Tetrahedral DNA Nanostructures as Multifunctional Drug-Delivery Vehicles for Treating Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, characterized by a relatively slow growth rate and a propensity toward distant metastases following local spread. These factors present significant challenges in both diagnosis and treatment of NSCLC, particularly for early stage NSCLC. In this study, based on the self-assembled functionalized tetrahedral DNA nanostructure (TDN), a multifunctional drug delivery system has been constructed for NSCLC adenocarcinoma cell line A549 (A549 cells) to achieve intracellular imaging and combined drug delivery. The TDN was self-assembled in vitro and the four vertices of TDN were functionalized with Cy5, s6 aptamer, p28 cell-penetrating peptide and siRNA, respectively. Subsequently, daunorubicin (DAU) was loaded to TDN to obtain DAU@TDN-p28-s6-siRNA through the intercalation in double-stranded DNA. While Cy5 is employed for intracellular tracking and imaging, s6 aptamer is used to target A549 cells and enrich TDN around the cells, and p28 cell-penetrating peptide can facilitate the entrance of TDN into the cells via endocytosis. Once DAU@TDN-p28-s6-siRNA is taken inside the cell, the modified siRNA can bind to the mRNA guiding the translation of ERBB3 protein and down-regulate its expression, ultimately leading to the inhibition of cell growth. Simultaneously, through the targeted delivery, DAU accurately inhibits the tumor cell activity, and thus achieving the synergy with siRNA to inhibit the growth of tumor cells. In vitro experiments have demonstrated that compared to the control, DAU@TDN-p28-s6-siRNA reduces the expression of ERBB3 protein by 71.27%, and reduces the viability of the target cell to 37.84%, as well as exhibits high targeting specificity. Therefore, the development of TDN assemblies provides an efficient way for diagnosis and treatment of tumor cells and has potential in the biomedical field.