Smart vaccine delivery based on microneedle arrays decorated with ultra-pH-responsive copolymers for cancer immunotherapy

Despite the tremendous potential of DNA-based cancer vaccines, their efficacious delivery to antigen presenting cells to stimulate both humoral and cellular response remains a major challenge. Although electroporation-based transfection has improved performance, an optimal strategy for safe and pain-free vaccination technique remains elusive. Herein, we report a smart DNA vaccine delivery system in which nanoengineered DNA vaccine was laden on microneedles (MNs) assembled with layer-by-layer coating of ultra-pH-responsive OSM-(PEG-PAEU) and immunostimulatory adjuvant poly(I:C), a synthetic double stranded RNA. Transcutaneous application of MN patches onto the mice skin perforate the stratum corneum with minimal cell damage; subsequent disassembly at the immune-cell-rich epidermis/dermis allows the release of adjuvants and DNA vaccines, owing to the ultra-sharp pH-responsive nature of OSM-(PEG-PAEU). The released adjuvant and DNA vaccine can enhance dendritic cell maturation and induce type I interferons, and thereby produce antigen-specific antibody that can achieve the antibody-dependent cell-mediated cytotoxicity (ADCC) and CD8⁺ T cell to kill cancer cells. Strikingly, transcutaneous application of smart vaccine formulation in mice elicited 3-fold greater frequencies of Anti-OVA IgG1 serum antibody and 3-fold excess of cytotoxic CD8⁺ T cell than soluble DNA vaccine formulation. As a consequence, the formulation rejected the murine B16/OVA melanoma tumors in C57BL/6 mice through the synergistic activation of antigen-specific ADCC and cytotoxic CD8⁺ T cells. The maneuvered use of vaccine and adjuvant poly(I:C) in MNs induces humoral and cellular immunity, which provides a promising vaccine technology that shows improved efficacy, compliance, and safety.