Design and Self-Assembly of Therapeutic Nucleic Acid Nanoparticles (NANPs) with Controlled Immunological Properties

Abstract

Nucleic acids carry out a diverse number of functions as carriers and regulators of gene expression. By combining naturally occurring structural motifs with known base pairing rules, nucleic acids have also been demonstrated to rationally assemble into nucleic acids nanoparticles (NANPs) of varying shapes, sizes, and compositions. These constructs can be utilized as scaffolds for the delivery of therapeutic moieties and, owing to their programmable nature, can be designed to interact and perform dynamic functions within the cellular environment. However, in order to defend against pathogenic nucleic acids, cells have long since evolved signaling pathways capable of recognizing patterns of nucleic acids which are distinctly nonself in order to elicit a respective immune response. While unknown immunostimulation was previously a hurdle for therapeutic nucleic acids, these established pathways now offer an additional facet of design for therapeutic NANPs, which can be constructed to fit a favorable immunostimulatory profile depending on the therapeutic application.KeywordslncRNAsmiRNAsiRNAsRNA interference (RNAi)RNA-induced silencing complex (RISC)shRNAsDicer substrate RNAsRiboswitchesRibozymesAptamersSystematic evolution of ligands by exponential enrichment (SELEX)PharmacophoreDianophoreTNAsNucleic acid nanoparticles (NANPs)Rational designKissing loopImmunostimulationPattern recognition receptors (PRRs)Toll-like receptors (TLRs)RIG-IMDA5MAVSInterferonscGASIFI16AIM2Pathogen-associated molecular patterns (PAMPs)Peripheral blood mononuclear cells (PBMCs)ImmunoquiescentNF-κBChemical modificationsPseudouridine2′-O-methyl5′ capT7 RNA polymeraseDelivery