While DNA origami nanotubes have been often used in the biomedical field, the technical challenges in the assembly at large scale and the susceptibility to degradation limit their exploration for clinical application. In the current contribution, we propose a structural DNA nanotechnology (TMM) for the construction of a degradation-resistant DNA nanotube (DNT) via periodically tiling two structural modules (M) into a modularized (M) tubular DNA nano-architecture. The tube circumference is 118.6 nm, the tube length is 478 nm and the assembly efficiency is almost up to 90%. Upon installation of up-down tumor cell-binding aptamers onto each structural module in a highly precise manner, a protective outer layer was formed. Compared with Biotin-DNA nanowire, the relative nuclease degradation resistance of AS1411-DNT is improved by about 92-fold. Via using commercially synthesized 5-FU-embedded DNA components, we constructed a tumor cell-targeting therapeutic agent-loaded nanoconjugate, AS1411-DNT-5-FU, which exhibits significantly higher therapeutic outcomes than clinic free 5-FU in MCF-7 tumor-bearing mouse models without observable systemic toxicity. While DNA DNT holds great potential for precise drug delivery for cancer therapy, the modularization-based TMM structural DNA nanotechnology is expected to promote the development of next-generation multifunctional 3D-DNA nanostructures and clinical application in precision medicine.
Weijun Wang, Jingting Wu, Yu-xi Yang et al.· Small· 0 citations
Epidermal growth factor receptor-targeted therapies such as afatinib provide clinical benefits to patients with advanced-stage non-small cell lung cancer (NSCLC); however, acquired resistance frequently develops, with the underlying mechanisms remaining undefined in 20–30% of cases. The present study established afatinib-resistant (AR) NSCLC cell lines and confirmed their resistance phenotype using Cell Counting Kit-8 (CCK-8) cell viability assays. Notably, these cells also exhibited cross-resistance to osimertinib. To elucidate the molecular basis of resistance acquisition, the time-resolved transcriptomic profiling of A549 cells was performed across three stages: Parental, afatinib-exposed (adaptive phase) and stable resistant cells. The analyzed results revealed the persistent upregulation of ABLIM3, HTR1D and HSPA1A, which was validated by reverse transcription-quantitative polymerase chain reaction. The meta-analysis of hazard ratios from The Cancer Genome Atlas demonstrated that the elevated expression level of the three-gene signature was significantly associated with tumor progression and an increased risk of disease recurrence. These transcriptional alterations were accompanied by the sustained activation of the MAPK/ERK signaling pathway, as evidenced by increased ERK1/2 phosphorylation detected using western blot analysis, which was positively associated with the expression level of the three-gene signature. Functional analyses further demonstrated that the pharmacological inhibition of MAPK/ERK signaling using selumetinib effectively re-sensitized AR cells to both afatinib and osimertinib, as demonstrated by restored drug sensitivity in CCK-8 assays. Collectively, these findings suggest that MAPK/ERK signaling contributes to the transition from adaptive tolerance to stable resistance to afatinib and highlight a tractable therapeutic vulnerability for overcoming resistance to tyrosine kinase inhibitors in NSCLC.