新抗原作为开发个人化癌症疫苗的有吸引力的靶点正在崭露头角，但它们的免疫效力受到严重的限制，因为它们只能在淋巴组织中接受免疫反应引发。通过利用红细胞（RBCs）在外周血中捕获和呈现病原体给脾脏中的抗原呈递细胞（APCs）的能力，我们开发了一种RBC驱动的脾靶向策略，用于递送编码肝细胞癌（HCC）新抗原的DNA疫苗。故意搭乘在预分离的红细胞上的DNA疫苗包裹的聚合物纳米颗粒可以优先在脾脏中积累，促使APCs表达新抗原，从而引发新抗原特异性T细胞免疫，以个人化方式预防肿瘤发生，并减缓已建立的快速生长HCC的肿瘤生长。显着的是，当与抗-PD-1结合时，该疫苗实现了完全的肿瘤消退，并产生了强大的全身性免疫应答和长期的肿瘤特异性免疫记忆，从而彻底预防了肿瘤复发和自发性肺转移。本研究为在免疫"冷"的HCC中增强癌症免疫治疗效果提供了有前景的策略。© 2023 The Authors. 依据CC BY 4.0许可协议发布。

Neoantigens are emerging as attractive targets to develop personalized cancer vaccines, but their immunization efficacy is severely hampered by their restricted accessibility to lymphoid tissues where immune responses are initiated. Leveraging the capability of red blood cells (RBCs) to capture and present pathogens in peripheral blood to the antigen-presenting cells (APCs) in spleen, we developed a RBC-driven spleen targeting strategy to deliver DNA vaccine encoding hepatocellular carcinoma (HCC) neoantigen. The DNA vaccine-encapsulating polymeric nanoparticles that were intentionally hitchhiked on the preisolated RBCs could preferentially accumulate in the spleen to promote the neoantigen expression by APCs, resulting in the burst of neoantigen-specific T-cell immunity to prevent tumorigenesis in a personalized manner, and slow down tumor growth in the established aggressively growing HCC. Remarkably, when combined with anti-PD-1, the vaccine achieved complete tumor regression and generated a robust systemic immune response with long-term tumor-specific immunological memory, which thoroughly prevented tumor recurrence and spontaneous lung metastasis. This study offers a prospective strategy to develop personalized neoantigen vaccines for augmenting cancer immunotherapy efficiency in immune "cold" HCC.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.