For years, scientists have steered CRISPR enzymes toward their targets using RNA guides. Engineers at the University of Florida have now flipped that approach. Their newly published system uses DNA as the guide molecule instead—a switch that they say sharpens precision, lowers cost, and could broaden the technology's reach in both research and the clinic.
The work first appeared as a 2024 preprint and is now formally published in Nature Biotechnology. The team describes it as the first CRISPR platform built around DNA guidance, breaking from a long-standing convention.
The shift is rooted in a basic feature of cell biology. While DNA carries the original genetic blueprint, cells operate from RNA—essentially working copies—when manufacturing proteins. Sometimes those copies are flawed, and in conditions such as cancer, faulty or excessive RNA messages can drive runaway cell growth.
"Those RNA copies are like Xerox copies of the original manual, and sometimes those copies have errors," said Piyush Jain, the study's lead author.
Most current CRISPR applications make permanent edits to DNA itself. Newer tools have moved toward editing or silencing RNA, sidestepping permanent changes to the genome. But the RNA-guided versions of these tools carry drawbacks.
"Existing RNA-targeting CRISPR systems rely on RNA guides to find their targets," Jain said. "While effective, they can sometimes affect unintended molecules, creating off-target effects. They can also be costly and less stable."
By substituting DNA for RNA in the guide role, the UF system locks onto its intended RNA target with substantially fewer errors—improving precision by orders of magnitude in some cases, the authors report. The platform was also able to flag HIV at an early stage and to identify hepatitis C with 100% accuracy in their tests.
"It gives us a way to fix or tune the instructions the cell is using in real time, without immediately changing the DNA," Jain said. He added that DNA guides "are far cheaper and easier to manufacture than RNA guides, and they are far more stable. While RNA molecules degrade quickly, DNA can remain intact for long periods."
The group is now exploring uses outside the body, such as repairing donor organs prior to transplant. Jain estimates that early, highly targeted applications could emerge within a few years.
The work first appeared as a 2024 preprint and is now formally published in Nature Biotechnology. The team describes it as the first CRISPR platform built around DNA guidance, breaking from a long-standing convention.
The shift is rooted in a basic feature of cell biology. While DNA carries the original genetic blueprint, cells operate from RNA—essentially working copies—when manufacturing proteins. Sometimes those copies are flawed, and in conditions such as cancer, faulty or excessive RNA messages can drive runaway cell growth.
"Those RNA copies are like Xerox copies of the original manual, and sometimes those copies have errors," said Piyush Jain, the study's lead author.
Most current CRISPR applications make permanent edits to DNA itself. Newer tools have moved toward editing or silencing RNA, sidestepping permanent changes to the genome. But the RNA-guided versions of these tools carry drawbacks.
"Existing RNA-targeting CRISPR systems rely on RNA guides to find their targets," Jain said. "While effective, they can sometimes affect unintended molecules, creating off-target effects. They can also be costly and less stable."
By substituting DNA for RNA in the guide role, the UF system locks onto its intended RNA target with substantially fewer errors—improving precision by orders of magnitude in some cases, the authors report. The platform was also able to flag HIV at an early stage and to identify hepatitis C with 100% accuracy in their tests.
"It gives us a way to fix or tune the instructions the cell is using in real time, without immediately changing the DNA," Jain said. He added that DNA guides "are far cheaper and easier to manufacture than RNA guides, and they are far more stable. While RNA molecules degrade quickly, DNA can remain intact for long periods."
The group is now exploring uses outside the body, such as repairing donor organs prior to transplant. Jain estimates that early, highly targeted applications could emerge within a few years.