DNA nanovaccines derived from ferritin-modified glycogens for targeted delivery to immature dendritic cells and for promotion of Th1 cell differentiation

DNA vaccines have emerged as a powerful approach for advanced cancer therapy. Despite the development of various delivery systems to enhance the immunogenicity of DNA vaccines, many still face challenges such as limited DNA condensation, rapid degradation in vivo and insufficient targeting to lymph nodes (LNs). Synthetic dendrimers with modifiable surfaces exhibit high efficiency in DNA condensation, but their synthesis is extremely complex. This study utilizes cationic glycogen, a natural branched dendrimer-like polymer, as the core structure for efficient DNA condensation and delivery, ensuring good biocompatibility. By connecting ferritin light chain to the glycogen surfaces, active targeting of LNs can be achieved due to its affinity for the SCARA5 receptor on immature dendritic cells (DCs), facilitating vaccine migration to the LNs. In addition, a seperate plasmid encoding adjuvant IL-12 was co-delivered to further boost the immunogenicity of the DNA nanovaccine. In vivo and in vitro experiments confirmed the effective transfection capability of this DNA vaccine, demonstrating promoted DC maturation, increased antigen presentation, and Th1 cell differentiation, resulting in improved anti-tumor efficiency in vivo. This innovative multi-gene co-loaded DNA vaccine offers valuable insights into combined gene therapy and broadens the research horizon on non-viral gene carriers. STATEMENT OF SIGNIFICANCE: The DNA vaccine encounters challenges such as limited DNA condensation, rapid degradation and insufficient targeting to lymph nodes (LNs), resulting in generally weak immunogenicity. In the current study, a novel nanovaccine is developed by connecting ferritin light chain to natural dendrimer glycogen, for simultaneous delivery of dual plasmids. The cationized glycogen provides strong DNA condensation ability, while ensuring excellent stability of the nanovaccine. The presence of ferritin light chain leads to effective targeting of dendritic cells (DCs), facilitating its migration to LNs. Moreover, the plasmid encoding the adjuvant IL-12 is co-incorporated with the antigen plasmid to mitigate the immunosuppression environment. This strategy significantly improves the immunogenicity of DNA vaccines, demonstrating high efficiency in cancer immunotherapy.