Opportunities and challenges for the clinical translation of structuredDNAassemblies as gene therapeutic delivery and vaccine vectors

Abstract

Gene therapeutics including siRNAs, anti‐sense oligos, messenger RNAs, and CRISPR ribonucleoprotein complexes offer unmet potential to treat over 7,000 known genetic diseases, as well as cancer, through targeted in vivo modulation of aberrant gene expression and immune cell activation. Compared with viral vectors, nonviral delivery vectors offer controlled immunogenicity and low manufacturing cost, yet suffer from limitations in toxicity, targeting, and transduction efficiency. Structured DNA assemblies fabricated using the principle of scaffolded DNA origami offer a new nonviral delivery vector with intrinsic, yet controllable immunostimulatory properties and virus‐like spatial presentation of ligands and immunogens for cell‐specific targeting, activation, and control over intracellular trafficking, in addition to low manufacturing cost. However, the relative utilities and limitations of these vectors must clearly be demonstrated in preclinical studies for their clinical potential to be realized. Here, we review the major capabilities, opportunities, and challenges we foresee in translating these next‐generation delivery and vaccine vectors to the clinic. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology‐Inspired Nanomaterials > Nucleic Acid‐Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Epigenetic therapy targeting bone marrow mesenchymal stem cells for age-related bone diseases

“…Recently, structured DNA assemblies fabricated using the principle of scaffolded DNA origami have been applied as a new nonviral delivery vector. The vector has the properties of controllable immunostimulatory, virus-like spatial presentation of ligands and immunogens for cell-specific targeting, intracellular trafficking, and low manufacturing cost, providing a novel tool for delivery of nucleic acids [ 111 ].…”

Induction of Cytokines by Nucleic Acid Nanoparticles (NANPs) Depends on the Type of Delivery Carrier

“…A variety of NANPs are now being investigated for broad applications in detection and diagnostics [ 16 , 17 , 18 ], targeting specific disease sites [ 19 ], and as therapeutic approaches [ 9 , 20 , 21 , 22 ] for various illnesses. As the technology approaches the stage of preclinical development and clinical translations, many researchers in the field have consolidated their efforts to overcome translational gaps and accelerate the transition of DNA and RNA nanoassemblies from bench to clinic [ 23 , 24 , 25 , 26 , 27 , 28 ]. Among these efforts is the understanding of the immunological properties of NANPs as a new class of therapeutic nucleic acids.…”

In Situ Covalent Functionalization of DNA Origami Virus-like Particles

“…Structural DNA nanotechnology − has been extensively applied to biological applications, , including therapeutic delivery, − due to its geometric and chemical programmability at the nanoscale. The DNA origami method uses a long single-stranded DNA (ssDNA) “scaffold” and short oligonucleotide “staples” to fold complex DNA nanostructures with quantitative yields. − Polyhedral wireframe nanostructures have been developed to provide precise control over 2D and 3D structures. , Overcoming bottlenecks with recent efforts in top-down sequence design − and large-scale custom scaffold production, − DNA origami is imminently positioned for translational research. , As recently reviewed by Madsen and Gothelf, this will require the efficient functionalization of DNA nanostructures, a field that remains underdeveloped …”

“…15,16 Overcoming bottlenecks with recent efforts in top-down sequence design 17−20 and large-scale custom scaffold production, 21−23 DNA origami is imminently positioned for translational research. 3,24 As recently reviewed by Madsen and Gothelf, this will require the efficient functionalization of DNA nanostructures, a field that remains underdeveloped. 25 Precise functionalization of DNA origami is commonly achieved through postassembly hybridizations, where ssDNA overhangs on the DNA nanostructure hybridize to a complementary nucleic acid strand attached to the desired conjugate.…”