University of Florida researchers developed ΨDNA, a CRISPR system that uses a DNA guide scaffold to direct Cas12 nucleases to RNA targets, expanding the CRISPR toolkit beyond RNA-guided approaches. The study, published in Nature Biotechnology, describes DNA-guided CRISPR–Cas12 for cellular RNA targeting. The platform is designed to reprogram Cas12 activity to recognize and act on RNA through DNA-based guidance, addressing perceived limitations of RNA guides around stability and off-target effects. In human cell line experiments, ΨDNA reported knockdown of endogenous RNA transcripts in the 70% to 95% range, supported by mechanistic evidence including ribosome stalling and RNase H1 recruitment. The authors also report 100% accurate hepatitis C virus RNA detection in clinical samples. If validated broadly, DNA-guided guidance could offer a practical alternative for RNA therapeutics and diagnostics, potentially improving delivery and reducing variability compared with standard RNA guide requirements.