University of Florida researchers reported a new CRISPR approach in Nature Biotechnology that uses DNA—not RNA—to guide Cas12 nucleases to cellular RNA targets. The platform, called ΨDNA, uses a DNA-based guide scaffold engineered to mimic the crRNA architecture, enabling Cas12a and Cas12i1 to bind RNA and trigger activity via single-stranded DNA trans-cleavage. The team framed the work as a conceptual shift in controlling transcriptomes without the instability challenges seen in RNA-guided systems. In clinical-sample testing, the system achieved 100% accurate hepatitis C virus RNA detection (as reported by the authors). In human cell line experiments, ΨDNA delivered 70–95% knockdown of endogenous transcripts, with mechanistic drivers including ribosome stalling and RNase H1 recruitment.