Nanoparticle vaccines have been established firmly as a cornerstone of modern immunization strategies, with a compelling history that trace their pioneering use in human being back to 1981. Within the past four decades, these vaccines have not only demonstrated their efficacy, but have also been developed as powerful tools in fighting against a range of infectious diseases, most notably hepatitis B virus (HBV) and human papillomavirus (HPV). Their success can be attributed to their exceptional immunogenicity and impeccable safety as well, making them invaluable in curbing the spread of viruses and safeguarding the health and well-being of human being. The global outbreaks of the COVID-19 pandemic, driven by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has made vaccination into the forefront of public health priorities. This unprecedent challenge has accelerated the progress of various vaccine technologies, with nanoparticle vaccines attracting considerable attention. However, due to their relatively empirical design approaches and complicated manufacturing processes, progress in the clinical trials of SARS-CoV-2 nanoparticle vaccines has not been highlighted particularly. Therefore, the imperative for developing nanoparticle vaccines is to figure out their rational design, requiring groundbreaking advancement in novel technologies and theories. In this endeavor, synthetic biotechnology has emerged as an indispensable tool, driving the technological innovations of the production of nanoparticle vaccines. This article begins with an overview of technological advancements in the development of nanoparticle vaccines, encompassing progress from self-assembled nanoparticles to assist-assembled nanoparticles, and ultimately to antigen-display on formed nanoparticles. Furthermore, discoveries in understanding the unique roles of nanoparticle vaccines in enhancing antigen immunogenicity are updated, particularly in the function of nanoparticles with novel antigen presentation pathways. Finally, a comprehensive summary of the clinical trials of nanoparticle vaccines on fighting the COVID-19 pandemic is presented. In conclusion, we firmly believe that nanoparticle vaccines, bolstered by the scaffolding of synthetic biotechnology, are poised to emerge as steadfast guardians in the global battle against emerging and highly infectious diseases, and ongoing progress in this regard not only holds great promise, but also has potentials to revolutionize contagious disease prevention and control on a global scale.