Engineering of mRNA vaccine platform with reduced lipids and enhanced efficacy

Oct 7, 2025Nature communications

Improving mRNA vaccines with fewer fats for better effectiveness

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

L@Mn-mRNA achieved nearly twice the mRNA loading capacity compared to conventional mRNA vaccine formulations.

The metal ion mediated mRNA enrichment strategy uses manganese ions to form a high-density mRNA core.
L@Mn-mRNA shows a 2-fold increase in cellular uptake efficiency compared to conventional formulations.
Enhanced stiffness from the Mn-mRNA core is associated with improved cellular uptake.
L@Mn-mRNA demonstrates significantly enhanced antigen-specific immune responses and therapeutic efficacy.
This approach may reduce the risk of generating anti-PEG IgG/IgM.

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(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 capacity of mRNA in LNPs not only compromises the vaccine's efficacy but also heightens the risk of non-specific immune responses, accelerates clearance caused by anti-PEG IgG/IgM. These problems underscore the urgent need for improving mRNA loading capacity in LNPs to provide dose-sparing effects. Herein, we develop a metal ion mediated mRNA enrichment strategy to efficiently form a high-density mRNA core, and manganese ion (Mn) exhibits a unique capability to match the need. The prepared Mn-mRNA nanoparticle is subsequently coated with lipids to form the resulting nanosystem, L@Mn-mRNA, which achieved nearly twice the mRNA loading capacity compared to conventional mRNA vaccine formulations (LNP-mRNA). Remarkably, L@Mn-mRNA also demonstrates 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 achieves significantly enhanced antigen-specific immune responses and therapeutic efficacy as vaccines. We elucidate the mechanism behind Mn-mRNA construction and optimize the L@Mn-mRNA formulations, and this method is suitable for types of lipids and mRNAs. Moreover, L@Mn-mRNA also reduces the risk of anti-PEG IgG/IgM generation. Thus, this strategy holds significant potential as a platform for the next generation of lipid-based mRNA vaccines. 2+

Key numbers

2×

Increase in loading capacity

vs. conventional - formulations.

2×

Increase in cellular uptake efficiency

vs. -.

4.1×

Increase in antigen presentation

L@Mn-mOVA vs. -mOVA.

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Engineering of mRNA vaccine platform with reduced lipids and enhanced efficacy

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