Co-upregulation of MEG۳ and TUG۱ lncRNAs by Hyaluronic Acid-based Nanoparticles Confers Selective Toxicity in Lung Adenocarcinoma

Lung cancer remains a leading cause of cancer-related mortality globally, underscoring the need for novel targeted therapies. Dysregulation of long non-coding RNAs (lncRNAs), such as the tumor suppressor MEG۳ and the context-dependent lncRNA TUG۱, plays a critical role in non-small cell lung cancer (NSCLC) pathogenesis and chemoresistance. This study aimed to develop a targeted nanotherapeutic system to modulate these lncRNAs and selectively eliminate cancer cells. Hyaluronic acid (HA) and Gallic acid (GA)-conjugated to Glucose (Glu)-functionalized Fe₃O₄ nanoparticles (Fe₃O₄@Glu-HA-GA NPs) were synthesized and characterized by scanning electron microscopy, transmission electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, and thermogravimetric analyses. These nanoparticles target CD۴۴-overexpressing cancer cells via HA functionalization. In vitro studies on A۵۴۹ (lung adenocarcinoma) and MRC۵ (normal lung fibroblast) cells revealed that Fe₃O₄@Glu-HA-GA NPs exhibited potent and selective cytotoxicity, with an IC₅₀ of ۷۰ µg/mL in A۵۴۹ cells, significantly lower than in MRC۵ cells (IC₅₀= ۲۱۴ µg/mL). qRT-PCR analysis demonstrated a cancer cell-specific transcriptional response, where the treatment significantly upregulated MEG۳ by ۱.۵۸-fold (p< ۰.۰۱) and TUG۱ by ۱.۳۳-fold (p< ۰.۰۱) in A۵۴۹ cells compared to untreated controls. This selective lncRNA dysregulation correlated with the observed anticancer activity. In conclusion, the Fe₃O₄@Glu-HA-GA nanoplatform represents a promising strategy for targeted lung cancer therapy by selectively perturbing key lncRNA networks, offering a potential avenue to overcome nonspecific toxicity and enhance therapeutic efficacy.

کلیدواژه ها:

CD۴۴ targeting ، Long non-coding RNA ، Lung cancer ، MEG۳ ، TUG۱