At the Intersection of Biomaterials and Gene Therapy: Progress in Non-viral Delivery of Nucleic Acids

Abstract

Biomaterials play a critical role in technologies intended to deliver therapeutic agents in clinical settings. Recent explosion of our understanding of how cells utilize nucleic acids has garnered excitement to develop a range of older (e.g., antisense oligonucleotides, plasmid DNA and transposons) and emerging (e.g., short interfering RNA, messenger RNA and non-coding RNAs) nucleic acid agents for therapy of a wide range of diseases. This review will summarize biomaterials-centered advances to undertake effective utilization of nucleic acids for therapeutic purposes. We first review various types of nucleic acids and their unique abilities to deliver a range of clinical outcomes. Using recent advances in T-cell based therapy as a case in point, we summarize various possibilities for utilizing biomaterials to make an impact in this exciting therapeutic intervention technology, with the belief that this modality will serve as a therapeutic paradigm for other types of cellular therapies in the near future. We subsequently focus on contributions of biomaterials in emerging nucleic acid technologies, specifically focusing on the design of intelligent nanoparticles, deployment of mRNA as an alternative to plasmid DNA, long-acting (integrating) expression systems, and in vitro/in vivo expansion of engineered T-cells. We articulate the role of biomaterials in these emerging nucleic acid technologies in order to enhance the clinical impact of nucleic acids in the near future.

Keywords: T-cell therapy; biomaterials; gene medicine; mRNA; nanoparticle; nucleic acid delivery; pDNA delivery; siRNA.

Figure 1

Different nucleic acids that could be used to derive therapeutic outcomes. (A) Major types of nucleic acids used to modulate cell behavior and could serve as therapeutic agents. (B) Intracellular trafficking and site of action for intervention with different types of nucleic acids.

Figure 2

Design of intelligent NPs for delivery of nucleic acids.

Figure 3

A schematic of ideal scaffolds to expand and/or activate T-cells for disease management. A sophisticated scaffold could be designed to support cell survival and expansion based on cell-attachment ligands, free/released cytokines, and immobilized ligands to promote cell proliferation. The cells could be activated with local presentation of antagonists of checkpoint inhibitors. The scaffolds could serve for ex vivo expansion of T-cells, as well as in vivo activation of T-cells.