Use of Iontophoresis Technology for Transdermal Delivery of a Minimal mRNA Vaccine as a Potential Melanoma Therapeutic

Abstract

mRNA vaccines have attracted considerable attention as a result of the 2019 coronavirus pandemic; however, challenges remain regarding use of mRNA vaccines, including insufficient delivery owing to the high molecular weights and high negative charges associated with mRNA. These characteristics of mRNA vaccines impair intracellular uptake and subsequent protein translation. In the current study, we prepared a minimal mRNA vaccine encoding a tumor associated antigen human gp100 25-33 peptide (KVPRNQDWL), as a potential treatment for melanoma. Minimal mRNA vaccines have recently shown promise at improving the translational process, and can be prepared via a simple production method. Moreover, we previously reported the successful use of iontophoresis (IP) technology in the delivery of hydrophilic macromolecules into skin layers, as well as intracellular delivery of small interfering RNA (siRNA). We hypothesized that combining IP technology with a newly synthesized minimal mRNA vaccine can improve both transdermal and intracellular delivery of mRNA. Following IP-induced delivery of a mRNA vaccine, an immune response is elicited resulting in activation of skin resident immune cells. As expected, combining both technologies led to potent stimulation of the immune system, which was observed via potent tumor inhibition in mice bearing melanoma. Additionally, there was an elevation in mRNA expression levels of various cytokines, mainly interferon (IFN)-γ, as well as infiltration of cytotoxic CD8 T cells in the tumor tissue, which are responsible for tumor clearance. This is the first report demonstrating the application of IP for delivery of a minimal mRNA vaccine as a potential melanoma therapeutic.

Intradermal Delivery of Naked mRNA Vaccines via Iontophoresis

“…Husseini et al [101] Naked mRNA encoding tumor-associated antigen gp100 [25][26][27][28][29][30][31][32][33] Melanoma-bearing mice; 0.17 mA/0.5 cm 2 for 1 h.…”

“…Vaccination with mRNA results in expression of tumorassociated or tumor-specific antigens in APCs that induce humoral or cell-mediated immune responses [106]. Husseini et al investigated ItP-mediated intradermal delivery of a naked, minimal mRNA-based vaccine encoding tumor-associated human gp100 [25][26][27][28][29][30][31][32][33] (KVPRNQDWL) as an immunotherapy for melanoma [101]. The authors introduced a short poly (A) tail into the mRNA sequence that protects the mRNA from de-capping and degradation.…”

Cancer Therapy Empowered by Extracellular Vesicle-Mediated Targeted Delivery

“…To improve the efficacy, the mRNA vaccine is injected subcutaneously into the body by iontophoresis to effectively induce anti-tumor immunity. 68) In addition, the biological characteristics of EVs enable the induction of effective tumor-specific immunity. EVs are injected into the body as a vaccine to induce tumor-specific immunity, stimulating antigen-presenting cells and anti-tumor immunity.…”