Naphthazarin Mounted on the Manganese Carbonate Nanocube Induced Enrichment of Endogenous Copper and Fenton-like Reaction for Enhanced Chemodynamic Therapy

Chemodynamic therapy (CDT), which utilizes transition metal ions to catalyze Fenton-like reactions for the eradication of tumor cells, has attracted substantial attention in the field of nanocatalysis. However, the therapeutic efficacy of CDT as a monotherapy is often limited by an insufficient level of hydrogen peroxide (H 2 O 2 ) and the overexpressed glutathione (GSH) within tumor cells. Because of the high copper content in tumor tissues, a copper ionophore was strategically employed to enhance the intracellular accumulation of copper, thereby potentiating the CDT effect. Additionally, bovine serum albumin (BSA) was used to modify the copper ionophore, naphthazarin (Nap), to promote its targeting efficacy for tumor cells and to ensure its biosafety. The BSA-coated Nap nanoparticles, which could recruit Cu 2+ in situ, were further deposited onto the surface of a manganese carbonate nanocube (Nap-BM NPs). The synergistic action of copper and manganese ions accelerated the decomposition of H 2 O 2 into hydroxyl radicals (•OH) and consumed intracellular GSH, leading to cellular mortality via mitochondrial pathways. With low cytotoxicity and good biocompatibility in normal cells, the developed Nap-BM NPs significantly enhanced therapeutic outcomes by leveraging multiple Fenton-like reaction mechanisms to augment CDT, offering promising potential for clinical applications and contributing valuable insights into the field.