Lantern-shaped flexible RNA origami for Smad4 mRNA delivery and growth suppression of colorectal cancer

Abstract

AbstractmRNA delivery has shown high application value in the treatment of various diseases, but its effective delivery is still a major challenge at present. Herein, we propose a lantern-shaped flexible RNA origami for mRNA delivery. The origami is composed of a target mRNA scaffold and only two customized RGD-modified circular RNA staples, which can compress the mRNA into nanoscale and facilitate its endocytosis by cells. In parallel, the flexible structure of the lantern-shaped origami allows large regions of the mRNA to be exposed and translated, exhibiting a good balance between endocytosis and translation efficiency. The application of lantern-shaped flexible RNA origami in the context of the tumor suppressor gene, Smad4 in colorectal cancer models demonstrates promising potential for accurate manipulation of protein levels in in vitro and in vivo settings. This flexible origami strategy provides a competitive delivery method for mRNA-based therapies.

Bioinspired Spatiotemporal Management toward RNA Therapies

“…These mRNA nanoassemblies demonstrated a 17-fold increase in mRNA amount and significantly higher transfection efficiency in the mouse brain compared to the naked mRNA group when administrated via intraventricular injection. A recent work has designed a lantern-shaped flexible RNA origami, consisting of a mRNA scaffold and two customized RGD-modified circular RNA staples . Following cellular uptake, mRNA can efficiently dissociate from the nanostructures and be recognized by ribosomes for protein translation.…”

“…A recent work has designed a lantern-shaped flexible RNA origami, consisting of a mRNA scaffold and two customized RGD-modified circular RNA staples. 87 Following cellular uptake, mRNA can efficiently dissociate from the nanostructures and be recognized by ribosomes for protein translation. This mechanism effectively inhibits colorectal cancer both in vitro and in vivo.…”

Single-Stranded RNA Origami-Based Epigenetic Immunomodulation

“…N ucleic acid nanotechnology facilitates the precise assembly of nucleic acid molecules into nanostructures with tailored sizes, shapes, and chemical compositions. 1−7 These programmable nanostructures, characterized by their controllable synthesis process and excellent biocompatibility, 8 have found diverse applications in fields, such as cell protein translation, 9 cell motion, 10 and immune activation. 11 Recently, single-stranded RNA (ssRNA) origamis have been extensively explored as a promising platform that can be transcribed from DNA templates and self-folded into defined structures both in vitro 12 and in vivo.…”

“…11 Recently, single-stranded RNA (ssRNA) origamis have been extensively explored as a promising platform that can be transcribed from DNA templates and self-folded into defined structures both in vitro 12 and in vivo. 13,14 These ssRNA origamis can be equipped with various "structure" or "sequence" modules to enrich specific biomedical functions, including drug delivery, 15 gene editing, 9,16 regulation of molecular interactions, 17,18 and the facilitation of high-resolution structural characterization. 18,19 Though many endowed properties have been brought from external structural motifs and sequences to ssRNA origami, the versatility and the function of the intrinsic RNA molecular signature of RNA structures have not been fully utilized.…”

“…Nucleic acid nanotechnology facilitates the precise assembly of nucleic acid molecules into nanostructures with tailored sizes, shapes, and chemical compositions. − These programmable nanostructures, characterized by their controllable synthesis process and excellent biocompatibility, have found diverse applications in fields, such as cell protein translation, cell motion, and immune activation . Recently, single-stranded RNA (ssRNA) origamis have been extensively explored as a promising platform that can be transcribed from DNA templates and self-folded into defined structures both in vitro and in vivo . , These ssRNA origamis can be equipped with various “structure” or “sequence” modules to enrich specific biomedical functions, including drug delivery, gene editing, , regulation of molecular interactions, , and the facilitation of high-resolution structural characterization. , Though many endowed properties have been brought from external structural motifs and sequences to ssRNA origami, the versatility and the function of the intrinsic RNA molecular signature of RNA structures have not been fully utilized. The integration of functional modules at the “molecular” level holds significant potential for further expanding and diversifying the applications of ssRNA origami nanotechnology .…”