Neoantigen vaccines are among the most potent immunotherapies for personalized cancer treatment. Therapeutic vaccines containing tumor-specific neoantigens that elicit specific T cell responses offer the potential for long-term clinical benefits to cancer patients. Unlike immune-checkpoint inhibitors (ICIs), which rely on pre-existing specific T cell responses, personalized neoantigen vaccines not only promote existing specific T cell responses but importantly stimulate the generation of neoantigen-specific T cells, leading to the establishment of a persistent specific memory T cell pool. The review discusses the current state of clinical research on neoantigen nanovaccines, focusing on the application of vectors, adjuvants, and combinational strategies to address a range of challenges and optimize therapeutic outcomes.