Nucleic acid vaccines have emerged as revolutionary platforms for infectious disease prevention and cancer immunotherapy. However, their clinical translation is significantly hindered by sequential biological barriers, necessitating highly efficient delivery systems. Biomedical polymers, owing to their tunable physicochemical properties, versatile structural engineering, and robust biocompatibility, have become a cornerstone in the development of nucleic acid nanocarriers. This review provides a comprehensive overview of polymeric delivery vehicles for nucleic acid vaccines, with a specific focus on rational design strategies tailored to overcome complex physiological barriers. We systematically dissect how functional polymer engineering-including interfacial shielding, targeted ligand modification, membrane perturbation, and stimuli-responsive disassembly-facilitates systemic circulation, antigen-presenting cell uptake, endosomal escape, and intracellular cargo release. Furthermore, we critically examine the persistent bottlenecks in current delivery platforms, such as the restricted uptake in primary immune cells and the fundamental inefficiencies of endosomal escape, while outlining future perspectives for the development of next-generation, clinically translatable polymeric nucleic acid vaccines.
