Poly(β-amino ester)s-based delivery systems for targeted transdermal vaccination

Abstract

Abstract Nucleic acid vaccines have become a transformative technology to fight emerging infectious diseases. However, pursuing alternative routes of administration such as the transdermal could boost their therapeutic merit given the complex immune cell reservoir present in the skin capable of engendering robust immune responses. We have generated a novel library of vectors derived from poly(β-amino ester)s (PBAEs) that include oligopeptide-termini and a natural ligand, mannose, for targeted transfection of antigen presenting cells (APCs) in the epidermal milieu. Our results reaffirmed terminal decoration of PBAEs with oligopeptide chains as a powerful tool to induce cell-specific transfection, identifying an outstanding candidate with a ten-fold increased transfection efficiency over commercial controls in vitro. The inclusion of mannose in the PBAE backbone rendered an additive effect and increased transfection levels, achieving superior gene expression in human monocyte-derived dendritic cells such as Langerhans cells and other accessory antigen presenting cells. Moreover, top performing candidates were capable of mediating surface gene transfer when deposited as polyelectrolyte films onto transdermal devices such as microneedles, offering alternatives to conventional hypodermic administration. We predict that the use of highly efficient delivery vectors derived from PBAEs could advance clinical translation of nucleic acid vaccination over protein- and peptide-based strategies.