A team of researchers at the University of Florida has developed what it says is the world’s first CRISPR system guided by DNA rather than RNA, a breakthrough that could improve the precision, safety, stability, and affordability of gene-editing and diagnostic technologies.
The research, first reported in a 2024 preprint and formally published in Nature Biotechnology, challenges the long-standing CRISPR paradigm by replacing RNA guides with DNA guides to direct CRISPR enzymes toward RNA targets inside cells.
According to the researchers, the approach could enable scientists to better control disease-causing cellular activity without permanently altering DNA. Instead, the technology focuses on RNA, the temporary “working copies” cells use to carry out instructions encoded in DNA.
Piyush Jain, an associate professor and Shah Rising Professor in the department of chemical engineering at the University of Florida and lead author of the study, explained that cells rely on RNA copies of DNA instructions to produce proteins and perform essential biological functions. Errors in those RNA copies can contribute to diseases such as cancer.
Traditional RNA-targeting CRISPR systems typically use RNA guides to locate targets. While effective, those systems can introduce unintended effects and rely on guides that are comparatively expensive and unstable.
The new platform instead uses DNA guides, which researchers say are naturally more durable, easier to manufacture and significantly cheaper than RNA guides. The team also reported that the system reduces unintended off-target effects by orders of magnitude in some cases.
The researchers believe the platform could have broad implications across therapeutics, diagnostics and disease research. Potential applications include early virus detection, precision RNA editing and improved disease monitoring. The team said the technology demonstrated the ability to detect hepatitis C with 100% accuracy while also enabling earlier HIV detection.
The study’s co-first authors included Carlos Orosco, Boyu Huang and Santosh Rananaware, doctoral students and postdoctoral researchers from Jain’s lab.
In collaboration with researchers at University of Texas at Austin, the team also released the structure of its first DNA-guided CRISPR system in a separate preprint published in March 2026.
Researchers are now exploring additional applications, including organ transplantation, where gene-editing systems could potentially repair donor organs outside the body before transplantation into patients.
Federal agencies including the National Institutes of Health, the U.S. Food and Drug Administration and the Advanced Research Projects Agency for Health are supporting broader efforts to accelerate the development and clinical translation of gene-editing technologies.
Jain said the earliest applications for the DNA-guided CRISPR system could emerge within a few years, particularly in ex vivo settings where cells or tissues are modified outside the body before being returned to patients. Wider clinical deployment will require further testing and regulatory approval.
KEY QUOTES:
“Those RNA copies are like Xerox copies of the original manual, and sometimes those copies have errors.”
Piyush Jain, Associate Professor And Shah Rising Professor, University Of Florida
“Existing RNA-targeting CRISPR systems rely on RNA guides to find their targets. While effective, they can sometimes affect unintended molecules, creating off-target effects. They can also be costly and less stable.”
“It gives us a way to fix or tune the instructions the cell is using in real time, without immediately changing the DNA.”
“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.”
“At its core, this is about giving us better control. Not just rewriting the instruction manual but also precisely managing how those instructions are used.”
Piyush Jain, Associate Professor And Shah Rising Professor, University Of Florida
“This project required a great deal of persistence and creativity because we were exploring an idea that challenged conventional thinking. It was a powerful reminder that scientific progress often begins by questioning ideas we take for granted.”
Carlos Orosco, Doctoral Student And Researcher, University Of Florida
