Critical review of nucleic acid nanotechnology to identify gaps and inform a strategy for accelerated clinical translation

Abstract

With numerous recent advances, the field of therapeutic nucleic acid nanotechnology is now poised for clinical translation supported by several examples of FDA-approved nucleic acid nanoformulations including two recent mRNA-based COVID-19 vaccines. Within this rapidly growing field, a new subclass of nucleic acid therapeutics called nucleic acid nanoparticles (NANPs) has emerged in recent years, which offers several unique properties distinguishing it from traditional therapeutic nucleic acids. Key unique aspects of NANPs include their well-defined 3D structure, their tunable multivalent architectures, and their ability to incorporate conditional activations of therapeutic targeting and release functions that enable diagnosis and therapy of cancer, regulation of blood coagulation disorders, as well as the development of novel vaccines, immunotherapies, and gene therapies. However, non-consolidated research developments of this highly interdisciplinary field create crucial barriers that must be overcome in order to impact a broader range of clinical indications. Forming a consortium framework for nucleic acid nanotechnology would prioritize and consolidate translational efforts, offer several unifying solutions to expedite their transition from bench-to-bedside, and potentially decrease the socio-economic burden on patients for a range of conditions. Herein, we review the unique properties of NANPs in the context of therapeutic applications and discuss their associated translational challenges.

Keywords: Dna origami; Non-viral vector; Nucleic acid nanotechnology; Therapeutic nucleic acids; Vaccine.

Graphical abstract

Fig. 1

Overview of diverse NANP formulations and their biomedical applications. (A) DNA origami composed of a long single-stranded DNA folded with shorter, synthetic oligos can be used to formulate site-specific, responsive nanomaterials for cancer vaccines. Tumor antigens are co-formulated with RNA and DNA adjuvants, resulting in functional NANPs, which stimulate dendritic cells site-specifically for CTL activation. Figure reproduced from . (B) NANPs architectural parameters and chemical compositions define specific immunorecognition upon their intracellular delivery , , . (C) Messenger RNA scaffold or various NANPs, made of short oligos, can be co-formulated with therapeutic RNAi inducers to facilitate Dicer assisted release of siRNAs and consequent gene silencing , , . Upper panel of figure reproduced from . (D) Functionally interdependent NANPs can be designed for conditional activation of various split functionalities among which are RNAi, FRET, transcription, aptamers, etc .

Fig. 2

NCI R01 nanotechnology-based applications submitted and awarded per fiscal year in the period of 2012–2020. (A) R01 applications associated with nanotechnology and RNA research (B) R01 applications associated with any nanotechnology and cancer research area. (B). The data were obtained using an internal NIH grant database and contains information on both new and resubmitted grants. Nanotechnology (A) submissions were identified using a search with the NIH RCDC (Research, Condition, and Disease Categorization) term of “nano AND RNA” “nano”, while nanotechnology submissions (B) used search term “nano”.

Fig. 3

Costs of drug products. Manufacturing costs (A) and the annual cost per patient (B) depend on the category of the drug product (small molecule (SM), biotechnology (BT) or therapeutic nucleic acid (TNA)). Annual costs also depend on dosing and treatment cycles. Each bar shows the mean cost at initial FDA approval; error bars show the range. Costs may vary significantly between individual products, and are influenced by the availability of a generic version of a drug. *Signifies non-GMP manufacturing; costs vary widely based on the type of TNA, length, chemical modifications, and purity. The data plotted are based on Refs. , , , , .