mRNA vaccines have become a clinically validated vaccine platform, as demonstrated by the success of COVID-19 vaccines such as Comirnaty and Spikevax, owing to their rapid design, manufacturing scalability, and capacity to induce in situ antigen expression. A key factor underlying this success is the lipid nanoparticle (LNP) delivery system, which protects mRNA from degradation and promotes efficient cellular uptake and cytoplasmic delivery, thereby enabling the full potential of mRNA technology. The continued advancement of mRNA-LNP vaccines requires integrated optimization of mRNA design, LNP composition, and delivery strategies to achieve improved stability, efficient intracellular delivery, and balanced immune responses. Despite remarkable progress, challenges related to formulation stability, long-term storage stability, safety and reactogenicity concerns, and durability of immune protection continue to hinder the broader application of mRNA-LNP vaccine platforms. This review provides an integrated overview of recent advances in mRNA-LNP vaccines, covering mRNA molecular engineering, LNP composition and delivery mechanisms, immune responses, clinical progress, and current developmental challenges. Furthermore, emerging strategies, including thermostable formulations, next-generation LNPs with improved targeting capability, emerging RNA platforms, and artificial intelligence-assisted optimization of RNA sequences and lipid materials, are discussed. By summarizing current achievements and future opportunities, this review highlights key principles guiding the rational design of safer, more stable, and more precise mRNA-LNP vaccine platforms and provides insights into accelerating their clinical translation.
