PURPOSE: Lung cancer is the second most common Cancer in the United States; however, it remains the leading cause of cancer-related death in the United States and worldwide. 5-fluorouracil (5-FU) is among the most administrated chemotherapeutic agents for various neoplasms. This study focused on synthesizing and characterizing P(AAm/SA)/5-Fu nanogels as a potential drug delivery system. METHODS: The nanogels were prepared by combining sodium alginate (SA) and acrylamide (AAm) monomers, followed by gamma irradiation-induced polymerization at a dose of 5 kGy. Then, the obtained nanogel was loaded with 500 ppm of 5-Fu. Transmission electron microscopy (TEM) imaging was utilized to characterize the nanogels' morphology and monodispersity with a particle size of (50 nm). Rats were randomly assigned to four groups (six animals per group): Group 1: (Control): normal healthy. Group 2: Cancer-bearing animals (animals injected with diethylnitrosamine (DEN) 20 mg/kg body weight for 3 months. Group 3: Cancer+ 5-fluorouracil (12 mg/kg body weight). Group4: Cancer+ 5-Flurouracil- Loaded P (AAm/SA) Nanogel. RESULTS: DEN markedly increased PTGS2, Cox2, PKB, PFKm, and ERK1 levels. Also, observed up-regulation in ALKBH5, Beclin1, ULK1, and P53 gene expressions in the cancer-bearing animal group compared with the control group. 5-fluorouracil nano gel significantly ameliorated the above-mentioned parameters and immunohistochemistry study. 5-fluorouracil nanogel significantly ameliorated the parameters mentioned above, as well as the immunohistochemistry study. CONCLUSION: The 5-FU-loaded P(AAm/SA) nanogel could serve as a promising approach for targeting tumor cell proliferation, speeding up autophagic processes, and overcoming chemotherapy resistance in lung carcinoma.