Abstract
Therapeutic nucleic acids hold immense potential in combating undruggable, gene-based diseases owing to their high programmability and relative ease of synthesis. While the delivery of this class of therapeutics has successfully entered the clinical setting, extrahepatic targeting, endosomal escape efficiency, and subcellular localization remain as major roadblocks. On the other hand, viruses serve as natural carriers of nucleic acids and have acquired a plethora of structures and mechanisms that confer remarkable transfection efficiency. Thus, understanding the structure and mechanism of viruses can guide the design of synthetic nucleic acid vectors. This review revisits relevant structural and mechanistic features of viruses as design considerations for efficient nucleic acid delivery systems. This article explores how viral ligand display and a metastable structure are central to the molecular mechanisms of attachment, entry, and viral genome release. For comparison, accounted for are details on the design and intracellular fate of existing nucleic acid carriers and nanostructures that share similar and essential features to viruses. The review, thus, highlights unifying themes of viruses and nucleic acid delivery systems such as genome protection, target specificity, and controlled release. Sophisticated viral mechanisms that are yet to be exploited in oligonucleotide delivery are also identified as they could further the development of next-generation nonviral nucleic acid vectors.
Highlights
Undruggable targets are disease-implicated proteins that lack easy-to-bind pockets where conventional therapeutics like small molecules can bind (Crews, 2010; Duffy and Crown, 2021)
Binding to surface CD30 overexpressed in anaplastic lymphoma kinase (ALK) + anaplastic large cell lymphoma (ACLC) promotes endocytosis Binding to cell surface transferrin receptor mediates endocytosis Binding to integrins facilitates clathrin- or receptor- mediated endocytosis Binding to glucagon-like peptide 1 receptor (GLP1R) on pancreatic islet beta cells facilitates endocytosis Cationic naked or conjugated peptide can enter cells via macropinocytosis or receptor-mediated endocytosis Acid-labile hydrazone linkages are cleaved around tumor cells, revealing cationic cellpenetrating peptide (CPP) that mediates endocytosis Hydrophobic domain of peptide facilitates direct cytosolic entry Multivalent binding to hepatocyte asioglycoprotein receptor (ASGPR) mediates endocytosis Binding to folate-receptors overexpressed in cancer cells mediates endocytosis
Recombinant Dynein binding protein (DBP)-containing protein condensed with plasmid DNA (pDNA), small interfering RNA (siRNA) and double-stranded RNA (dsRNA) pDNA condensed with cationic Nuclear localization signal (NLS); gold nanoparticle (AuNP) conjugated complex of CRISPR/ Cas9-gRNA, Cas9, and NLS; pDNANLS conjugates HA/PEI1800-Dex/pDNA ternary complexes
Summary
Viruses serve as natural carriers of nucleic acids and have acquired a plethora of structures and mechanisms that confer remarkable transfection efficiency. Understanding the structure and mechanism of viruses can guide the design of synthetic nucleic acid vectors. This review revisits relevant structural and mechanistic features of viruses as design considerations for efficient nucleic acid delivery systems. This article explores how viral ligand display and a metastable structure are central to the molecular mechanisms of attachment, entry, and viral genome release. Accounted for are details on the design and intracellular fate of existing nucleic acid carriers and nanostructures that share similar and essential features to viruses. The review, highlights unifying themes of viruses and nucleic acid delivery systems such as genome protection, target specificity, and controlled release.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
