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A modular mRNA platform for programmable induction of tumour-specific immunogenic cell death

Nature Nanotechnology volume 20, pages 1856–1870 (2025)Cite this article

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Abstract

Messenger RNA (mRNA) therapeutics hold great promise for oncology but their efficacy is limited by systemic off-target effects and immunosuppressive tumour microenvironments. Here we present TITUR, a tumour-customizable mRNA nanomedicine platform that integrates tumour-customizable ionizable lipids (TIs) and tumour-specific untranslated regions (TURs) to enhance tumour-selective mRNA delivery and expression. This dual-engineered approach enables the precise intratumoural expression of 4HB, an immunogenic cell death-inducing protein, while mitigating systemic toxicities. Using murine models of immunologically cold tumours, including melanoma and triple-negative breast cancer, TITUR-mediated 4HB delivery induced tumour-specific immunogenic cell death, remodelled the tumour microenvironment and enhanced immune cell infiltration. When combined with immune checkpoint inhibitors, 4HB TITUR suppressed primary and metastatic tumour growth, while also exhibiting vaccine-like properties by reducing tumour recurrence and eliciting systemic antitumour immunity. Furthermore, it demonstrated a superior safety profile compared with conventional mRNA delivery methods. Our data indicate that TITUR may serve as a versatile approach to address the limitations of current immunotherapies and support the development of personalized mRNA nanomedicines.

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Fig. 1: 4HB mRNA promotes ICD in vitro with greater potency compared to MLKL mRNA.
Fig. 2: High-throughput combinatorial screening identifies TI-LNPs with enhanced delivery to B16 and 4T1 tumours with reduced off-target delivery to the liver.
Fig. 3: TI-LNPs encapsulating 4HB mRNA inhibit tumour growth and promote an immunologically hot tumour immunophenotype.
Fig. 4: TURs restrict translation to tumours and reduce non-target expression of encoded genes.
Fig. 5: m4HB TITUR in combination with anti-PD-1 leads to a ‘vaccination’ effect in mice, stalling the progression of distal tumours and protecting against tumour recurrence.
Fig. 6: Combination therapy of m4HB TITUR and anti-PD-1 suppresses tumour growth in the 4T1-Fluc liver metastasis model, and CD8+ T cells, macrophages and γδ T cells play key roles in the antitumour response of the m4HB TITUR platform.

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Data availability

The main data supporting the findings of this study are available within this paper and its Supplementary Information. The raw and analysed datasets are too large to readily share publicly but are available for research purposes from the corresponding author on reasonable request. Source data are provided with this paper.

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Acknowledgements

The authors are grateful to the staff at STTARR and ARC at the University Health Network for their assistance with animal work. Special gratitude is extended to L. Radvanyi for providing the 4T1-Fluc cell line, and to J. Hu and P. Zhang for generously providing the reporter T-cell line. This work was supported by the Princess Margaret Cancer Foundation’s Invest in Research Grant, Natural Sciences and Engineering Research Council of Canada (number RGPIN-2023-05124), the Canada Research Chairs Program (number CRC-2022-00575), Canadian Institutes of Health Research (numbers PJH-185722, PJT-190109, PJT-192011, PJT-195669), the Connaught Fund (number 514681), the J. P. Bickell Foundation (number 515159), New Frontiers in Research Fund—Exploration (number NFRFE-2023-00203) and the Canada Foundation for Innovation—John R. Evans Leaders Fund (number 43711).

Author information

Author notes

  1. These authors contributed equally: Songtao Dong, Shannon N. Tsai.

Authors and Affiliations

  1. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

    Songtao Dong, Shannon N. Tsai, Yue Xu, Tiana L. Young, David X. W. Chen, Muye Zhou, Alex Golubovic, Rick X. Z. Lu, Tingzhen He & Bowen Li

  2. Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada

    Fanglin Gong, Nicholas C. Solek, Margarita Savguira, Jingan Chen & Bowen Li

  3. Department of Chemistry, University of Toronto, Toronto, Ontario, Canada

    Lauren Healy & Bowen Li

  4. Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada

    Bell X. Wu, Benjamin H. Lok, Housheng Hansen He & Bowen Li

  5. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Bell X. Wu, Benjamin H. Lok & Housheng Hansen He

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Contributions

S.D., S.N.T. and B.L. conceived the study and designed the experiments. S.D., S.N.T., Y.X., F.G., N.C.S., D.X.W.C., L.H., M.S., M.Z., J.C., A.G., R.X.Z.L., T.L.Y., T.H., B.X.W., B.H.L. and B.L. performed the experiments and data analysis. S.D., S.N.T. and B.L. wrote and edited the paper. H.H.H. and B.L. acquired funding and supervised the project. All authors provided feedback and helped shape the research, data analysis and paper.

