RNA/Polymer-Based Supramolecular Approaches for mRNA Delivery

ABSTRACT

Messenger RNA (mRNA) therapeutics garner growing attention, especially after the approval of two mRNA vaccine formulations for COVID-19. Meanwhile, as a therapeutic modality, mRNA still has issues of poor bioavailability, showing rapid enzymatic degradation in physiological environments and inducing uncontrollable inflammatory responses. Chemical modification of mRNA is a prevalent approach to these issues and effectively reduces mRNA immunogenicity. However, available modified nucleotide species are limited to protect mRNA from enzymatic attacks with preserved mRNA translational activity. Alternatively, in supramolecular approaches, mRNA can be formulated with other molecules to improve its bioavailability. This approach requires minimal modification of mRNA and thus preserves its translational activity. Nano-particulated mRNA formulations using lipids and polymers are widely studied. Among them, polymeric micelles effectively prevent enzymatic mRNA degradation in biological milieu after recent advances in polymer design, allowing safe and efficient mRNA delivery to various organs. Supramolecular approaches also include mRNA formulation using complementary RNA oligonucleotides, which allows the installation of protective moieties to mRNA or crosslinking of several mRNA strands to improve mRNA stability against nucleases. This chapter reviews these strategies to effectively transport mRNA therapeutics to target cells in vivo. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.