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DNA foldings provide variant possibilities to develop DNAzymes with remarkable catalytic performance. In spite of fruitful reports on G-quadruplex DNAzymes, four-stranded cytosine-rich i-motifs have not been explored as the potential skeletons of DNAzymes. In this work, we developed a visible light-driven DNAzyme based on human telomeric i-motifs using a natural photosensitizer of hypericin (Hyp) as the cofactor and dissolved oxygen as the oxidant source. The i-motif folding in acidic solution caused the distal thymine overhangs at the 3' a