IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-60789-z.html
   My bibliography  Save this article

Engineered Sdd7 cytosine base editors with enhanced specificity

Author

Listed:
  • 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
    Seoul National University Hospital
    Seoul National University College of Medicine)

  • Jong-Sun Kang

    (Sungkyunkwan University School of Medicine)

  • Jae-Hyun Park

    (Sungkyunkwan University School of Medicine)

  • Daesik Kim

    (Sungkyunkwan University School of Medicine
    Sungkyunkwan University)

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.

Suggested Citation

  • Hye-Yeon Hwang & Minyoung Lee & Hwalin Yi & Cheong Seok & Kayeong Lim & Yi Rang Na & Jong-Sun Kang & Jae-Hyun Park & Daesik Kim, 2025. "Engineered Sdd7 cytosine base editors with enhanced specificity," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60789-z
    DOI: 10.1038/s41467-025-60789-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-60789-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-60789-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60789-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.