Hybrid mRNA Nano Vaccine Potentiates Antigenic Peptide Presentation and Dendritic Cell Maturation for Effective Cancer Vaccine Therapy and Enhances Response to Immune Checkpoint Blockade

Abstract Cancer vaccines combined with immune checkpoint blockades (ICB) represent great potential application, yet the insufficient tumor antigen presentation and immature dendritic cells hinder improved efficacy. Here, a hybrid nano vaccine composed by hyper branched poly(beta‐amino ester), modified iron oxide nano adjuvant and messenger RNA (mRNA) encoded with model antigen ovalbumin (OVA) is presented. The nano vaccine outperforms three commercialized reagents loaded with the same mRNA, including Lipofectamine MessengerMax, jetPRIME, and in vivo‐jetRNA in promoting dendritic cells’ transfection, maturation, and peptide presentation. In an OVA‐expressing murine model, intratumoral administration of the nano vaccine significantly induced macrophages and dendritic cells’ presenting peptides and expressing co‐stimulatory CD86. The nano vaccine also elicited strong antigen‐specific splenocyte response and promoted CD8+ T cell infiltration. In combination with ICB, the nano vaccine aroused robust tumor suppression in murine models with large tumor burdens (initial volume >300 mm 3 ). The hybrid mRNA vaccine represents a versatile and readily transformable platform and augments response to ICB.