SitoC7A-modified lipid nanoparticles for integrated mRNA delivery and targeted STING activation.

Messenger RNA (mRNA) vaccine efficacy requires delivery systems that maximize antigen expression while precisely modulating innate immune activation. However, many conventional adjuvants induce type I interferons that inadvertently suppress mRNA translation, compromising vaccine efficacy. To overcome this limitation, we engineered a multifunctional lipid nanoparticle (LNP) by partially substituting a fraction of the structural lipid cholesterol with SitoC7A - a conjugate of sitosterol and the STING (Stimulator of Interferon Genes) agonist (C7A) linked via a reducible disulfide bond. This single SitoC7A component serves dual roles: its disulfide bond markedly enhances LNP uptake by dendritic cells (DCs) and boosts mRNA translation, while its C7A moiety selectively triggers STING signaling within DCs, avoiding systemic interferon responses. This integrated design yielded robust DC maturation and superior antigen presentation. In murine models, SitoC7A-LNPs encapsulating SARS-CoV-2 mRNA elicited potent protective immunity, while tumor antigen-loaded LNPs significantly suppressed lymphoma progression. We introduce a principle for the novel LNP design wherein a single engineered lipid simultaneously provides structural support, enhances mRNA delivery and expression specifically in key immune cells, and delivers spatially controlled adjuvanticity creating a versatile and potent platform for next-generation mRNA vaccines.