Ala-Ce@Ce6 hybrid supramolecular nanozyme for oxygen self-supplying hypoxia photodynamic therapy

The efficacy of photodynamic therapy (PDT) is often hindered by factors such as the poor bioavailability of photosensitizers, insufficient oxygen levels, and the elevated presence of glutathione (GSH) and hypoxia-inducible factor 1-alpha (HIF-1α) in tumor cells. To address these challenges, a controlled supramolecular assembly approach was explored to construct uniform cerium oxide nanoparticles, denoted Ala-Ce@Ce6. Specifically, water-soluble alanine-cerium clusters were constructed using natural l-alanine as the ligand. Subsequently, these clusters are subjected to self-assembly using the photosensitizer Chlorin e6 under ice-bath and ultrasonication conditions, yielding uniform nanoparticles with favorable water solubility. This nanostructure not only enhances the delivery efficiency of Ce6 but also confers dual functionalities, namely reacting with hydrogen peroxide (H₂O₂) to simultaneously generate oxygen and deplete GSH. In vivo, the reaction with endogenous H₂O₂ produces O₂, thereby alleviating hypoxia and lowering HIF-1α expression. Additionally, Ala-Ce@Ce6 reduces the levels of GSH, downregulates Glutathione Peroxidase 4 to induce ferroptosis, and releases Ce6 upon laser irradiation to boost reactive oxygen species generation and suppress tumor growth, demonstrating strong clinical potential for use in PDT.