The article reviews the advancements, challenges, and prospects of next-generation DNA vaccine platforms and delivery systems. DNA vaccines, which have emerged as a promising approach for treating both genetic and acquired diseases, face significant challenges in achieving optimal immunogenicity due to the lack of an effective delivery system. The review highlights the importance of viral and non-viral DNA delivery systems, including their strengths and weaknesses. Viral vectors, such as adenoviruses, recombinant adeno-associated viruses, retroviruses, and lentiviruses, offer high transfection efficiency and natural delivery mechanisms but carry the risk of integrating into the host genome. Non-viral delivery systems, particularly nanoparticles (NPs), have shown promise in overcoming these limitations by enhancing DNA stability, targeting specific cells, and improving immune responses. Cationic liposomes, polyethyleneimine (PEI), chitosan, and anionic polymers like poly(D, L-lactide-co-glycolic acid) (PLGA) are discussed for their roles in DNA vaccine delivery. The article also emphasizes the need for further clinical trials to validate the safety and efficacy of these advanced DNA vaccine platforms.The article reviews the advancements, challenges, and prospects of next-generation DNA vaccine platforms and delivery systems. DNA vaccines, which have emerged as a promising approach for treating both genetic and acquired diseases, face significant challenges in achieving optimal immunogenicity due to the lack of an effective delivery system. The review highlights the importance of viral and non-viral DNA delivery systems, including their strengths and weaknesses. Viral vectors, such as adenoviruses, recombinant adeno-associated viruses, retroviruses, and lentiviruses, offer high transfection efficiency and natural delivery mechanisms but carry the risk of integrating into the host genome. Non-viral delivery systems, particularly nanoparticles (NPs), have shown promise in overcoming these limitations by enhancing DNA stability, targeting specific cells, and improving immune responses. Cationic liposomes, polyethyleneimine (PEI), chitosan, and anionic polymers like poly(D, L-lactide-co-glycolic acid) (PLGA) are discussed for their roles in DNA vaccine delivery. The article also emphasizes the need for further clinical trials to validate the safety and efficacy of these advanced DNA vaccine platforms.