Messenger RNA (mRNA) has already transformed medicine, most notably through COVID‑19 vaccines that taught cells to act as “protein factories” producing protective molecules. But while vaccines succeed without needing to control which cells make the protein, cancer therapies demand far greater precision: the treatment must hit tumor cells while sparing healthy tissue. Achieving that selectivity has been a major challenge with current lipid nanoparticle (LNP) delivery systems.
A new study titled “A tumor-selective mRNA system enables precision cancer treatment,” and published in Molecular Therapy, introduces a breakthrough approach building on lessons from mRNA vaccines. Researchers developed the selective modified RNA translation system (SMRTS), an engineered form of mRNA designed to activate therapeutic genes in certain cell populations. In proof‑of‑concept experiments in mice, the team created cancer‑specific variants—bcSMRTS for breast cancer and ccSMRTS for colon cancer—that demonstrated striking selectivity.
“Our goal was to rethink how mRNA therapies work,” explained first author Magdalena M. Żak, PhD. “So much effort goes into trying to deliver mRNA to the right place, and even then, you get a lot of off‑target effects.” Żak, an instructor in the Cardiovascular Research Institute and the department of genetics and genomic sciences, added, “We wondered whether we could shift the burden from the delivery vehicle to the mRNA itself. We engineered the mRNA to recognize whether it’s inside a cancer cell or a healthy one. If it senses the wrong environment, it simply shuts off. That built‑in decision‑making is what makes this technology different.”
The system uses two pieces of mRNA. One encodes Cas6, an RNA‑cutting enzyme, and includes a site recognized by cancer‑related microRNAs. The other carries the therapeutic gene along with a short RNA loop (“hairpin”) that Cas6 can cut. In cancer cells, microRNAs attach to the Cas6 mRNA and silence it, allowing the therapeutic gene to turn on. In healthy cells, where those microRNAs are absent, Cas6 is produced and cuts the therapeutic mRNA, preventing unwanted activation. This design effectively gives the therapy an internal on/off switch controlled by the molecular environment of the cell.
The results from mouse models were striking. “Systemic delivery of lipid nanoparticle (LNP)-encapsulated SMRTS constructs yielded a 114‑fold and 141‑fold increase in tumor‑specific expression in 4T1 and MC‑38 models, respectively, while reducing off‑target expression by over 380‑fold. Therapeutic deployment of Pten ccSMRTS suppressed tumor growth by 45%, and combination with modRNA‑derived anti‑checkpoint inhibitor antibodies (modRNabs) resulted in up to 93% tumor inhibition,” the authors wrote. These findings underscore the system’s ability to achieve high selectivity, activating therapeutic genes in tumors while sharply limiting activity in healthy organs such as the liver and spleen. The study highlights how SMRTS could overcome one of the biggest hurdles in mRNA therapeutics—off‑target toxicity—by engineering selectivity directly into the payload rather than relying solely on delivery vehicles.
“What’s exciting about this system is how flexible it is,” said senior author Lior Zangi, PhD, associate professor of medicine, and genetics and genomic sciences. “Because it’s designed to be cell‑selective, it’s not tied to just one disease or one type of therapy. In principle, this platform could be adapted to many different precision medicines, from cancer to inflammatory and metabolic conditions. I’m particularly intrigued by the potential of this technology to safely target specific cells or organs…without invasive procedures.”
By expanding the mRNA toolbox, SMRTS represents a new potential frontier in translational medicine. While most mRNA therapies today are limited to vaccines, this approach may open the door to safer, more precise treatments across a wide range of diseases.
