G-Quadruplex-Proximized Aptamers (G4PA) Efficiently Targeting Cell-Surface Transferrin Receptors for Targeted Cargo Delivery

Abstract

DNA-assembled multiaptamer systems have been demonstrated to significantly promote the aptamer capacity of binding cell-surface-expressed proteins. However, how to conveniently harness them for efficient transmembrane delivery of targets remains a challenge. Toward this goal, here we engineer a G-quadruplex-proximized aptamer (G4PA) system in which a DNA aptamer specific for transferrin receptor (TfR) is guided by a bimolecular G4 and assembles into a dimerized proximity form that well matches homodimeric TfR highly expressed on the cancer cell surface. This system displays a higher capacity for targeting cell-surface TfR than the monomeric aptamer and super transmembrane transportation of nucleic acid cargoes, which is comparable to that of conventional liposome transfection but overcomes the lack of targeting ability of the latter. The G4PA system is then applied to the targeted delivery of siRNA for PLK1 gene silencing in positive cells rather than negative controls, showing great promise for use in precise anticancer therapy.

DNA nanostructures for exploring cell–cell communication

“…2(d)). [40][41][42][43] It is noteworthy that the polyvalent structure is more efficient than the monovalent structure in identifying the target, or promoting cell-cell recognition. 44 In addition, the combination of static DNA nanostructures with stimulus-response components can be assembled into dynamic DNA nanostructures.…”

TfR Aptamer-Functionalized MSNs for Enhancing Targeted Cellular Uptake and Therapy of Cancer Cells

“…Transferrin receptor (TfR) is a cell-surface-located transmembrane protein involved in intracellular iron transport and typically overexpressed in many cancer cells. – Studies have showed that high expression of TfR is associated with increased demand for iron in cancer cells, and it has been an attractive target for targeted delivery in cancer treatment . Recently, TfR aptamers with high affinity toward TfR have been screened, which could readily get inside the cells via clathrin-mediated endocytosis, enabling its use in cancer-targeted therapies. – Although transferrin-modified MSNs for drug delivery have been previously reported, , aptamers exhibit more promising clinical applications than proteins because of their advantages of lower cost, more stable chemical properties, easier accessibility, and lower immunogenicity.…”

A Tumor‐Specific Cascade‐Activating Smart Prodrug System for Enhanced Targeted Therapy

“…[17] In particular, our recent work shows that G4-proximized transferrin receptor (TfR) aptamers can better match TfR on the surface of cancer cells and exhibit excellent super-transmembrane transport capabilities. [18] Moreover, even in complex biological environments, G4s can bind a large amount of molecular ligands with high affinity, often accompanied by changes in fluorescence properties. [19,20] Of particular interest is that, as reported previously [21,22] and we show here, ligand binding significantly promotes the nuclease-resistant capacity of DNA scaffolds.…”

“…[29] In this DNA scaffold (ApG4), the TfR aptamer is induced to be dimerized in a proximity state, contributing to super transmembrane efficiency as compared to the monomeric. [18] Furthermore, LDCs, sodium nitroprusside (SNP, NO donor), [30] and doxorubicin (DOX) [31] were loaded into ApG4 in one pot to construct the final smart prodrug system ApG4/LDCs. Under high levels of TfR, GSH, and NOXs in tumor cells, ApG4/LDCs first enter the cancer cells efficiently, and then generate NO and O 2…”