Multifunctional Fe3O4-PEI@HA nanoparticles in the ferroptosis treatment of hepatocellular carcinoma through modulating reactive oxygen species

Ferroptosis is a novel form of regulated cell death induced by iron-dependent lipid peroxidation imbalance. It has emerged as a promising antitumor therapeutic strategy in recent years. In this work, we successfully synthesized a complex magnetic nanocube Fe3O4 modified with PEI and HA by the thermal decomposition method. While loading a ferroptosis inducer RSL3 inhibited cancer cells through the ferroptosis signal transduction pathway. The drug delivery system could actively target tumor cells through an external magnetic field and HA-CD44 binding. Zeta potential analysis showed that Fe3O4-PEI@HA-RSL3 nanoparticles were more stable and uniformly dispersed in tumor acidic environment. Moreover, cellular experiments demonstrated that Fe3O4-PEI@HA-RSL3 nanoparticles could significantly inhibit the proliferation of hepatoma cells without a cytotoxic effect on normal hepatic cells. In addition, Fe3O4-PEI@HA-RSL3 played a vital role in ferroptosis by accelerating ROS production. The expression of ferroptosis-related genes Lactoferrin, FACL 4, GPX 4 and Ferritin was significantly suppressed with increasing treatment of Fe3O4-PEI@HA-RSL3 nanocubes. Therefore, this ferroptosis nanomaterial has great potential in Hepatocellular carcinoma (HCC) therapy.