Chitooligosaccharide-alginate selenium nanoparticles induce ferroptosis in hepatocellular carcinoma by amplifying redox imbalance.

Augmenting redox imbalance has become a promising strategy for effective cancer therapy. Selenium nanoparticles (SeNPs) have potential in this respect but are limited by instability. In this study, we constructed novel chitooligosaccharide-sodium alginate (COS-SA)-modified SeNPs (COS-SA-SeNPs) and optimized the synthesis process via response surface methodology for size control. The formation, morphology, physicochemical characteristics and stability mechanism were investigated. The results indicated that the COS-SA-SeNPs were orange‒red, had zero-valent Se, and were uniform spherical nanoparticles with an average diameter of 158 nm. Owing to the intermolecular forces between COS-SA and SeNPs, the heating and storage stability of the COS-SA-SeNPs were better. Moreover, the stable nanoparticles demonstrated potent antiproliferation activity in HepG2 cells. ROS overproduction, increased iron content, decreased antioxidant enzyme activity, and downregulation of ferroptosis-related genes (e.g., Nrf2/HO-1, SLC7A11, and GPX4) were observed, indicating the disruption of cellular redox homeostasis and the occurrence of ferroptosis. COS-SA-SeNPs exert antitumor effects by disrupting redox homeostasis and inducing ferroptosis through the simultaneous impairment of cellular antioxidant defenses. This study not only provides an alternative candidate for nutritional selenium supplementation but also offers fresh perspectives on ferroptosis-mediated cancer therapy through the enhancement of redox imbalance.