A team reported a DNA-guided CRISPR–Cas12a system that reprograms Cas12a into an RNA-targeting effector using DNA as the guide input. In the described SLEUTH approach, synthetic DNA engages Cas12a to form a deoxyribonucleoprotein complex while RNA is used as the programmable target. The work presents structural, biophysical, and biochemical evidence supporting an activation pathway distinct from canonical RNA-guided systems. Reported capabilities include direct RNA detection and efficient intracellular RNA knockdown. For diagnostics and therapeutics, a DNA-guided architecture could expand programmability and modularity for RNA detection and RNA-interference modalities—especially where guide formats, delivery, or timing constraints differ from standard crRNA-based systems.