“Kill Switch” CRISPR Variant Shreds the DNA of Diseased Cells

CRISPR is best known as a gene editing technology, but a newly discovered CRISPR system offers a way to kill diseased cells—by ripping their DNA apart. 

 

The Cas12a2-based technology can target harmful cancer or virus-infected cells while leaving healthy cells untouched, offering promise for treating various diseases. 

A new kind of CRISPR 

“Most CRISPR enzymes, such as Cas9, are designed to make a precise cut at a specific DNA sequence to edit genes,” Dr. Yang Liu, an assistant professor at the University of Utah and one of the senior authors of the new work, told Technology Networks. “In contrast, Cas12a2 acts more like a molecular ‘kill switch’.” 

Like other CRISPR-Cas systems, Cas12a2 targets a specific nucleic acid sequence. However, once it recognizes its target RNA, Cas12a2 is activated and starts causing extensive DNA damage, leading to cell death. If CRISPR/Cas9 acts like a precisely controlled pair of scissors, CRISPR/Cas12a2 acts like a paper shredder.

 

By using a target RNA sequence that is only present in diseased cells, the researchers can harness the destructive power of Cas12a2 for good. 

“Cas12a2 combines this potent DNA-damaging and cell-killing activity with very high specificity,” explained Liu. “It can distinguish even single-nucleotide differences, allowing it to selectively target cancer cells carrying specific mutations or cells infected with viral sequences, while sparing healthy cells.” 

Using Cas12a2 to destroy cancer cells 

Diseased cells often contain unique RNA molecules.  

“In cancer, these molecules can be mutant RNAs or virally infected RNAs that promote tumor growth,” said Liu. “We programmed Cas12a2 with guide RNAs designed to recognize these disease-specific RNA sequences.” 

KRAS is one of the most frequently mutated oncogenes. With a single gene mutation, the K-Ras protein becomes stuck in its “on” conformation, triggering uncontrolled tumor growth. 

This single gene mutation, G12C, offered Liu and his team an opportunity to employ Cas12a2 against cancer cells. 

Firstly, they identified a guide RNA (gRNA) candidate that targets the KRAS^G12C transcript. Then, in cell lines that overexpressed either wild-type KRAS or the KRAS^G12C transcript, they introduced Cas12a2 equipped with the gRNA. 

Cas12a2 depleted the KRAS^G12C –expressing cell line by 62% and didn’t measurably deplete the wild-type KRAS-expressing cell line.  

In cancer cells that naturally harbor the KRAS G12C mutation, Cas12a2 with the same gRNA reduced cell growth by 50%. 

 

The researchers then asked whether KRAS^G12C –targeting Cas12a2 could complement the existing treatment strategy for KRAS-mutated cancers. Treatment with sotorasib alone depleted cancer cells by 65%, but the addition of KRAS^G12C –targeting Cas12a2 increased this to 85%.  For cells that had acquired resistance to sotorasib, KRAS^G12C –targeting Cas12a2 reduced growth by over 50%. 

The Cas12a2 approach worked about as well as established anticancer drugs in these tests, but unlike chemotherapeutics, Cas12a2 doesn’t affect healthy cells, which could translate to a reduction in side effects. 

Cas12a2 kills cells infected with HPV 

Liu and his collaborators also investigated whether Cas12a2 could eliminate cells that harbor high-risk strains of human papillomavirus (HPV), which have been linked to cancer. 

As the viral transcripts are only present in infected cells, this offered numerous targets for gRNAs. Using gRNAs targeting HPV transcripts encoding oncogenic E6 or E7 proteins led to robust Cas12a2 activation in HPV-infected cells, reducing cell numbers by 94%.  

Importantly, cells that didn’t contain HPV were unaffected by the Cas12a2 treatment. 

“Of course, any therapeutic application will still require extensive validation to ensure that each guide design avoids unintended activity in healthy tissues,” said Liu. 

Beyond KRAS and HPV 

The programmable nature of Cas12a2 means it could be used against many types of RNA targets to tackle different diseases. 

“Like Cas9, Cas12a2 can be easily reprogrammed to target virtually any RNA sequence of interest in diseased cells simply by changing the guide RNA,” explained Liu. “In that sense, it is a highly adaptable platform, as long as we can identify RNA sequences that are unique to the harmful cells and absent from healthy ones.” 

As many diseases alter RNA expression, the potential applications of Cas12a2 are broad. 

“Beyond cancer and infectious disease, there may also be opportunities in blood and neurodegenerative disorders if specific pathogenic cell populations can be defined by distinct RNA signatures,” noted Liu. 

Towards human therapies 

There is still a way to go before Cas12a2 can be used in humans. As the majority of research on Cas12a2 has been performed in vitro, questions remain surrounding its potential off-target effects in whole systems. 

“Although Cas12a2 can be highly specific, especially when targeting unique mutant or viral RNAs, we still need to carefully test and ensure it does not unintentionally damage healthy cells or tissues,” Liu explained. “We also need a much deeper understanding of how cells respond to Cas12a2 activation, including any possible immune responses.” 

Like other CRISPR-based therapeutics, Cas12a2 faces a major hurdle in its deliverability to target cells. “One of the biggest challenges is delivery,” said Liu. “We need efficient and safe ways to deliver the Cas12a2 system into cells inside the body.” 

Extensive preclinical studies to assess safety and specificity in both animal models and patient samples will also be needed before Cas12a2 makes its way to the clinic. 

Despite the long road to in-human therapies, Liu and his team are optimistic about the possibilities that Cas12a2 offers. “Cas12a2-mediated cell elimination represents a unique and important entry into the CRISPR–Cas toolbox,” they say in the paper.

 

Reference: Scholz P, Thompson J, Crosby KT, et al. RNA-triggered cell killing with CRISPR–Cas12a2. Nature. 2026. doi: 10.1038/s41586-026-10466-y 

 

About the interviewee: 

Dr. Yang Liu is an assistant professor in the Department of Biochemistry at the University of Utah and an investigator at the Huntsman Cancer Institute. He received his PhD in chemistry from Emory University and completed postdoctoral training at Johns Hopkins University and the Howard Hughes Medical Institute. His laboratory develops innovative CRISPR technologies and high-resolution live-cell imaging approaches to investigate how cells detect, signal, and repair DNA damage with high spatial and temporal precision. Liu is recognized for pioneering very fast CRISPR systems for studying DNA repair dynamics and RNA-triggered Cas12a2 technologies for selective elimination of diseased cells.