Viral Mimicry as a Design Template for Nucleic Acid Nanocarriers

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. 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.

Think like a Virus: Toward Improving Nanovaccine Development against SARS-CoV-2

“…Moreover, these nanoparticles have a higher risk of triggering immune responses. Hence, these two challenges make it essential for developing tuning techniques that can enhance the nanoparticle’s stability, immunomodulatory effect, targeting specificity, and thus localization properties [ 73 ]. Such tuning techniques involve the incorporation of materials in the synthesis of the viral nanoparticles.…”

“…Moreover, existing nanoparticles can be coated with viral proteins to mimic the virus. Additionally, it is crucial to study the nanoparticles’ uptake, escape, and trafficking mechanism, as these mechanisms often involve different signaling cascades that can affect the cells/organs or tissues in the long term [ 73 ].…”

Mesenchymal Stem Cells Engineered by Nonviral Vectors: A Powerful Tool in Cancer Gene Therapy

“…The structure and function of the virus can provide insights. Biomimetic nonviral vectors are designed to mimic viral characteristics and overcome cellular barriers [ 178 ]. For example, liposomes or polymers can be used to construct the scaffolds of the vector and then to embed certain important functional motifs into them, such as CPPs, fusion peptides and histone H1.…”

Nanoparticles-Based Oligonucleotides Delivery in Cancer: Role of Zebrafish as Animal Model

“…Lipid nanoparticles (LNPs) gained much attention in the 1980s when Felgner and colleagues demonstrated that the association of plasmid DNA (pDNA) with cationic lipids such as 1,2-di- O -octade-cenyl-3-trimethylammonium propane (DOTMA) and dioleyl phosphatidylethanolamine (DOPE) induced the in vitro and, lately, the in vivo transfection of cells [ 61 ]. All the subsequent studies on LNPs culminated in 2018 with the US Food and Drug Administration (FDA) approval of Patisiran (ONPATTRO) as a carrier for siRNA delivery into cells for the treatment of hereditary transthyretin (hATTR) amyloidosis [ 62 ]. Due to successful results in preclinical and clinical studies, LNPs are currently the only structures approved by the FDA as drug delivery carriers.…”

“…In the last decade, inorganic NPs (INPs) have been extensively studied because of their tunable size and surface properties, chemical and thermal stability, and low toxicity [ 62 , 89 ]. Of the INPs, gold NPs (AuNPs) are the most studied because they can be produced with low size dispersity and they can be functionalized by the creation of multifunctional monolayers to modulate cytotoxicity, biodistribution, and excretion [ 89 ].…”