A Self‐Assembled Transdermal Nanomedicines Incorporating Pendant Disulfides for Non‐Invasive, Synergistic Treatment of Melanoma

Abstract Transdermal drug delivery system (TDDS) offers lower systemic toxicity and good patient compliance, making it a promising treatment option for skin‐related cancers. However, physiological barriers in the skin frequently impede the therapeutic efficiency of TDDS. To address this, a unique self‐assembled TDDS that incorporates disulfide pendant groups (termed Sup‐TDDS) is presented. It is formulated with dithiolane‐containing lipoic acid (LA), photosensitizers Ce6, and chemotherapeutic agents trametinib. Pendant disulfide moieties on Sup‐TDDS facilitate thiol‐disulfide exchange reactions with exofacial thiols on cell surfaces, thus enhancing stratum corneum penetration. In contrast to intravenous injection, topical administration of Sup‐TDDS can penetrate deeper into the skin (> 500 µm) and promote drug accumulation in subcutaneous tumors. In a B16F10‐bearing mouse model, Sup‐TDDS treatment demonstrates significant anti‐tumor effects in primary and recurrent melanoma, benefiting from the synergistic effects of Ce6 and trametinib. These results underscore that Sup‐TDDS's transdermal properties allow non‐invasive melanoma therapy, implying the potential of nanodrugs containing pendant disulfides for transdermal treatment of skin illnesses.