Advanced medical nanotechnology supplies safe and efficacious systems for anticancer agent delivery to target cancer cells efficiently. The preferred and healthiest alternative for people involves targeted treatment using nanocarriers. Among different cancers the lung cancer is one of the most common diseases that afflicts humans around the world. Lung cancer is the persistent malignant abnormal cell growth anywhere in the airways or parenchymal tissue of the lungs. Primary lung cancer begins in the lungs; secondary lung cancers are malignant diseases of other organs that spread or metastasize into the lungs. Lung cancer is the most commonly diagnosed cancer worldwide, and it has many traditional treatment methods. Most lung cancer statistics include both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). This study aims to prepare a therapeutic nanosystem synthesized with a new nanoformulation superparamagnetic iron oxide nanoparticle (SPION) coated by biocompatible dextran (DEX) polymer encapsulation with Etoposide (ETP) anticancer drug and surface functionalized by folic acid as target drug delivery system for the treatment of cancer, as well as for the treatment of normal cell lines, and to confirm its therapeutic efficacy against malignant cells for treatment lung cancer. Dynamic light scattering (DLS), X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), vibrating sample magnetometry (VSM), and Fourier transform infrared spectroscopy (FTIR), drug loading efficiency and its release profile was perfume to evaluate SPION@DEX-ETP-FA NPs. The SPION@DEX-ETP-FA NPs were spherical with an average diameter, zeta potential and polydispersity of 66.25±7 nm, - 43.8 mV, 0.12, respectively. The MTT assay conducted on the lung cancer CMT-64 cell lines and LA-4 cell lines demonstrated that the SPION@DEX-FA NPs loaded with ETP reduced cancer cells\\\\\\\' viability in comparison to ETP alone. Drugs placed onto NPs were tested for their ability to inhibit the growth and development of cancer cells by inducing apoptosis. These findings suggest that SPION@DEX-ETP-FA significantly enhances ETP-induced apoptosis in lung cancer cells.BCL-2, BAX, BCL-XL, and BAK gene expression was examined in MCT-64 by using quantitative real-time PCR (RT-PCR). The results showed a significant increase in the expression of pro-apoptotic genes BAK and BAX, while a significant decrease in the expression of anti-apoptotic genes BCL-2 and BCL-XL a decrease was recorded. In addition, in vivo results showed that SPION@DEX-ETP-FA led to a decrease in the size of a tumor in treated mice when compared to free ETP and control samples, resulting to prolonged survival, significantly increased splenocyte proliferation. The SPION@DEX-ETP-FA-treated mice had a considerable increase in IFN-γ and a significant decrease in IL-4 production. In conclusion, the prepared SPION@DEX-ETP-FA could be a useful therapeutic combination for the treatment of clinical lung cancer.

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