Regulating the T-cell phenotype between activation and exhaustion remains a major challenge for messenger RNA-based cancer immunotherapy. One potential approach to improving the activity of anti-cancer T cells is to co-deliver interleukin-12 (IL-12) to stimulate effector T cells, and an indoleamine 2,3-dioxygenase (IDO) inhibitor to inhibit T cell exhaustion. In this study, we designed prodrug ionizable lipid nanoparticles (pLNP) from a library of prodrug ionizable lipids. This library embedded intracellularly cleavable IDO inhibitors in the pIL structure and encapsulated IL-12 messenger RNA. The lead pIL demonstrated enhanced mRNA transfection ability on clinically used ionizable lipids and exerted a potent immunomodulatory effect through the release of IDO inhibitors. In a subcutaneous colon cancer mouse model, pLNP induced effector T cell infiltration, promoted complete regression of the primary tumor, reduced exhaustion, induced memory T cell responses, and stimulated systemic immune responses, enabling the regression of distant tumors, as demonstrated in this study. These results highlight the potential of pLNPs in the combined cancer immunotherapy of small molecule drugs and messenger RNA. This research was published in Nature Nanotechnology under the title "Prodrug-tethered lipid nanoparticles for synergistic messenger RNA cancer immunotherapy".
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DOI: 10.1038/s41565-025-02102-z