Design of modular non-viral gene therapy vectors

Abstract

Gene delivery has numerous potential applications both clinically and for basic science research. Non-viral vectors represent the long-term future of gene therapy and biomaterials are a critical component for the development of efficient delivery systems. Biomaterial development combined with fundamental studies of virus function and cellular processes will enable the molecular level design of modular vectors. Vectors are being developed based on cationic polymers or lipids that contain functional groups to mediate appropriate interactions with the extracellular environment or to interface with specific cellular processes. This review describes recent progress on the development of biomaterials for non-viral vectors and highlights opportunities for future development. Ultimately, efficient vectors will expand the traditional applications of gene therapy within the clinic and may enable numerous other opportunities within diagnostics, biotechnology, and basic science research.

Fig. 1

Modular design of non-viral vectors schematic. Modules associated with vector design are: vector backbone (grey), functional groups for regulating environmental interactions (purple), and intracellular trafficking (red). The vector backbone, typically containing polymers, lipids, or polysaccharides, is designed for DNA binding and complexation, which can protect against nuclease degradation, create a small, less negatively charged particle that can be internalized by cells, and facilitate some intracellular trafficking. The function of the vector backbone is being augmented by the attachment of groups that address the extracellular and intracellular barriers. The environmental functional groups can serve to limit interactions with serum components, promote specific cell binding or tissue targeting, or facilitate interactions with the extracellular matrix or biomaterials. The intracellular functional groups aim to enhance nuclear accumulation of the DNA either by facilitating endosomal escape, movement along the cytoskeleton, or nuclear pore trafficking. The individual modules can be assembled in different ways (a–c) for complexation with DNA (green), which may affect the structure and function of the resulting non-viral vector. (d) Schematic illustrating the distribution of the modules and DNA throughout the vector cross section, with the desired organization of functional groups regulating the environmental interactions presented primarily on the exterior and the groups for intracellular trafficking protected within the vector interior for activity following internalization. (e) Vectors are internalized by endocytosis and must subsequently escape the endosome for transport to the nucleus. Additionally, the modular components must dissociate from the DNA to allow for transcription. Adapted from Martin-Herranz [3].