Background <p>Thyroid cancer is a common endocrine malignancy. Conventional treatments, such as surgery, radioiodine therapy, radiotherapy, and chemotherapy, often result in significant side effects and toxicity. Nanoparticle-based drug delivery systems have emerged as a promising strategy to overcome these challenges. In this study, we investigated the effects of free metformin, a PLGA-PEG copolymer, and PLGA-PEG-MET nanoparticles on FTC-133 thyroid cancer cells.</p> Methods and Results <p>PLGA-PEG-MET nanoparticles were synthesized using the double-emulsion method and characterized using FT-IR and ZetaSizer. At the same time, drug loading was determined using a UV–Vis spectrophotometer. Drug-loading analysis showed the successful encapsulation of metformin within the nanoparticles. Colony formation assays revealed that both free metformin and PLGA-PEG-MET nanoparticles significantly reduced cell viability in a dose-dependent manner. Western blot analysis indicated that free metformin decreased mTOR expression while increasing AMPK and p-AMPK levels.</p> Conclusions <p>These findings suggest that PLGA-PEG-MET nanoparticles have potential as an effective therapeutic strategy for thyroid cancer. However, further studies are needed to enhance their effectiveness, both in vitro and in vivo. Additionally, the use of polymeric nanoparticle-based combination therapies may confer synergistic anticancer effects, as evidenced by improved therapeutic outcomes across various cancer types.</p> Graphical abstract <p></p>