A Smart DNA‐Based Nanosystem Containing Ribosome‐Regulating siRNA for Enhanced mRNA Transfection

Abstract

Messenger RNA (mRNA) transfection is the prerequisite for the application of mRNA‐based therapeutics. In hard‐to‐transfect cells, such as macrophages, the effective transfection of mRNA remains a long‐standing challenge. Herein, a smart DNA‐based nanosystem is reported containing ribosome biogenesis‐promoting siRNA, realizing efficient mRNA transfection in macrophages. Four monomers are copolymerized to form a nanoframework (NF), including N‐isopropylacrylamide (NIPAM) as the skeleton and acrydite‐DNA as the initiator to trigger the cascade assembly of DNA hairpins (H1‐polyT and H2‐siRNA). By virtue of the phase transition characteristic of polymeric NIPAM, below the lower critical solution temperature (LCST, ≈34 °C), the NF swells to expose polyT sequences to hybridize with the polyA tail of mRNA. Above the LCST, the NF deswells to encapsulate mRNA. The disulfide bond in the NF responds to glutathione, triggering the disassembly of the nanosystem; the siRNA and mRNA are released in response to triphosadenine and RNase H. The siRNA down‐regulates the expression of heat shock protein 27, which up‐regulates the expression of phosphorylated ribosomal protein S6. The nanosystem shows satisfactory mRNA transfection and translation efficiency in a mouse model. It is envisioned that the DNA‐based nanosystem will provide a promising carrier to deliver mRNA in hard‐to‐transfect cells and promote the development of mRNA‐based therapeutics.

DNA-Based Nanostructured Platforms as Drug Delivery Systems

“…(Hsp27 siRNA) augmented the mRNA transfection in macrophages. 37 A similar DNA nanoframework was reported by Song et al made up of Nisopropylacrylamide (NIPAM) as the primary skeleton and N,N-bis(acryloyl)cystamine (BACA) and acrylamide-modified DNA (acDNA) as cross-linkers. Because of dynamic assembly/ disassembly, the resulting nanoframework (NF) was capable of enabling regulated release of Cas9 RNP.…”

“…The NF deswells above the LCST in order to enclose mRNA. (Hsp27 siRNA) augmented the mRNA transfection in macrophages . A similar DNA nanoframework was reported by Song et al made up of N -isopropylacrylamide (NIPAM) as the primary skeleton and N , N -bis­(acryloyl)­cystamine (BACA) and acrylamide-modified DNA (acDNA) as cross-linkers.…”

Self-Delivery Nanomedicines Reverse Thermal Resistance to Enhance Tumor Mild-Temperature Photothermal Therapy

“…Heat shock proteins (HSPs; e.g., HSP70 and HSP90) are key tumor defense proteins in PTT. , When stimulated by high temperatures, HSPs are rapidly upregulated to exert central antiapoptotic and cytoprotective effects as chaperones and restore denatured proteins, thereby preventing cell death . Specific HSP inhibitors − or small interfering RNA (siRNA) − have been introduced into nanoscale drug-delivery systems to improve the thermal sensitivity of tumor cells. However, they present some disadvantages such as complicated synthesis, low drug-loading efficiency, delayed HSP inhibition, and lack of universality.…”

A “dual-key-and-lock” DNA nanodevice enables spatially controlled multimodal imaging and combined cancer therapy

“…27 In recent years, functional nucleic acid-assisted therapeutic platforms have shown significant potential against tumors. 28,29 For example, DNAzyme has emerged as an effective tool for gene silencing due to its advantages of flexible design and high specificity, which can catalyse the specific cleavage of intracellular mRNA to regulate the expression level of tumour-related proteins. 30 However, since tumour cells can easily bypass apoptosis through a variety of antiapoptotic signal transductions, a single-mode therapy pathway usually constrains the treatment performance.…”