Engineered bacterial membrane vesicles as transdermal cancer vaccines

Transdermal vaccines, leveraging the abundant antigen-presenting cells (APCs) resident in the skin to elicit antigen-specific immune responses, have progressed rapidly in recent years. However, successful transdermal vaccines still require effective transdermal delivery systems with potent immune adjuvant functions. Herein, we discovered that bacterial membrane vesicles (BMVs) with unique transdermal penetration behaviors and inherent immune-stimulating abilities could act as a nanoscale platform to engineer transdermal vaccines. In our system, BMVs produced from VNP20009 exhibited superior skin penetration compared to mammalian cell-derived membrane vesicles (CMVs) owing to their marked advantage in paracellular transport. Cholesterol-modified antigenic peptides are then incorporated into the lipid bilayer of BMVs to form a transdermal nanoscale vaccine, in which BMVs serve simultaneously as a transdermal carrier and an adjuvant. Notably, such BMV-based vaccine stimulated dendritic cell (DC) maturation and facilitated antigen cross-presentation, thereby promoting antigen-specific T-cell immunity. After topical application, tumor-antigen-loaded BMVs trigger robust anti-tumor immune responses and achieve efficient protective effects against melanoma tumors. This work highlights the potential of BMVs as a simple yet robust platform to develop transdermal vaccines.