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Correspondence to Bowen Li.

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S.D., S.T., H.H.H. and B.L. have filed an invention disclosure for the TITUR platform. The other authors declare no competing interests.

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Nature Nanotechnology thanks Guideng Li and Michael Mitchell for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Tumour customized UTRs (TURs) improves therapeutic outcomes and of 4HB mRNA in B16 tumour models.

a, Summary of groups and experimental timeline for testing 4HB TI-LNPs or 4HB TITUR alone and in combination with anti-PD-1 in B16 tumour-bearing mice. b, Therapeutic efficacy and safety in B16 tumour models. Monitoring of B16 tumour size, shown as the mean and standard deviation at each timepoint, as well as the individual curves for each treatment group, for n=5 mice per group. Data are plotted as the mean ± s.d. c. Endpoint tumour size for the B16 model, shown as a box plot with the mean, maximum, and minimum measurements from n=5 mice per group. The endpoint represents the final tumour size monitoring day or once tumour size exceeded 1000 mm3. d. Weight changes relative to the mouse body weight on the first LNP injection day in the B16, for n=5 mice per group. Data are plotted as the mean ± s.d. e.Tissue sectioning and H&E staining of the liver of B16 models, as well as serum levels of liver damage markers, ALT and AST, at the endpoint of the study. Shown are box plots representing the mean, maximum, and minimum measurement in each organ with n=5 mice per group. Scale bar, 100 um. Statistical significance was determined by one-way ANOVA with multiple comparisons. All data are plotted as the mean ± s.d.

Source data

Extended Data Fig. 2 Tumour customized UTRs (TURs) improves therapeutic outcomes and of 4HB mRNA in 4T1 tumour models.

a, Summary of groups and experimental timeline for testing 4HB TI-LNPs or 4HB TITUR alone and in combination with anti-PD-1 in 4T1-Fluc tumour-bearing mice. b, Monitoring of 4T1-Fluc tumour model based on changes in tumour luminescence signals with representative IVIS images of 4T1-Fluc tumour luminescence from Day 0 to Day 30 following the first LNP dose. Colour bar corresponds to luminescence intensity corresponding to this scale. c. Quantification of 4T1-Fluc tumour bioluminescence signal overtime, shown as individual curves for each mouse in a treatment group. d. Endpoint tumour luminescence for 4T1-Fluc models, shown as a box plot with the mean, maximum, and minimum measurements from n=5 mice per group. e. Weight changes relative to the mouse body weight on the first LNP injection day in the 4T1-Fluc tumour models. Data are plotted as the mean ± s.d. f. Tissue sectioning and H&E staining of the liver and spleen in 4T1-Fluc models, as well as serum levels of liver damage markers. Scale bar, 100 um. g. ALT and AST, at the endpoint of the study. Shown are box plots representing the mean, maximum, and minimum measurement in each organ with n=5 mice per group. Statistical significance was determined by one-way ANOVA with multiple comparisons.

Source data

Extended Data Fig. 3 Cancer vaccination effect of TITUR-B16 LNPs in bilateral B16 tumour model.

a, Tumour growth on both the treated and untreated flanks was monitored in B16 tumour-bearing mice following treatment with PBS, free 4HB mRNA, anti-PD-1, m4HBCtrlTIB16-2+anti-PD-1, m4HB TITURB16, m4HB TITURB16+anti-PD-1. Data are presented as mean ± standard deviation for each group (n = 5), along with individual tumour growth curves for each mouse. b, Violin plots representing the percentage of each immune cell population in the tumour, spleen, and lymph nodes with n=5 mice per treatment group. c. Heatmaps showing cytokine levels of tumour tissues at the endpoint of the B16 dual tumour. Statistical significance was determined by one-way ANOVA with multiple comparisons.

Source data

Extended Data Fig. 4 Cancer vaccination effect of TITUR-4T1 LNPs in 4T1 recurrence tumour model.

a, Tumour luminescence monitoring for primary and rechallenge 4T1-Fluc orthotopic tumours. Data is shown as IVIS images for each mouse, with n=5 mice per treatment group. Colour bar corresponds to luminescence intensity corresponding to this scale. b, Violin plots representing the percentage of each immune cell population in the tumour, spleen, and lymph nodes with n=5 mice per treatment group. c. Cytokine levels for each mouse per treatment group are shown in the heatmap, with n=5 mice per group. Statistical significance was determined by one-way ANOVA with multiple comparisons.

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Dong, S., Tsai, S.N., Xu, Y. et al. A modular mRNA platform for programmable induction of tumour-specific immunogenic cell death. Nat. Nanotechnol. 20, 1856–1870 (2025). https://doi.org/10.1038/s41565-025-02045-5

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