This review systematically evaluates research on self-assembling protein nanoparticles (SPNPs)-based vaccine, focusing on three major categories: virus-like particles (VLPs), natural protein nanoparticles (e.g., ferritin and encapsulin), and computationally designed protein nanoparticles—with comparative analyses of their design strategies, immunogenicity, and applicability in next-generation vaccines. VLPs can elicit robust humoral and cellular immune responses due to their virus-mimetic structures. Natural protein nanoparticles provide excellent biocompatibility and controllable self-assembly for multivalent antigen presentation. Artificially designed protein nanoparticles allow precise structural optimization to facilitate tailored antigen display and immune modulation. Overall, SPNPs constitute a versatile and powerful platform for vaccine development. By integrating natural and engineered design principles, they offer new opportunities for rational vaccine design and the development of safer and more effective immunization strategies.