Prodrug-tethered lipid nanoparticles for synergistic messenger RNA cancer immunotherapy.

Regulating T cell phenotypes between activation and exhaustion remains a significant challenge for messenger RNA-based cancer immunotherapy. A potential approach to improve anti-cancer T cell activity is to co-deliver interleukin-12 (IL-12), to stimulate effector T cells, and indoleamine 2,3-dioxygenase (IDO) inhibitor, to suppress T cell exhaustion. Here we design prodrug ionizable lipid nanoparticles (pLNPs), via a library of prodrug ionizable lipids (pILs), incorporating an intracellularly cleavable IDO inhibitor within the pIL structure and encapsulating IL-12 messenger RNA. The lead pIL shows enhanced mRNA transfection over a clinically utilized ionizable lipid, as well as strong immunomodulatory effects via release of the IDO inhibitor. In a subcutaneous colon cancer mouse model, pLNP drives complete regression of primary tumours by eliciting effector T cell infiltration while reducing exhaustion, induces a memory T cell response and stimulates a systemic immune response that allows for regression of distal tumours in this study. These results highlight the promise of pLNPs for small-molecule drug and mRNA combination cancer immunotherapy.