Microneedle-assisted dendritic cell-targeted nanoparticles for transcutaneous DNA immunization

Abstract

Transcutaneous immunization (TCI) is an attractive vaccination strategy for targeting the epidermal dendritic cells (DCs). TCI has been widely explored for protection against infectious diseases. Recently, its promising application in cancer immunotherapy has also attracted great attention. However, effective percutaneous delivery of the vaccines must overcome the formidable stratum corneum, as well as specifically target DCs; both are big challenges. We developed the mannosylated grafted cell-penetrating peptide-low molecular weight PEI copolymer (CPP-PEI₁₈₀₀-Man) with the combination of microneedles for DC-targeting percutaneous delivery of DNA vaccine for malignant melanoma (MM) therapy. Mannose receptors are overexpressed on the surface of DCs. The microneedle-assisted in vivo skin penetration of the CPP-PEI₁₈₀₀-Man/DNA nanoparticles was investigated, and the DC-targeting efficiency was measured. The induction of protective and therapeutic anti-tumor immunity by the CPP-PEI₁₈₀₀-Man/DNA nanoparticles was significantly enhanced compared to the PEI_25k/DNA vaccines. Transcutaneous vaccination with the microneedle-assisted CPP-PEI₁₈₀₀-Man/DNA efficiently promoted Trp2-specific cellular immune responses, resulting in effective protection against B16 melanoma challenge in BALB/c mice. Importantly, the CPP-PEI₁₈₀₀-Man/DNA nanoparticles strongly induced CD8⁺ cytotoxic T lymphocyte activity and CD4⁺ T cells that secreted the interferon-γ and interleukin-12 cytokines against melanoma cells. As a result, cancer growth was inhibited and the survival time of B16-xenografted BALB/c mice was prolonged. Therefore, the CPP-PEI₁₈₀₀-Man copolymer is promising for DC-specific vaccination, and microneedle-assisted CPP-PEI₁₈₀₀-Man/DNA delivery represents a potential immunotherapeutic strategy for MM.