Over the past decades CRISPR, short for “clustered regularly interspaced short palindromic repeats”, has become somewhat of a household name, holding the promise of directly addressing genetic mutations by effectively removing, silencing, or even fixing them. Yet the original purpose of CRISPR is slightly less cute and cuddly: the evolutionary origin of these DNA sequences is that of a core component of the prokaryotic immune system.In most medical applications today we only try to use CRISPR to detect sequences and then apply enzymes such as the well-known Cas9 to cut DNA at specific locations in the process of gene-editing. In a recent study (paywalled, bioRxiv pre-print) by Jingkun Zheng et al. in Nature such benign enzymes are dropped for Cas12a2, which turns a detection event into the release of a DNA-destroy enzyme as the molecular equivalent of a guided missile.The pitched use case here is the detection of cancer-cell specific mutations in the DNA, following which the tumor cells will be instantly shredded from the inside. This could theoretically provide a cure for many cancer types, but should we expect to see this kind of therapy approved any time soon?The Original CRISPRCRISPR-based immunity overview. (Credit: Guido4, Wikimedia)What we call CRISPR is quite literally what the name says: clustered occurrences of repeats with spacers made of genetic code fragments in the prokaryotic DNA. These can be considered to be the memory of the prokaryotic immune system, with genetic sequences from e.g. invasive viruses and bacteriophages embedded in the organism’s own DNA as these spacers.In prokaryotic organisms like bacteria these CRISPR arrays are accompanied by multiple CRISPR-associated systems (CAS, or Cas): genes that are translated into proteins which are associated with these CRISPR arrays. Of these, CRISPR-associated protein 9 (Cas9) is a protein that that performs double-strand DNA cutting action when provided with a transcribed RNA copy (crRNA) of the CRISPR spacer in question after it has been attached to a protospacer adjacent motif (PAM). This PAM ensures that the original sequence in the CRISPR locus is not attacked.Directly attacking the genetic material of an intruder in this manner is somewhat more aggressive than the comparable system eukaryotes called RNA interference. This merely silences target mRNA genes, which incidentally is a problem with mRNA-based vaccines and thus require a special coating of the mRNA particles.Cas12a2Although we could conceivably use Cas9 for an anti-cancer therapy as well by damaging the DNA with a double-strand DNA break and pray it’s enough, the Cas12a protein lineage offers us an even more suitable protein, since it’s less complex and yet much more versatile than Cas9. The first step remains the same, with a transcription of the target RNA fragment containing the mutated gene’s signature with PAM used to track down any affected cells in the patient’s body.Abortive infection strategy compared with uncontained infection in bacterial colony. (Credit: Lopatina et al., Annu Rev Virol. 2020)The variant of Cas12a that has received a lot of attention lately is Cas12a2, which as Oleg Dmytrenko et al. reported in 2023 induces cell death. This effectively means that the infected bacteria commits suicide if it detects via Cas12a2 that it has become infected, destroying itself before it can be used by e.g. a bacteriophage to replicate itself and infect the rest of the colony.How Cas12a2 exactly achieves the shredding of the host cell’s DNA is elucidated in a 2026 study by Paul Scholz et al. in Nature. The simple version is that rather than performing a targeted cut of double-stranded DNA (dsDNA), Cas12a2 continues making cuts to the host’s dsDNA and chromatin until said cell enters apoptosis.Crucial here in the context of using Cas12a2 for cancer treatments is that it accurately recognizes the crRNA sequence and does not have a high off-target activation rate. In this study by Scholz et al. in human cells they found minimal off-target activation. This finding makes sense in that bacteria wouldn’t want to needlessly self-terminate due to a Cas12a2 nuclease having a bad day.TP53With the above background information we can now understand the June 2026 study by Jingkun Zeng et al., with the most interesting aspect of their study being the chosen target gene for an anti-cancer treatment. This being the tumor protein 53 (TP53) gene, also known as p53.This particular gene is a regulatory transcription factor that is classified as a tumor-suppressing gene. It does this through multiple mechanisms, including:Activating DNA repair proteins in case of DNA damage.Halting the cell cycle upon damage to allow for repairs.Initiating apoptosis if the damage is too severe.Pushing cells into senescence once the telomeres have become too short.It’s known that this particular gene is mutated in a variety of ways in about half of all analyzed cancers, making it a solid target once you know the specific mutation via a biopsy or such method. In this study an in-vivo study was also performed using mice models featuring lung tumors.In-vivo anti-tumor test. (Credit: Jingkun Zeng et al. 2026, Nature)By using the same liquid nanoparticles (LNPs) encapsulation method referenced earlier for e.g. SARS-CoV-2 mRNA vaccines, the Cas12a2 protein was encoded as mRNA and injected into the mice, with the designed target on TP53 packaged alongside it in the LNP. Theoretically the LNPs would deliver the mRNA to the cells, whose cellular machinery would then assemble the Cas12a2 protein, following which the targeting information would then allow the protein to scan and assess the cell for the particular TP53 mutation.Not Quite Prime TimeFew things are easy or straightforward in medical sciences, with this being sadly no exception. Although in the in-vivo experiment the mouse tumors got suppressed compared to the controls – indicating that the Cas12a2 mRNA and tagging payload were being delivered and working – the ultimate effect was more suppressive than curative.Especially for advanced tumors the lung tumor burden wasn’t noticeably reduced, which could be due to a variety of reasons. For this reason this study should probably be treated as yet another step forward in what could one day become another very effective anti-cancer treatment, right along with e.g. immunotherapy.Perhaps the biggest take-away here is that within the realm of molecular biology there are many fascinating constructs and mechanisms that are just waiting for us to discover and use them, whether it is to cure diseases or to fix genetic defects including very lethal ones.