rate of desired mutations in albino mouse models via microinjection.

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