17 Dec Icahn Mount Sinai Scientists Engineer mRNA to Selectively Target Cancer Cells
Dr. Zak
MedicalResearch.com Interview with:
Magdalena M. Żak, PhD
Zangi Lab
Instructor | Cardiovascular Research Institute
Instructor | Genetics & Genomic Sciences
Icahn School of Medicine at Mount Sinai
Hess Center for Science and Medicine
New York, NY 10029
MedicalResearch.com: What is the background for this study?
Response: mRNA has proven to be a groundbreaking technology through COVID-19 vaccines, and most mRNA-based therapeutics in development today are still focused on vaccines. However, in principle, mRNA could be used for many diseases in which expression of a therapeutic protein would be beneficial. A major reason mRNA is less commonly used outside of vaccines is the lack of robust targeting: for vaccination, broad expression can be acceptable because the goal is antigen production for immune recognition, but for other applications – especially cancer – targeted delivery and minimized off-target expression are critical to reduce side effects. Current targeting strategies largely rely on lipid nanoparticles (LNPs), which act as lipid “carriers” for systemic delivery. Although LNPs can be designed to show some tissue tropism, this is often limited to organs such as the liver, spleen, and lungs.
MedicalResearch.com: What are the main findings?
Response: In this study, we instead focused on engineering the mRNA itself so that expression of the therapeutic protein is preferentially activated in the desired target cells. We developed a cell-Selective mRNA Translation System (cSMRTS) and tested it in two cancer models. Following systemic administration, cSMRTS achieved a >114-fold increase in tumor-selective gene expression and a >380-fold reduction in off-target expression, including in the liver and spleen. Functionally, using cSMRTS to deliver the tumor suppressor gene Pten inhibited tumor growth by 45%, and combining cSMRTS with mRNA-based immunotherapy reduced tumor size by 93%.
MedicalResearch.com: Does the cSMRTS need to make microRNAs specifically for each patient’s tumor or could a more generalized therapeutic be developed?
Response: That’s a very interesting question. Indeed, we are planning to perform wide-ranging analyses of microRNA profiles from various tumors to answer whether cSMRTS could exist as an off-the-shelf, ready-to-use product for multiple cancer types (in case we find recurring microRNA patterns among tumors of the same class), or whether we would develop cSMRTS toward patient-tailored applications. Importantly, this kind of patient-specific customization is clinically realistic, as illustrated by patient-tailored mRNA-based anticancer vaccines currently in clinical trials by BioNTech and Moderna.
MedicalResearch.com: What should readers take away from your report?
Response: The most important takeaway is that mRNA can be targeted, and that the cSMRTS system is highly adaptable to meet a wide range of therapeutic goals.
MedicalResearch.com: What recommendations do you have for future research as a results of this study?
Response: Having demonstrated that cSMRTS is versatile and can be tailored to different cancer types, the same principle could be applied to any condition in which cell-selective delivery of therapeutic genes would be beneficial – for example, cardiovascular or metabolic diseases, and currently underserved autoimmune disorders. I believe mRNA is driving a major shift in modern medicine, and I hope the cSMRTS system will help deliver solutions for patients, especially in diseases that require complex biologics whose availability remains severely limited worldwide, largely due to cost. Because mRNA can be a highly cost-efficient technology, I believe it has the potential to enable more equitable global access to advanced therapies.
Any disclosures? Magdalena M. Żak and Lior Zangi are inventors on provisional patent applications “Regulatory System for Expression of a Gene of Interest in a Target Cell and Methods of Use Thereof” and “System for Gene Expression in Colon Cancer Cells and Method of Use Thereof,” which cover the results described in the publication.
Citation: Żak MM, Yoo J, Utrero-Rico A, Walter W, Mainkar G, Adjmi M, Kurian AA, Rahaman A, Ojalvo DL, Ochando J, Haferlach T, Parsons RE, Swirski FK, Zangi L. A tumor-selective mRNA system enables precision cancer treatment. Mol Ther. 2025 Nov 15:S1525-0016(25)00954-2. doi: 10.1016/j.ymthe.2025.11.015. Epub ahead of print. PMID: 41243282. https://pubmed.ncbi.nlm.nih.gov/41243282/
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Last Updated on December 17, 2025 by Marie Benz MD FAAD