Spleen‐targeted neoantigen DNA vaccine for personalized immunotherapy of hepatocellular carcinoma.

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. Synopsis: To address the limited efficacy of current personalized cancer vaccines and improve hepatocellular carcinoma (HCC) immunotherapy, a red blood cell (RBC) hitchhiking strategy was developed for targeted delivery of a neoantigen DNA vaccine to the spleen.Polymer‐lipid nanoparticles (NPs) were designed to encapsulate neoantigen‐carrying plasmid DNA (pDNA). These nanovaccines were then attached to pre‐isolated RBCs to spread DNA vaccine delivery.RBC‐hitchhiking DNA nanovaccines preferentially accumulated in the spleen, promoting neoantigen expression by antigen‐presenting cells (APCs) and inducing a strong neoantigen‐specific T cell response.This vaccination regimen prevented tumorigenesis in a personalized manner and slowed down tumor growth in the aggressively growing HCC tumor characterized by an immune "cold" microenvironment.Combining RBC‐hitchhiking DNA nanovaccines with anti‐PD‐1 checkpoint blockade led to complete tumor regression (75 and 100% in subcutaneous and orthotopic HCC mouse models, respectively) and prolonged mouse survival. [ABSTRACT FROM AUTHOR]