CRISPR-Cas12a (Cpf1) proteins, which are RNA-guided DNA targeting enzymes, exhibit a novel, target-activated non-specific single-stranded DNA (ssDNA) cleavage activity. This activity, catalyzed by the same active site responsible for site-specific double-stranded DNA (dsDNA) cutting, is also observed in other type V CRISPR-Cas12 enzymes. The activation of ssDNA cutting requires precise recognition of a DNA target sequence complementary to the 20-nucleotide guide RNA sequence. The researchers developed a method called DNA Endonuclease Targeted CRISPR Trans Reporter (DETECTR), which combines target-dependent Cas12a ssDNase activation with isothermal amplification, achieving attomolar sensitivity for nucleic acid detection. DETECTR enables rapid and specific detection of human papillomavirus (HPV) in patient samples, providing a simple platform for nucleic acid-based, point-of-care diagnostics.CRISPR-Cas12a (Cpf1) proteins, which are RNA-guided DNA targeting enzymes, exhibit a novel, target-activated non-specific single-stranded DNA (ssDNA) cleavage activity. This activity, catalyzed by the same active site responsible for site-specific double-stranded DNA (dsDNA) cutting, is also observed in other type V CRISPR-Cas12 enzymes. The activation of ssDNA cutting requires precise recognition of a DNA target sequence complementary to the 20-nucleotide guide RNA sequence. The researchers developed a method called DNA Endonuclease Targeted CRISPR Trans Reporter (DETECTR), which combines target-dependent Cas12a ssDNase activation with isothermal amplification, achieving attomolar sensitivity for nucleic acid detection. DETECTR enables rapid and specific detection of human papillomavirus (HPV) in patient samples, providing a simple platform for nucleic acid-based, point-of-care diagnostics.