A New Breakthrough in mRNA Therapy: Targeting Only the Right Cells
New York, NY — December 15, 2025 — A team from the Icahn School of Medicine at Mount Sinai has unveiled a pioneering mRNA system that activates therapeutic genes only in the intended cell types. Demonstrated in mouse models, this development could pave the way for safer, more precise treatments for cancer and other illnesses by reducing effects on healthy cells.
The technology, named the cell-selective modRNA translation system (cSMRTS), is an engineered mRNA design that begins gene expression within specific cell populations. The researchers reported their findings in the online issue of Molecular Therapy on November 15, 2025. This article underscores a shift in how mRNA therapies can be directed, moving beyond traditional delivery-focused strategies toward an intrinsic selectivity built into the mRNA itself.
The work extends lessons learned from mRNA vaccines for COVID-19, which showed how cells can be tuned to produce beneficial proteins. However, treating cancer requires striking a balance: the therapeutic protein must be produced primarily in tumor cells while minimizing activity in healthy tissue. Existing lipid nanoparticle (LNP) targeting methods often struggle to achieve this level of precision, the scientists note.
Lead author Magdalena M. Żak, PhD, explains, “Our aim was to rethink mRNA therapy from the ground up. Rather than only optimizing where to deliver the mRNA, we redesigned the mRNA so it can decide whether it’s inside a cancer cell or a healthy one. If it detects the wrong cellular environment, it shuts itself off. That built-in decision-making is what sets this approach apart.”
In mouse experiments, cSMRTS was tested in two cancer models. The system functions like an internal on/off switch, responding to distinct patterns of microRNAs—tiny regulators of gene activity—present in cancer cells. This design relies on two separate mRNA components. One encodes Cas6, an RNA-cutting enzyme, and includes a sequence that cancer-related microRNAs can recognize. The other carries the therapeutic gene along with a short RNA hairpin loop that Cas6 can bind and cut.
The cancer-specific microRNAs effectively determine whether the treatment is activated. In cancer cells, these microRNAs bind the Cas6 mRNA and suppress it, allowing the therapeutic gene to be expressed. In healthy cells lacking these microRNAs, Cas6 is produced and cleaves the therapeutic mRNA, preventing unwanted activation.
Systemic delivery using generic lipid nanoparticles yielded striking cell selectivity, including:
- More than 100-fold higher gene activity in breast and colon tumors
- Over 380-fold reduction of activity in major organs such as the liver and spleen
- A 45 percent slowdown of tumor growth when using a tumor-suppressor gene (PTEN)
- Up to 93 percent tumor reduction when paired with mRNA-based immunotherapy
The researchers emphasize the flexibility of cSMRTS. Because the system is designed to be cell-selective, it is not limited to a single disease or therapy. In principle, it could be adapted to a broad range of precision medicines, from cancer to inflammatory and metabolic disorders, the team notes. Senior author Lior Zangi, PhD, an Associate Professor of Medicine (Cardiology) and Genetics and Genomic Sciences, highlights the potential to target specific cells or organs without triggering off-target gene expression, even with delivery methods that avoid invasive procedures.
By shifting the emphasis from delivery vehicles to the mRNA payload itself, this approach aims to reduce toxicity and expand the therapeutic reach of mRNA medicines. For patients, this could translate into more targeted and better-tolerated cancer treatments, with the possibility of applying the approach to other diseases in the future.
The Mount Sinai team has filed patent applications and is moving toward preclinical development and commercialization.
The paper is titled “A tumor-selective mRNA system enables precision cancer treatment.” The listed authors are Magdalena M. Żak, Jimeen Yoo, Alberto Utrero-Rico, Wencke Walter, Gayatri Mainkar, Matthew Adjmi, Ann Anu Kurian, Ashikur Rahaman, Daniel Lozano Ojalvo, Jordi Ochando, Torsten Haferlach, Ramon E. Parsons, Filip K. Swirski, and Lior Zangi. Funding came from a NantRNA-sponsored research agreement and NIH grants R01 HL142768-01 and R01 HL149137-01.
About Mount Sinai and Its Research Community
The Icahn School of Medicine at Mount Sinai is recognized worldwide for its research, education, and clinical care. It is the standalone academic partner for the Mount Sinai Health System’s seven member hospitals, a network that serves New York City’s diverse population. The school offers MD, PhD, MD-PhD, and master’s programs, hosting one of the largest graduate medical education programs in the country and supporting a robust community of researchers, clinicians, and educators.
Mount Sinai’s engagement with innovation extends through Mount Sinai Innovation Partners (MSIP), which helps translate discoveries into real-world therapies. The health system emphasizes translational research, safe and effective treatments, and patient-centered care across New York and beyond.
