Iontophoresis-Driven Microneedle Arrays Delivering Transgenic Outer Membrane Vesicles in Program that Stimulates Transcutaneous Vaccination for Cancer Immunotherapy

Transdermal delivery of antigen and chemokine proteins that activates the maturation of skin dendritic cells (DCs) and direct the migration of activated DCs to lymph and spleen is an important alternative to conventional vaccines. However, stratum corneum forms a barrier to skin penetration. The poor cellular uptake of free antigens and chemokines also limits transcutaneous immunization efficacy. In this work, a pair of iontophoresis-driven microneedle patches is constructed, of which, two kinds of outer membrane vesicles (OMVs) derived from Escherichia coli transformed by plasmid encoding gp100 (IPMN-G) and chemokine ligand 21 (IPMN-C) are incorporated within microneedles, respectively. The topical application of IPMN-G and IPMN-C shows the effectiveness of transdermally delivering gp100 and CCL21 secreting vesicles to skin DCs. With iontophoresis as a driving generator, the release and uptake of transgenic OMVs in target cells are significantly enhanced, with transcutaneous immunization initiated. The in vivo applications of IPMN-G and IPMN-C with a 12 h interval retard the progression and prevent the occurrence of tumor spheroids. IPMN-GC is shown as a promising triplatform in engineering transgenic OMV-incorporated microneedles, driven by iontophoresis into a transcutaneous vaccine, providing a noninvasive system for the transdermal delivery of antigen and chemokine proteins for transcutaneous vaccination-meditated immunotherapy.