Delivery strategies for RNA-targeting therapeutic nucleic acids and RNA-based vaccines against respiratory RNA viruses: IAV, SARS-CoV-2, RSV

Abstract

Therapeutic nucleic acids, including small interfering RNA (siRNA), and antisense oligonucleotides (ASOs), targeting RNA viruses such as influenza A virus (IAV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and respiratory syncytial virus (RSV), play a crucial role in contemporary medicine. The primary goal of short oligonucleotide-based antivirals is to precisely inhibit viral mechanisms by interacting with viral RNA, thereby opening new avenues for infection treatment. RNA recently was also used to invent mRNA vaccine for different illness prevention. Therapeutic nucleic acids and mRNA vaccine attracted considerable attention during the COVID-19 pandemic due to the pressing necessity to develop an effective strategy to address this global threat. In addition to the advancement of therapeutic nucleic acids aimed at targeting respiratory viruses, the effective delivery of these molecules to infected cells is of paramount importance. Similarly, mRNA vaccine's effectiveness also depends on effective delivery. This article offers a comprehensive summary and analysis of various delivery strategies, along with the challenges encountered in their development. Representative studies conducted in cellular models, model organisms, and human are presented for examination. Furthermore, the article explores future perspectives regarding the delivery of therapeutic nucleic acids and mRNA vaccines aimed at combating IAV, SARS-CoV-2, and RSV.

Keywords: ASO; MT: Delivery Strategies; RNA therapeutics; RSV; SARS-CoV-2; delivery methods; influenza A; mRNA vaccine; oligonucleotides.

Graphical abstract

Figure 1

Outline diagram visualizing the structure of the manuscript

Figure 2

Schematic representation of SARS-CoV-2, IAV, and RSV, along with their genomes The virions structure includes each virus’s main structural proteins, whereas the genome diagrams show their organization and key functional elements. In the IAV genome, the orange boxes at the ends of each vRNA segments represent the 5′ and 3′ untranslated regions (UTRs); the blue boxes represent the packaging signals in the coding region. The numbers inside the boxes represent the nucleotide length for the UTRs and the packaging signals. These values are based on a reference model.

Figure 3

Molecular mechanisms of action of ASO and siRNA on the example of mRNA as a target

Figure 4

Generations of antisense oligonucleotides. (1) The chemical structure of the first, second, and third generations of oligonucleotides, compared to DNA and RNA structures. DNA, deoxyribonucleic acid; RNA, ribonucleic acid; oligonucleotides modifications: PS, phosphorothioate oligonucleotide; PA, phosphoramidate oligonucleotide; MP, methylphosphonate oligonucleotide; 2′-MOE, 2′-O-methoxyethyl RNA; 2′-OMe, 2′-O-methyl RNA; 2′F, 2′-fluoro RNA; LNA, locked nucleic acid; PNA, peptide nucleic acid; PMO, phosphorodiamidate morpholino oligonucleotide. (2) Chemical structure of modifications used in RNA vaccines. Cap-1, Cap structure on 5′ end of mRNA: m7GpppNm, where Nm is a 2′ -methylated nucleotide; m1Ψ, N1-methylpseudouridine.

Figure 5

Scheme of delivery technologies for nucleic acids