STING Agonist-Functionalized LNPs Enhance mRNA Vaccine CD8+ T-Cell and Antibody Responses in a Th1/Th2 Bias-Dependent Manner

Abstract Messenger RNA (mRNA) vaccines delivered by lipid nanoparticles (LNPs) can elicit strong antibody responses but comparatively limited cytotoxic CD8+ T-cell immunity. STING agonists can enhance cross-presentation and T-cell priming, but systemic administration is toxicity-limited. We engineered mRNA LNPs bearing the cyclic dinucleotide STING agonist STG968, which was surface-conjugated through a linker designed to be susceptible to cathepsin-mediated cleavage. In THP-1 dual-reporter cells, LNP-STG968 induced robust, dose-dependent IRF signaling with minimal NF-κB activation and partial suppression of protein expression. In mice, LNP–STG968 preserved local antigen expression while increasing early systemic IFN-α, IFN-γ, IL-6, IP-10, and MCP-1. Interestingly, these innate cytokine responses were mRNA-payload dependent. In prime-boost vaccination model with SARS-CoV-2 Delta S2P mRNA, LNP-STG968 enhanced adaptive immune responses in a Th1-/Th2-immune background-dependent manner relative to control LNP. These findings support further evaluation of STG968-functionalized LNPs as a formulation strategy for modulating innate and adaptive immune responses for next-generation mRNA vaccines.