Anticancer activity of NF?B decoy oligonucleotide-loaded nanoparticles against human lung cancer

Non-small cell lung cancer (NSCLC) is among the leading global causes of cancer-related mortality. Current treatment options have limited efficacy and severe adverse effects, underlining the necessity for innovative therapeutic strategies. Among emerging strategies, NF kappa B inhibition is particularly promising, as NF kappa B is considered a master regulator of NSCLC pathogenesis. NF kappa B activity can be efficiently inhibited by double-stranded decoy oligodeoxynucleotides (ODNs). However, therapeutic use of ODNs is strongly limited by enzymatic degradation and poor transport across cell membranes. In this study, we report the encapsulation of a small hydrophilic NF kappa B decoy ODN into a biodegradable, biocompatible, and acid-responsive dextran-based nanoparticle (NP) system. This formulation has shown excellent encapsulation efficiency (up to 99.5%) with 185 nm average particle size and pH-dependent ODN release at acidic pH. NF kappa B decoy ODN NPs showed promising anticancer activity, with significant anti-proliferative, anti-migratory, and anti-colony formation activity. These were measured by MTT assay, Boyden chamber and scratch wound healing assays, and crystal violet staining, respectively. Mechanistically, the anti-proliferative effect was exerted through the activation of the expression of key genes regulating apoptosis and necroptosis such as TNF-alpha, RIPK1, RIPK3, and MLKL. The findings of this study provide the foundations for further investigation of the molecular mechanisms by which NF kappa B inhibition results in anticancer activity, simultaneously providing proof-of-concept of the therapeutic potential of dextran-based nanoparticles carrying NF kappa B decoy ODNs against NSCLC.