A tumor-selective mRNA system enables precision cancer treatment.

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.