Xu Ma, Shaoli Liu, Shuhui Zhang, Zongran Liu, Hui Wang, Wendi Luo, Mali Zu, Hao Qin, Zhongxian Li, Jie Zhong, Junxi Li, Qizhe Chen, Jiaqi Lin, Andong Liu, Xinzheng Zhang, Hongjun Li, Xueguang Lu, Xinghua Shi, Lele Li, Zhen Gu, Guangjun Nie, Tianjiao Ji
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 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 (Mn2+) 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. Lipid nanoparticles are the gold standard for mRNA delivery but suffer from low loading capacity. Here, the authors report on the use of manganese ions to form mRNA rich cores within lipid nanoparticles which increased mRNA loading, reducing the lipid needed and increasing transfection and immune response in vivo.