Nanoparticles-Delivered Circular RNA Strategy as a Novel Antitumor Approach

Abstract

Anticancer therapy urgently needs the development of novel strategies. An innovative molecular target is represented by circular RNAs (circRNAs), single-strand RNA molecules with the 5' and 3' ends joined, characterized by a high stability. Although circRNA properties and biological functions have only been partially elucidated, their relationship and involvement in the onset and progression of cancer have emerged. Specific targeting of circRNAs may be obtained with antisense oligonucleotides and silencing RNAs. Nanotechnology is at the forefront of research for perfecting their delivery. Continuous efforts have been made to develop novel nanoparticles (NPs) and improve their performance, materials, and properties regarding biocompatibility and targeting capabilities. Applications in various fields, from imaging to gene therapy, have been explored. This review sums up the smart strategies developed to directly target circRNAs with the fruitful application of NPs in this context.

Keywords: cancer therapy; circRNA; circRNA-based therapeutic; drug delivery; gene therapy; nanomaterial; nanomedicine; nanoparticles; theranostics.

Figure 1

Schematic representation of canonical and back-splicing events of a single-strand pre-mRNA molecule (created with Biorender.com).

Figure 2

Schematic representation of circular RNA biological roles: (a) EiciRNA and ciRNA form a complex with U1 and small nuclear ribonucleoprotein (snRNP) inducing the interaction with RNA polymerase, enhancing gene expression; (b) circRNAs bind the host gene, pausing or ending its transcription; (c) circRNAs bind to the promoter preventing the association of the transcription complex; (d) host gene transcription promotion due to TET1-induced hypomethylation on CpG islands promoter, driven by circRNA binding; (e) miRNA sponging mechanism; (f) RBP interaction may alter several cell life aspects; (g) QKI’s dimerization enhancing circRNA biogenesis; (h) IRES-driven and m6A-driven peptide translation (created with Biorender.com).

Figure 3

(a) Schematic representation of circRNAs present in tissues and biofluids, usable as diagnostic and prognostic biomarkers; (b) circRNAs in tissues exploitable as therapeutic targets (created with Biorender.com).

Figure 4

Nanoparticles’ classification based on their chemical composition (created with Biorender.com).

Figure 5

Differences between passive and active targeting. In the first case (on the left), naked NPs flow in the circulatory system and reach the tumor exploiting fenestrations in the vessels, but they are also distributed in other sites. In the active targeting (on the right), NPs are equipped with a targeting ligand, specifically recognized by the cancer cells; thus, they are captured preferably by these cells (created with Biorender.com).