mRNA LNP vaccine co-delivering STING agonists c-di-AMP and Mn2+ enhances antitumor immunity and efficacy

mRNA-based cancer vaccines hold promise for eliciting antitumor immunity, but their effectiveness is often hampered by inefficient mRNA delivery and inadequate activation of dendritic cells (DCs), crucial for robust cytotoxic T cell responses. This is particularly problematic in immunologically "cold" tumors. While STING (stimulator of interferon genes) agonists can enhance DC maturation and cross-presentation, their therapeutic utility is limited by poor intracellular delivery and insufficient colocalization with tumor antigens, creating a critical gap in current immunotherapy strategies.

Researchers developed a novel lipid nanoparticle (LNP) platform through high-throughput screening of ionizable lipids to optimize mRNA delivery to DCs in vitro and in vivo. To amplify immune activation, they coencapsulated the STING agonists c-di-AMP and manganese (Mn2+) alongside tumor antigen-encoding mRNA into the lead LNP formulation. This codelivery strategy was designed to synergistically activate innate immune pathways and enhance antigen presentation, with antitumor efficacy and immune activation as primary endpoints.

The codelivery strategy synergistically activated type I interferon signaling, upregulated costimulatory molecules, and significantly enhanced antigen presentation. This led to potent tumor-specific T cell responses and superior antitumor efficacy. Specifically, this LNP platform achieved remarkable tumor-free survival rates: > Against E.G7-OVA lymphoma, the polyplex yielded 83.3% tumor-free survival, and against 4T1 triple-negative breast cancer, it achieved 33.3% tumor-free survival. These results contrast sharply with conventional lipoplexes or SM102 LNP-based mRNA vaccines, which yielded 0% tumor-free survival in these models, demonstrating a substantial improvement in therapeutic outcome.