Engineered Sdd7 cytosine base editors with enhanced specificity

Hye-Yeon Hwang (), Minyoung Lee, Hwalin Yi, Cheong Seok, Kayeong Lim, Yi Rang Na, Jong-Sun Kang, Jae-Hyun Park and Daesik Kim ()
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Hye-Yeon Hwang: Sungkyunkwan University School of Medicine
Minyoung Lee: Sungkyunkwan University School of Medicine
Hwalin Yi: Sungkyunkwan University School of Medicine
Cheong Seok: Sungkyunkwan University School of Medicine
Kayeong Lim: Korea Institute of Science and Technology (KIST)
Yi Rang Na: Seoul National University Hospital
Jong-Sun Kang: Sungkyunkwan University School of Medicine
Jae-Hyun Park: Sungkyunkwan University School of Medicine
Daesik Kim: Sungkyunkwan University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Cytosine base editors (CBEs) revolutionize genome editing by enabling precise C-to-T conversions without double-strand breaks. Sdd7, a recently developed cytosine deaminase, exhibits high activity across a broad protospacer range but induces unintended off-target effects, including bystander mutations within and upstream of the protospacer and both gRNA-dependent and independent deamination. Here, we report that BE4max and Sdd7 induce bystander editing upstream of the protospacer. To overcome this, we engineer two Sdd7 variants, Sdd7e1 and Sdd7e2, enhancing specificity while preserving on-target efficiency. These variants display reduced bystander editing, narrowed editing windows, and significantly lower off-target activity. Delivery as ribonucleoproteins via engineered virus-like particles (eVLPs) further improves specificity, nearly eliminating bystander edits and increasing precise single-point mutations. Our findings establish Sdd7e1 and Sdd7e2, especially when delivered via eVLP, as high-fidelity CBEs poised for safe, precise therapeutic genome editing.

Date: 2025
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DOI: 10.1038/s41467-025-60789-z

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