Messenger RNA (mRNA) vaccines have reshaped modern vaccinology by enabling rapid antigen design, scalable manufacturing, and coordinated induction of humoral and cellular immunity. Their clinical success has established mRNA as a versatile platform for infectious diseases, cancer immunotherapy, and emerging therapeutic applications. However, expansion into cardiovascular, neurodegenerative, autoimmune, and metabolic disorders imposes indication-specific requirements that cannot be addressed by uniform design strategies. Vaccine performance depends not only on antigen output, but also on how RNA architecture and delivery systems regulate innate sensing, intracellular trafficking, tissue distribution, and adaptive immune programming. In this review, we summarize bioengineering strategies for improving mRNA vaccine immunogenicity by coordinating antigen-expression efficiency with innate immune regulation. We compare non-replicating mRNA, self-amplifying RNA, and circular RNA in terms of expression kinetics, translational logic, safety considerations, and innate immune activation. We then discuss molecular engineering approaches that enhance stability, translation, and immune control, including optimization of cap structures, untranslated regions, poly(A) tails, nucleotide modifications, codon usage, and platform-specific designs for saRNA and circRNA. We further examine delivery systems, including lipid nanoparticles, exosomes, polymer-based carriers, virus-like particles, and hybrid platforms, emphasizing their dual roles in cargo transport and immune modulation. Finally, we discuss indication-specific design principles, manufacturing constraints, and translational challenges. We propose that next-generation mRNA vaccines will require disease-matched co-design of RNA molecules and delivery platforms to enhance antigen expression, tune immune activation, and strengthen clinical translation.
