Polymeric Delivery of Therapeutic Nucleic Acids

Abstract

The advent of genome editing has transformed the therapeutic landscape for several debilitating diseases, and the clinical outlook for gene therapeutics has never been more promising. The therapeutic potential of nucleic acids has been limited by a reliance on engineered viral vectors for delivery. Chemically defined polymers can remediate technological, regulatory, and clinical challenges associated with viral modes of gene delivery. Because of their scalability, versatility, and exquisite tunability, polymers are ideal biomaterial platforms for delivering nucleic acid payloads efficiently while minimizing immune response and cellular toxicity. While polymeric gene delivery has progressed significantly in the past four decades, clinical translation of polymeric vehicles faces several formidable challenges. The aim of our Account is to illustrate diverse concepts in designing polymeric vectors towards meeting therapeutic goals of in vivo and ex vivo gene therapy. Here, we highlight several classes of polymers employed in gene delivery and summarize the recent work on understanding the contributions of chemical and architectural design parameters. We touch upon characterization methods used to visualize and understand events transpiring at the interfaces between polymer, nucleic acids, and the physiological environment. We conclude that interdisciplinary approaches and methodologies motivated by fundamental questions are key to designing high-performing polymeric vehicles for gene therapy.

Combinatorial Polycation Synthesis and Causal Machine Learning Reveal Divergent Polymer Design Rules for Effective pDNA and Ribonucleoprotein Delivery

“… 9 Viral delivery is confronted with logistical, technological, and commercial obstacles in the form of limited cargo capacity, 10 high manufacturing costs, 11 significant regulatory burdens, 12 and severe immune responses. 13 − 15 To circumvent these challenges, biomaterials researchers have designed chemically defined synthetic delivery platforms such as polymers 16 and lipids 17 whose performance meets or exceeds benchmarks set by clinically deployed viral vectors. 18 , 19 …”

Polyester materials for mRNA delivery

“…However, the clinical implementation of mRNA therapeutics is limited by their poor bioavailability and instability in vivo [7][8][9]. To address these obstacles and improve the druggability of mRNA, tremendous efforts have been invested in engineering mRNA molecules and developing mRNA delivery systems [10][11][12][13]. Lipids and polymers are the most advanced delivery systems for nucleic acid therapeutics [14][15][16].…”

Oxygen nanocarrier broke the hypoxia trap of solid tumors and rescued transfection efficiency for gene therapy

“…The therapeutic effect of gene therapy largely depends on the capacity of gene vectors to deliver exogenous genes and the efficiency of gene transfection in target cells [ 4 ]. Most of the related work focused on optimizing gene delivery systems to enhance the efficiency of gene therapy through effective encapsulation, enhanced cellular uptake of target cells, endosomal escape and promoted nuclear transport [ 5 , 6 ]. These methods only achieved highly efficient gene transfection in vitro, the therapeutic effect in vivo was still far from satisfactory [ 7 ].…”