Lysosomal vulnerability as a therapeutic target in thyroid cancer using fucoidan nanoparticles.

Thyroid cancer represents the ninth most common malignancy worldwide, and a subset of cases exhibits aggressive behaviour with limited therapeutic options. Fucoidan, a sulphated polysaccharide, has demonstrated anticancer activity with an undefined mechanism. Here, we investigated the biological effects of fucoidan (FU) and fucoidan nanoaggregates (NFU) in both thyroid cancer (SW1736) and non-tumorigenic thyroid cells (Nthy-ori 3.1). NFU showed a mean diameter of ~ 187 nm, a low polydispersity (~ 0.2) and a negative Zeta potential. NFU significantly reduced SW1736 cell viability, reaching ~ 60% inhibition at 0.01 mg/mL and ~ 80% at 0.1 mg/mL after 72 h, while sparing non-tumorigenic cells. Mechanistically, NFU induced marked lysosomal enlargement selectively in tumor cells and localized predominantly within LAMP-1-positive compartments. Consistently, tumor cells showed constitutive Cathepsin D maturation and enhanced sensitivity to NFU-induced lysosomal perturbation. Collectively, these findings identify lysosomes as a primary intracellular target of fucoidan-based nanosystems and reveal a tumor-selective vulnerability to NFU-mediated lysosomal stress. This study provides the first quantitative evidence of lysosomal targeting by fucoidan nanoparticles in thyroid cancer cells and supports NFU as a promising lysosome-directed nanotherapeutic strategy for aggressive thyroid malignancies.