Recent breakthroughs in cancer immunotherapy, exemplified by immune checkpoint blockade and CAR T cell therapy, have achieved remarkable clinical success. However, the majority of cancer patients fail to respond to immunotherapy or suffer from relapse. Nanotechnology shows promise in enhancing current immunotherapies through targeted delivery of anti-cancer vaccines and immune modulators to specific cells or tissues. In my Ph.D. thesis, I developed several nanotechnology-enabled delivery systems to enhance immunotherapies' efficacy and safety, including personalized vaccines and mRNA-based therapy. I developed the polycondensate-epitope vaccine (PEV) platform for lymph node-targeted delivery of MHC I and II-restricted peptides, which elicited potent antitumor T cell immunity. The PEV vaccine induced robust and long-lasting antigen-specific CD8+ and CD4+ T-cell responses in mice. In addition, I found the combination of PEV vaccine and a half-life-extended interleukin-10â Fc fusion protein reinvigorated exhausted T cells and restored their cytotoxic function and proliferative capacity in mouse tumor models. Finally, I employed a localized delivery strategy using lipid nanoparticles to deliver mRNA that encoded IL-10 to achieve local and durable metabolic reprogramming of tumor-infiltrating T cells for enhanced anti-cancer immunotherapy. These nanotechnology-enabled immunotherapies show the promise to further improve patientsâ response rates.