Peptides as a Material Platform for Gene Delivery: Emerging Concepts and Converging Technologies

Successful gene therapies rely on methods that safely introduce DNA into target cells and enable subsequent expression of proteins. To that end, peptides are an attractive materials platform for DNA delivery, facilitating condensation into nanoparticles, delivery into cells, and subcellular release to enable protein expression. Peptides are programmable materials that can be designed to address biocompatibility, stability, and subcellular barriers that limit efficiency of non-viral gene delivery systems. This review focuses on fundamental structure-function relationships regarding peptide design and their impact on nanoparticle physical properties, biologic activity, and biocompatibility. Recent technologies grown out of classic approaches are presented that utilize multi-dimensional structures, non-natural chemistries, and combinations of peptides with lipids to achieve efficient transfection. Advances in DNA design are also highlighted to show the potential for more efficient or prolonged expression compared to traditional plasmids, providing an additional component that can be synergized with peptide carriers for improved transfection. Modern peptide transfection systems are poised to become a flexible and efficient platform incorporating new chemistries, functionalities, and improved DNA cargos to usher in a new era of gene therapy.