Poly(β-amino ester)s-Based Delivery Systems for Targeted Transdermal Vaccination

Nucleic acid vaccines have become a transformative technology to fight emerging infectious diseases and cancer. Delivery of such via the transdermal route could boost their efficacy given the complex immune cell reservoir present in the skin that is capable of engendering robust immune responses. We have generated a novel library of vectors derived from poly(beta-amino ester)s (PBAEs) including oligopeptide-termini and a natural ligand, mannose, for targeted transfection of antigen presenting cells (APCs) such as Langerhans cells and macrophages in the dermal 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 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.

Automated summary

Nucleic acid vaccines are important in combating emerging infectious diseases and cancer. Delivery of these vaccines via the transdermal route has the potential to enhance their efficacy due to the presence of immune cells in the skin. Researchers have developed a new library of transfection vectors that can specifically target antigen presenting cells in the skin. These vectors have demonstrated high transfection efficiency and the ability to mediate gene transfer when applied to transdermal devices. The use of these efficient vectors derived from PBAEs has the potential to advance nucleic acid vaccination in clinical settings.