Self-assembled nucleolipid G-quadruplexes act as multitarget decoys for oncogene suppression in pancreatic cancer

Abstract KRAS mutations drive multiple cancers and represent an important therapeutic target, together with other oncogenic regulators such as MYC , KIT , and BCL2 that are critically involved in pancreatic cancer. Here we describe a novel therapeutic strategy based on stable nucleolipid-modified G-quadruplex (NLG4) structures. Cell viability assays demonstrate that the selected NLG4s strongly inhibit pancreatic cancer cell proliferation, whereas the same non-lipidic G-quadruplex sequences display minimal activity under comparable conditions. Owing to their distinctive physicochemical properties, including stabilization of parallel G-quadruplex structures and self-assembly into micellar aggregates, NLG4s efficiently internalize into cells and interact in a decoy approach, with key G-quadruplex unfolding factors, such as Unwinding Protein 1 (UP1) responsible for the activation of oncogenes’ promoters in cancer cells. This interaction leads to a marked downregulation of KRAS, cMYC, cKIT, and BCL2 expression. Suppression of these oncogenes profoundly affects pancreatic cancer cell fate, as evidenced by reduced expression of proliferation (Ki67) and anti-apoptotic (BCL2) markers. In addition, NLG4s treatment decreases inflammatory signaling mediated by NF-κB and inhibits major pro-proliferative kinase pathways, including ERK, AKT, and phosphorylated AKT. The therapeutic relevance of this decoy strategy is further supported by the observed potentiation of gemcitabine antitumor activity. Overall, these findings highlight NLG4s as a promising anticancer approach that simultaneously targets multiple oncogenic pathways through G-quadruplex-based decoy mechanisms, with translational potential for future pancreatic cancer treatment.