A team of engineers at the University of Florida has developed a new form of CRISPR technology that could make diagnostics and treatments safer, more precise and more affordable, while opening the door to entirely new ways of controlling disease.
First reported in a 2024 preprint and now formally published this week in Nature Biotechnology , the work establishes the world's first system that uses DNA, rather than RNA, to guide CRISPR enzymes to its target, overturning the long-standing paradigm.
To understand why that matters, it helps to think of how cells work.
Inside every cell is DNA, the body's master instruction manual. But cells don't use that original blueprint directly. Instead, they make working copies, or RNA, that carry instructions to build proteins and carry out functions.
"Those RNA copies are like Xerox copies of the original manual, and sometimes those copies have errors," said Piyush Jain, an associate professor and the Shah Rising Professor in the department of chemical engineering at UF and the study's lead author.
Those errors can have serious consequences. In diseases such as cancer, cells can produce too many faulty copies or follow incorrect instructions, leading to uncontrolled growth or other problems.
For years, scientists have used CRISPR to target and cut genetic material, often focusing on making permanent changes to DNA itself. More recently, researchers have developed tools to target RNA, what Jain called the working copies, offering a way to intervene without altering the underlying genetic code.
But those approaches come with tradeoffs, he said.
"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."
The new system takes a different approach.
Instead of using RNA as a guide, the team engineered CRISPR to use DNA, which is naturally more stable and easier to produce. This allows the system to more precisely identify and act on specific RNA molecules inside the cell.
In practical terms, that means scientists can focus on correcting or controlling the "Xerox copies" without disturbing the original blueprint.
"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.
That added level of control could be important for patient safety. By targeting RNA first, scientists may be able to reduce harmful activity, like disease-causing signals, before deciding whether permanent genetic edits are necessary.
The team also found that their system drastically reduces unintended effects compared with existing approaches, improving precision by orders of magnitude in some cases.
Beyond precision, the new technology could also lower costs.
"DNA guides are far cheaper and easier to manufacture than RNA guides, and they are far more stable," Jain said. "While RNA molecules degrade quickly, DNA can remain intact for long periods."
Together, those advantages could make CRISPR-based tools more accessible for both research and clinical use. The breakthrough tool simplifies clinical diagnostics by catching viruses like HIV early and detecting hepatitis C with 100% accuracy.
The study's co-first authors are doctoral students and postdoctoral researchers from Jain's lab: Carlos Orosco, Boyu Huang and Santosh Rananaware.
"This project required a great deal of persistence and creativity because we were exploring an idea that challenged conventional thinking," Orosco said. "It was a powerful reminder that scientific progress often begins by questioning ideas we take for granted."
Looking ahead, the researchers see potential applications ranging from more precise therapies to improved diagnostics and new ways to study how diseases develop.
In parallel, the team is exploring how similar technologies could be used in areas such as organ transplantation where gene-editing tools might help repair donor organs outside the body before they are transplanted into patients.
While the new DNA-guided CRISPR system is still in early stages, federal agencies, including the National Institutes of Health , the Federal Drug Administration and the Advanced Research Agencies for Health are all pushing development and translation of these tools to the clinic.
Jain estimates that early, highly targeted applications could emerge within a few years, particularly in settings where cells or tissues are treated outside the body. Broader clinical use will require additional testing and regulatory approval.
For now, the breakthrough represents a shift in how scientists think about CRISPR itself.
After decades of research and tens of thousands of published studies built around RNA-guided CRISPR systems, this work introduces a fundamentally new way to direct one of biology's most powerful tools.
"At its core, this is about giving us better control," Jain said. "Not just rewriting the instruction manual but also precisely managing how those instructions are used."
