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Review
. 2025 Mar;24(3):209-230.
doi: 10.1038/s41573-024-01086-0. Epub 2024 Dec 17.

Chemical engineering of CRISPR-Cas systems for therapeutic application

Halle M Barber #  1 , Adrian A Pater #  2 , Keith T Gagnon  3 , Masad J Damha  4 , Daniel O'Reilly  5   6
Affiliations
Review

Chemical engineering of CRISPR-Cas systems for therapeutic application

Halle M Barber et al. Nat Rev Drug Discov. 2025 Mar.

Abstract

Clustered regularly interspaced short palindromic repeats (CRISPR) technology has transformed molecular biology and the future of gene-targeted therapeutics. CRISPR systems comprise a CRISPR-associated (Cas) endonuclease and a guide RNA (gRNA) that can be programmed to guide sequence-specific binding, cleavage, or modification of complementary DNA or RNA. However, the application of CRISPR-based therapeutics is challenged by factors such as molecular size, prokaryotic or phage origins, and an essential gRNA cofactor requirement, which impact efficacy, delivery and safety. This Review focuses on chemical modification and engineering approaches for gRNAs to enhance or enable CRISPR-based therapeutics, emphasizing Cas9 and Cas12a as therapeutic paradigms. Issues that chemically modified gRNAs seek to address, including drug delivery, physiological stability, editing efficiency and off-target effects, as well as challenges that remain, are discussed.

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Conflict of interest statement

Competing interests: There are no competing interests to declare.

References

    1. Porteus, M. H. A new class of medicines through DNA editing. N. Engl. J. Med. 380, 947–959 (2019). - PubMed
    1. Taylor, D. W. The final cut: Cas9 editing. Nat. Struct. Mol. Biol. 26, 669–670 (2019). - PubMed
    1. Qi, L. S. et al. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152, 1173–1183 (2013). - PubMed - PMC
    1. Fernández, A., Josa, S. & Montoliu, L. A history of genome editing in mammals. Mamm. Genome 28, 237–246 (2017). - PubMed
    1. Wiedenheft, B., Sternberg, S. H. & Doudna, J. A. RNA-guided genetic silencing systems in bacteria and archaea. Nature 482, 331–338 (2012). - PubMed

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