DNA Vaccines in the Post-mRNA Era: Engineering, Applications, and Emerging Innovations.

Deoxyribonucleic acid (DNA) vaccines have re-emerged as a versatile and scalable platform by advances in synthetic biology and delivery systems, positioning them as powerful tools in the post-mRNA vaccine era. Historically considered less potent than viral or mRNA-based platforms, recent breakthroughs have dramatically improved their immunogenicity, safety, and precision. These innovations include synthetic gene circuits, self-amplifying DNA (saDNA), and DNA-encoded monoclonal antibodies (DMAbs), which enable programmable expression and robust immune activation. Clinically, DNA vaccines are expanding into diverse applications, from infectious disease prevention to therapeutic cancer immunotherapy and treatment of immune-mediated conditions. Compared to mRNA vaccines, DNA vaccines offer compelling advantages in terms of thermal stability, ease of manufacturing, and long-term storage. Furthermore, novel adjuvants, electroporation methods, and formulation strategies such as lyophilization and encapsulation continue to broaden their clinical potential. This review explores the full scope of DNA vaccine technology and its engineering foundations, emerging disease applications, and interdisciplinary innovations, while evaluating its comparative performance and future role in global vaccine strategy. With an emphasis on both mechanistic insights and translational feasibility, we propose a roadmap to integrate DNA vaccines into the next generation of precision immunotherapy.