Upconversion Dihydroartemisinin-Loaded Nanocomposites for NIR-Enhanced Ferroptosis of Glioblastoma Cells

Ferroptosis, a unique iron-dependent mode of cell death, has been identified as a potential treatment for glioblastoma (GBM). Dihydroartemisinin (DHA) is a ferroptosis inducer with cytotoxicity that is strongly dependent on intracellular Fe2+ levels. However, the effectiveness of DHA is limited by low levels of Fe2+ in tumor cells. To address this issue, a facile strategy was developed by combining near-infrared (NIR)-induced ferrous ion regeneration with DHA in a nanocomposite (ApoE-UPGs-DHA). This nanocomposite synergistically enhanced ferroptosis and offered highly efficient GBM treatment. ApoE-UPGs-DHA were prepared by loading upconversion nanoparticles (UCNPs) and DHA into micelles and subsequently attaching the peptide apolipoprotein E to enable penetration of the blood-brain barrier (BBB) and targeted treatment of GBM. NIR irradiation was applied to induce the regeneration of Fe2+ from Fe3+ mediated by ApoE-UPGs-DHA, thereby promoting ferroptosis in G422 glioma cells. Characterization studies confirmed the successful preparation of ApoE-UPGs-DHA, which had a diameter of 82.3 ± 5.8 nm. The nanocomposite demonstrated good GBM targeting ability in vivo and enhanced uptake by the G422 cells in vitro. ApoE-UPGs-DHA were toxic to G422 glioma cells, and this toxicity was further enhanced by NIR irradiation. Mechanistic studies revealed that ApoE-UPGs-DHA treatment led to a decrease in the intracellular Fe2+ concentration due to the Fenton-like reaction induced by DHA and Fe2+. NIR irradiation was transformed into UV light by ApoE-UPGs-DHA, and then, the Fe3+ generated by the Fenton reaction was photoreduced to Fe2+ by UV light. The replenished Fe2+ significantly promoted the generation of lipid peroxides (LPOs), leading to enhanced ferroptosis and toxicity to ApoE-UPGs-DHA-treated G422 glioma cells. Herein, an NIR-responsive Fe2+-regenerating nanocomposite was successfully prepared to enhance ferroptosis in G422 glioma cells, suggesting a promising alternative GBM treatment strategy.