Model selection in preclinical nucleic acid therapeutics research

Journal article : Review

Nucleic acid therapeutics (NATs) are a maturing drug class with many active clinical trials and a growing number of approvals. For NATs such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), a major hurdle during the research and development phase lies in selecting preclinical model systems with meaningful readouts on molecular and phenotypic efficacy. Key questions include: Which in vitro models are best positioned to quantify NAT activity and identify hits? In advancing a NAT from in vitro to in vivo studies, when is it appropriate to employ a surrogate or humanize a target locus; conversely, when is it appropriate to rely solely on human-derived cells? In this review, we will introduce and critique current approaches to ASO and siRNA preclinical efficacy studies and consider future advances in this fast-moving therapeutic area.

Authors: Oliver, PL; Hill, AC

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Communications Biology
• Volume: 9
• Issue: 1
• Article number: 200
• Publication date: 2026-02-09
• Acceptance date: 2026-01-27
• DOI: 10.1038/s42003-026-09650-7
• EISSN: 2399-3642
• ISSN: 2399-3642
• Language: English
• Subtype: Review