A lymph-targeted high-density lipoprotein-mimetic nanovaccine for multi-antigenic personalized cancer immunotherapy was developed. This nanovaccine, named R837/LNP-M-L, is designed to deliver tumor-associated antigens and the immune adjuvant R837, which is a Toll-like receptor 7/8 (TLR7/8) agonist. The nanovaccine is composed of lipid nanoparticles (LNPs) coated with the cell membrane of cancer cells, which carry multiple tumor-associated antigens. The nanovaccine is modified with an ApoA1-mimetic peptide, 22A, to enhance its lymphatic targeting and uptake by dendritic cells (DCs). The nanovaccine was optimized for lymphatic targeting and DC uptake by adjusting its core composition, particle size, surface charge, and peptide modification. The optimized R837/LNP-M-L showed enhanced accumulation in lymph nodes (LNs) and increased uptake by DCs. The nanovaccine was effective in eliciting antitumor immune responses, including the activation and maturation of DCs, and the differentiation of naive T cells into cytotoxic T lymphocytes (CTLs). These CTLs then recognize and eliminate tumor cells, leading to tumor suppression and growth inhibition. In prophylactic studies, R837/LNP-M-L significantly delayed tumor formation and reduced tumor size in melanoma models. It also enhanced the therapeutic efficacy of immune checkpoint inhibitors, such as anti-PD1, against high-stemness melanoma. In therapeutic studies, R837/LNP-M-L combined with anti-PD1 showed a stronger inhibitory effect on tumor growth compared to either treatment alone. The nanovaccine also increased the infiltration of CD8+ T cells and DCs into the lymph nodes, enhancing immune responses against the tumor. The nanovaccine was found to be safe, with no observable liver or kidney function impairment. It is a promising candidate for personalized cancer immunotherapy, as it can be tailored to target specific tumor antigens and overcome immune resistance. The study highlights the potential of HDL-mimetic nanovaccines in cancer immunotherapy, with the ability to enhance immune responses and improve therapeutic outcomes.A lymph-targeted high-density lipoprotein-mimetic nanovaccine for multi-antigenic personalized cancer immunotherapy was developed. This nanovaccine, named R837/LNP-M-L, is designed to deliver tumor-associated antigens and the immune adjuvant R837, which is a Toll-like receptor 7/8 (TLR7/8) agonist. The nanovaccine is composed of lipid nanoparticles (LNPs) coated with the cell membrane of cancer cells, which carry multiple tumor-associated antigens. The nanovaccine is modified with an ApoA1-mimetic peptide, 22A, to enhance its lymphatic targeting and uptake by dendritic cells (DCs). The nanovaccine was optimized for lymphatic targeting and DC uptake by adjusting its core composition, particle size, surface charge, and peptide modification. The optimized R837/LNP-M-L showed enhanced accumulation in lymph nodes (LNs) and increased uptake by DCs. The nanovaccine was effective in eliciting antitumor immune responses, including the activation and maturation of DCs, and the differentiation of naive T cells into cytotoxic T lymphocytes (CTLs). These CTLs then recognize and eliminate tumor cells, leading to tumor suppression and growth inhibition. In prophylactic studies, R837/LNP-M-L significantly delayed tumor formation and reduced tumor size in melanoma models. It also enhanced the therapeutic efficacy of immune checkpoint inhibitors, such as anti-PD1, against high-stemness melanoma. In therapeutic studies, R837/LNP-M-L combined with anti-PD1 showed a stronger inhibitory effect on tumor growth compared to either treatment alone. The nanovaccine also increased the infiltration of CD8+ T cells and DCs into the lymph nodes, enhancing immune responses against the tumor. The nanovaccine was found to be safe, with no observable liver or kidney function impairment. It is a promising candidate for personalized cancer immunotherapy, as it can be tailored to target specific tumor antigens and overcome immune resistance. The study highlights the potential of HDL-mimetic nanovaccines in cancer immunotherapy, with the ability to enhance immune responses and improve therapeutic outcomes.