Researchers at the Icahn School of Medicine at Mount Sinai built an mRNA system that switches on therapeutic genes preferentially in targeted cells for greater precision and safety. Credit: Mount Sinai Health System

Researchers at the Icahn School of Medicine at Mount Sinai have developed a first-of-its-kind mRNA system that switches on therapeutic genes preferentially inside targeted cells—an advance demonstrated in studies in mice that could lay the groundwork for safer, more precise treatments for cancer and other diseases.

The system, called the cell-selective modRNA translation system (cSMRTS), is an engineered form of mRNA designed to activate in specific cell populations. The findings were reported in the November 15 online issue of Molecular Therapy.

The approach builds on lessons from mRNA COVID-19 vaccines, which showed how cells can be turned into "protein factories" to produce helpful molecules. But unlike vaccines—where it doesn’t matter which cells produce the protein—treating cancer often requires hitting only tumor cells and sparing healthy ones. That level of precision has been difficult to achieve using current lipid nanoparticle (LNP) targeting technologies, say the investigators.

How the cSMRTS system works

"Our goal was to rethink how mRNA therapies work. Right now, so much effort goes into trying to deliver mRNA to the right place, and even then you get a lot of off-target effects," says first author Magdalena M. Żak, Ph.D., Instructor in the Cardiovascular Research Institute and the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai.

"We wondered whether we could shift the burden from the delivery vehicle to the mRNA itself. So we engineered the mRNA to recognize whether it’s inside a cancer cell or a healthy one. If it senses that it’s in the wrong environment, it simply shuts off. That built-in decision-making is what makes this technology different."

In the mouse studies, the researchers tested cSMRTS in two cancer models. The system acts like a built-in on/off switch that responds to the distinct patterns of microRNAs found in cancer cells. (MicroRNAs are tiny molecules that help control gene activity.)

The system uses two pieces of mRNA. One carries instructions for making Cas6, an enzyme that can cut RNA, and includes a spot that is recognized by cancer-related microRNAs. The other carries the therapeutic gene along with a short RNA loop ("hairpin") that Cas6 can recognize and cut.

This setup lets the cancer-related microRNAs decide whether the treatment turns on. In cancer cells, these microRNAs attach to the Cas6 mRNA and shut it down, allowing the therapeutic gene to turn on. In healthy cells, where these microRNAs are missing, Cas6 is made and cuts the therapeutic mRNA, preventing the treatment from turning on in the wrong cells.

Results and future potential

When delivered systemically in generic lipid nanoparticles, the platform showed striking selectivity:

• More than 100-fold higher gene activity in breast and colon tumors
• Over 380-fold lower activity in main organs including liver and spleen
• 45% reduction in tumor growth using a tumor-suppressor gene (Pten)
• Up to 93% tumor reduction when combined with mRNA-based immunotherapy

"What’s exciting about this system is how flexible it is. 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," says senior author Lior Zangi, Ph.D., Associate Professor of Medicine (Cardiology), and Genetics and Genomic Sciences, at the Icahn School of Medicine.

"As someone who has studied mRNA therapeutics in cardiovascular settings for over 15 years and relied on direct intracardiac injections for delivery, I’m particularly intrigued by the potential of this technology to safely target specific cells or organs without unwanted gene expression, using delivery methods that don’t require invasive procedures."

Current nanoparticle approaches limit most mRNA therapies to vaccines. By engineering the mRNA payload itself to be selective, the researchers hope that cSMRTS introduces a new strategy for reducing toxicity and expanding mRNA’s therapeutic reach. For patients, this could eventually mean access to more targeted, better-tolerated cancer treatments, with the long-term potential to adapt the technology to other diseases as well, say the researchers.

The team has filed patent applications and is now working toward commercialization and preclinical development.

More information: Magdalena M. Żak et al, A tumor-selective mRNA system enables precision cancer treatment, Molecular Therapy (2025). DOI: 10.1016/j.ymthe.2025.11.015

Citation: Scientists develop a smarter mRNA therapy that knows which cells to target (2025, December 15) retrieved 15 December 2025 from https://phys.org/news/2025-12-scientists-smarter-mrna-therapy-cells.html

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