Comparative Analysis of Immunostimulatory Activation Mechanisms and Design Strategies for Two Novel Vaccine Platforms: SLP+CpG and mRNA–LNP

With the continuous expansion of the spectrum of immune-related diseases, traditional vaccines and therapies are far from meeting the urgent needs with the required precision and durability. Therefore, there is a requirement for mechanistically programmable immune platforms. Because of their advantages in antigen design and innate immune regulation, synthetic long peptides combined with CpG and messenger RNA-lipid nanoparticles have become research hotspots over the last few years. This review focuses on core elements and the latest development of these two platforms: at the molecular and process level, the review outlines SLP multi-epitope concatenation and auxiliary epitope design, CpG regulation of the TLR9-MyD88 axis, mRNA nucleoside modifications, UTR/ORF optimization, and LNP delivery strategies; at the level of immunological mechanism, it makes a comparison between exogenous "pulsed" antigen presentation and endogenous short-term continuous expression. Generally speaking, SLP+CpG displays epitope-level precision and programmable personalization, while mRNA-LNP has potential in multi-antigen parallel processing and rapid iterative scaling. However, bottlenecks like cross-presentation, "pulsed" antigen availability, expression-innate balance, formulation immunogenicity, and cold chain consistency are still problems to be overcome. Future directions shall focus on high-precision antigen prediction and selection, cDC1-biased and organ-targeted delivery, heterologous sequential and dose-interval optimization, and biomarker-driven personalized combination therapies to further guarantee more reproducible and scalable clinical translation.