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. 2026 Feb 4;34(2):1066-1083.
doi: 10.1016/j.ymthe.2025.11.015. Epub 2025 Nov 15.

A tumor-selective mRNA system enables precision cancer treatment

Magdalena M Żak  1 , Jimeen Yoo  1 , Alberto Utrero-Rico  2 , Wencke Walter  3 , Gayatri Mainkar  1 , Matthew Adjmi  1 , Ann Anu Kurian  1 , Ashikur Rahaman  2 , Daniel Lozano Ojalvo  4 , Jordi Ochando  2 , Torsten Haferlach  3 , Ramon E Parsons  5 , Filip K Swirski  6 , Lior Zangi  7
Affiliations

A tumor-selective mRNA system enables precision cancer treatment

Magdalena M Żak et al. Mol Ther. .

Abstract

mRNA has revolutionized vaccine development, demonstrating high efficacy and safety in COVID-19 vaccines, and is now being explored for broader therapeutic applications. However, while vaccines rely on widespread antigen expression, many therapeutic strategies-particularly in oncology-require precise, cell-selective gene expression. Here, we present the selective modified RNA translation system (SMRTS), a versatile, engineered mRNA system that enables targeted gene expression in specific cell populations. As a proof of concept, we developed cancer-specific variants, bcSMRTS and ccSMRTS, for breast and colon cancer, respectively. 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. Beyond oncology, SMRTS introduces a novel mRNA tool, providing a versatile system for cell-selective gene expression. By expanding the mRNA therapeutics toolbox, SMRTS paves the way for precise mRNA-based interventions across a wide range of disease settings.

Keywords: mRNA therapeutics; precision anticancer therapy; targeted mRNA therapeutics.

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Conflict of interest statement

Declaration of interests L.Z. and M.M.Ż. 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 herein.

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