<p>Cationic nano-vaccine (CNV) has emerged as a promising immunotherapy platform by utilizing static interactions to promote antigen uptake, endosomal escape, and cross-expression. These functions enable strong cytotoxic T lymphocytes and antibody reactions, but CNV also faces important translation challenges such as charge-induced cytotoxicity, protein corona formation, complement activation, and tissue accumulation. Recent advances in nanoscale design have clarified how particle size, charge density, lipid and polymer chemistry, and formulation stability collectively shape biodistribution, immune programming, and safety. Here we provide an overview of the mechanistic basis of CNVs, their comparative advantages and limitations, and design strategies that improve physicochemical properties, biocompatibility, and formulation stability. We discuss infectious disease vaccines, including viral, bacterial, and parasitic platforms, and cancer immunotherapy, in which CNVs enhance synergy with lymph node targeting, CD8⁺ T-cell expansion, checkpoint blocking, and personalized neoantigen vaccines. Finally, we emphasize safety engineering approaches such as ionizable lipids, degradable linkers, and motifs that respond to stimuli, reducing off-target effects while maintaining their effectiveness. Together, these advances highlight the transformational potential of CNVs and unify robust immune activation and reasonable safety design. By integrating standardized functional analysis, scalable manufacturing, and next-generation antigen discovery, CNVs are poised to move toward a universal vaccine platform for infectious disease prevention and cancer treatment.</p>