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Tumor-selective protein translation of mRNA drugs for targeted tumor therapy

ABSTRACT: mRNA-based therapies necessitate precise, specific, and patient-friendly control of therapeutic protein translation to ensure treatment safety and efficacy. However, achieving tumor-specific mRNA translation regulation remains a significant challenge. Herein, we developed an mRNA 2’-OH cloaking reagent, CR-3, enabling tumor-specific regulation of mRNA translation. CR-3 can efficiently and effectively block the translational capacity of mRNA. Within tumor cells exhibiting high expression of NAD(P)H quinone dehydrogenase 1 (NQO1), the translational ability of this mRNA can be almost fully restored. The translational efficiency of cloaked mRNA in tumor cells is more than 100-fold greater than that in normal cells. Additionally, 2’-OH cloaking enhances the stability and half-life of mRNA, resulting in a 49% increase in target protein production. The cloaked apoptogenic protein BAX mRNA achieved tumor cell-specific clearance, and mitigated systemic toxicity in both subcutaneous xenograft mouse model and chemically induced mouse model of hepatocellular carcinoma, in contrast to conventional non-cloaked BAX mRNA. This approach may pave the way for the development of safe, convenient, and responsive tumor-targeted mRNA therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE337438 | GEO | 2026/07/07

REPOSITORIES: GEO

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Project description:The eukaryotic translation initiation factor (eIF) 3a is described in various tumor entities as potential tumor marker involved in development and progression of cancer. eIF3a is the largest subunit of the eIF3 complex, a key functional entity in 80S establishment and translation initiation. We hypothesize that eIF3a is more a specific than global translation initiator and involved in signalling pathways that are frequently targeted in UBC therapy. Methods: In FFPE samples of UBC patients eIF3a expression was analysed together with overall survival. In cell culture we investigated proliferation, migration, clonogenicity and tumorgenicity of UBC cell lines with and without knockdown of eIF3a and compared the cytotoxicity of eIF3a knockdown with other translational inhibitors, including the chemotherapeutic Rapamycine. Detailed information on changed gene expression and global translation initiation were gathered by mRNA expresssion and polysomal profiling. Results: and Conclusion eIF3a is upregulated in UBC and high expression of eIF3a corresponds with longer overall survival in low grade tumors. Knockdown of eIF3a in UBC cell lines reduces their malignant phenotype, including reduced tumor growth in xenotransplanted mice. eIF3a regulates DNA damage response (ATM, ATR, CDC25A) on a translational level and we show that reduction in eIF3a expression does not hamper global translation initiation. The knockdown of eIF3a strongly influences proliferation of UBC cell lines without dramatically disturbing general translation as depicted in polysomal profiles. We therefore analysed potential changes on the mRNA level in eIF3a knockdown compared to control HT1197 cells. Differential expression of genes between eIF3a knock-down and control samples was assessed with the moderated t-test (Bioconductor's limma package). Raw p-values were adjusted for multiple hypothesis testing using the method from Benjamini and Hochberg for a strong control of the false discovery rate.

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Tumor-selective protein translation of mRNA drugs for targeted tumor therapy

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