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.

Hydrogel-Based Localized Nonviral Gene Delivery in Regenerative Medicine Approaches—An Overview

“…Owing to the essential role that the extracellular matrix (ECM) plays in maintaining the physiological stability of the microenvironment and guiding tissue-specific function, biomaterials have been engineered in an effort to support tissue regeneration and serve as vehicles for cell transplantation, promoting survival, differentiation, and engraftment [15]. Likewise, these biomaterial scaffolds may be exploited to deliver therapeutic gene molecules, providing a controlled release of these agents in desired locations as a means to avoid clearance mechanisms and reinforce their stability in the physiological milieu [2]. The use of "gene medicines" offers an alternative to small drugs and recombinant growth factors that are prone to nonspecific effects on various cellular systems and may induce resistance once the innate physiological mechanisms are induced by the cells to overcome the drug effects [2].…”

“…Likewise, these biomaterial scaffolds may be exploited to deliver therapeutic gene molecules, providing a controlled release of these agents in desired locations as a means to avoid clearance mechanisms and reinforce their stability in the physiological milieu [2]. The use of "gene medicines" offers an alternative to small drugs and recombinant growth factors that are prone to nonspecific effects on various cellular systems and may induce resistance once the innate physiological mechanisms are induced by the cells to overcome the drug effects [2]. Further, compared with recombinant growth factors that exhibit half-life in the range of minutes and a rapid inactivation in physiological conditions, gene therapy offers the possibility of directly transferring genes encoding for the therapeutic factor into the target cell population [20].…”

“…Recent progress of our understanding of how cells utilize nucleic acids (NA) has focused the attention to develop a range of original (plasmid DNA (pDNA)) and emerging (RNA interference (RNAi) and messenger RNA (mRNA)) nucleic acid candidates for treatment of a wide range of diseases [1,2], to trigger (pDNA, mRNA) or suppress (small interfering RNA (siRNA) and micro RNA (miRNA)) the expression of specific genes and transcription factors [2,3].…”

“…Viral vectors rely on the natural cellular entry pathways of viruses from which they are derived, being highly efficient at internalizing these NA molecules into the cells [9]. However, gene therapy via viral vectors carries important shortcomings due to their risk of insertional mutagenesis, inherent cytotoxicity and/or immunogenicity [2], and tumorigenic risk [10,11]. Herein, gene delivery via nonviral systems is nowadays at the forefront of gene therapy [12].…”

Insights on the DNA Stability in Aqueous Solutions of Ionic Liquids

“…In the past decades, several studies pointed out DNA as a relevant biopharmaceutical for genetic therapy purposes (Uludag et al, 2019), namely in the development of DNA vaccination, in pluripotent stem cells research, cellular therapy in psychiatric diseases (Lissek, 2017) and to induce the expression of therapeutic transgenes (Yin et al, 2014). However, the therapeutic efficacy and biological activity of DNA mainly depends on its structural stability and integrity (Diamantino et al, 2016).…”