A Precision-Engineered DC-Targeting mRNA-LNP Neoantigen Vaccine Elicits Stronger T Cell Responses and Exhibits Superior Tumor Control

<b>Background/Objectives</b>: Messenger RNA (mRNA) vaccine technology has shown great potential in the prevention of infectious diseases and treatment of cancers, but its full potential is limited by non-specific delivery mediated by the current lipid nanoparticle (LNP) platform. <b>Methods</b>: Here, we developed a dendritic cell (DC)-targeting LNP incorporated with an ultra-high-affinity CLEC9A-specific nanobody that facilitates enhanced DC uptake but reduced liver accumulation. We assessed the therapeutic efficacy of nanobody-functionalized lipid nanoparticles (Nb-LNPs) in a mouse Lewis lung carcinoma (LLC) model, alongside an evaluation of T cell-mediated immune responses and dendritic cell activation, facilitated by the delivery of mRNA-based neoantigen vaccines. <b>Results</b>: Compared with the use of an unfunctionalized LNP, personalized mRNA cancer vaccines encapsulated with this Nb-LNP demonstrated not only superior anti-tumor effects but also a favorable bio-safety profile in a mouse Lewis lung carcinoma model. The mRNA Nb-LNP neoantigen vaccines also induced substantially higher levels of DC maturation and more potent antigen-specific T cell responses, in particular CD4⁺ T cell responses, which are critical for initiation of anti-tumor immunity and immune memory. <b>Conclusions</b>: Taken together, these results suggest that precision-engineered LNPs conjugated with a CLEC9A-specific antibody or nanobody could be a promising platform for delivering mRNA vaccines specifically to dendritic cells, improving their prophylactic or therapeutic effects.