Polymeric nanoparticle-loaded extracellular vesicles as biomimetic nucleic acid vaccines

Nucleic acid vaccination has expanded the traditional use of vaccines, ranging from infectious disease prophylaxis to therapeutic applications in oncology. However, nucleic acids require protection from nuclease degradation in vivo by using selective delivery vectors capable of transporting the cargo into targeted cells such as antigen-presenting cells (APCs) for efficient genetic material translation into proteins and immune system activation. Polymeric nanoparticles (NPs), particularly poly(beta aminoesters) (pBAEs), have demonstrated efficiency in transfecting cells in vitro and have also demonstrated promising results in vivo. Despite numerous attempts to target NPs to specific cells, selectivity still remains a challenge. In this study, we address this limitation by developing biomimetic nanosystems composed of pBAE NP-embedded in extracellular vesicles (EVs). These small vesicles, released by all cell types, facilitate intercellular communication among cells of the same lineage, making them ideal to be use as natural targeting moieties. Effective complexes were ensembled using a freeze-thaw method to efficiently entrap pBAE NPs loaded with nucleic acids in monocyte-derived EVs. Their in vitro safety, transfection, and monocyte activation capacity of these complexes outperformed the individual components of the nanosystem, demonstrating their suitability for parenteral use in vivo . Our findings confirm the potential of constructing efficacious biomimetic pBAE NPs-EVs nanocomplexes for nucleic acid vaccination for the first time.