Engineering of mRNA vaccine platform with reduced lipids and enhanced efficacy

Lipid nanoparticles (LNPs) are the most clinically relevant vehicles for mRNA vaccines. Despite the great successes, the toxicity caused by the high dose of lipid components still represents a great challenge. The suboptimal loading efficiency of mRNA in LNPs not only compromises the vaccine’s efficacy but also heightens the risk of non-specific immune responses, accelerates clearance from the bloodstream, and exacerbates side effects associated with the lipid carriers. These problems underscore the urgent need for improving mRNA loading in LNPs to provide dose-sparing effects. Herein, we developed a manganese ion (Mn²⁺) mediated mRNA enrichment strategy to efficiently form a high-density mRNA core, termed Mn-mRNA nanoparticle, which is subsequently coated with lipids. The resulting nanosystem, L@Mn-mRNA, achieved over twice the mRNA loading compared to conventional mRNA vaccine formulations (LNP-mRNA). Remarkably, L@Mn-mRNA also demonstrated a 2-fold increase in cellular uptake efficiency compared to LNP-mRNA, attributed to the enhanced stiffness provided by the Mn-mRNA core. By combining improved mRNA loading with superior cellular uptake, L@Mn-mRNA achieved significantly enhanced antigen-specific immune responses and therapeutic efficacy as vaccines. We elucidated the mechanism behind Mn-mRNA construction and optimized the L@Mn-mRNA formulations, and this method is suitable for types of lipids and mRNAs. Thus, this strategy holds significant potential as a platform for the next generation of lipid-based mRNA vaccines.