Photothermal Nano-Vaccine Promoting Antigen Presentation and Dendritic Cells Infiltration for Enhanced Immunotherapy of Melanoma via Transdermal Microneedles Delivery

摘要

Immunotherapy has demonstrated the potential to cure melanoma, while the current response rate is still unsatisfactory in clinics. Extensive evidence indicates the correlation between the efficacy and pre-existing T-cell in tumors, whereas the baseline T-cell infiltration is lacking in low-response melanoma patients. Herein, we demonstrated the critical contribution of dendritic cells (DCs) on melanoma survival and baseline T-cell level, as well as the efficacy of immunotherapy. Capitalized on this fact, we developed a photothermal nano-vaccine to simultaneously promote tumor antigens presentation and DCs infiltration for enhanced immunotherapy. The nano-vaccine was composed of polyserotonin (PST) core and tannic acid (TA)/Mn2+ coordination-based metal-organic-framework (MOF) shell for β-catenin silencing DNAzyme loading, which was further integrated into dissolving microneedles to allow noninvasive and transdermal administration at melanoma skin. The nano-vaccine could rapidly penetrate skin upon microneedles insertion and exert a synergistically amplified photothermal effect to induce immunogenic cell death (ICD). The MOF shell then dissociated and released Mn2+ as a cofactor to self-activate DNAzyme for β-catenin suppression, which in turn caused a persistent CCL4 excretion to promote the infiltration of DCs into the tumor. Meanwhile, the liberated PST core could effectively capture and facilitate tumor antigens presentation to DCs. As a result, potent antitumor efficacies were achieved for both primary and distal tumors without any extra treatment, indicating the great promise of such a nano-vaccine for on-demand personalized immunotherapy of melanoma.