A Smart Nitric Oxide (NO) Generating Immuno‐Trimetallic Nanocatalyst Triggering Chemodynamic Therapy in Breast Cancer Treatment

Abstract Chemodynamic therapy (CDT) has great potential in cancer treatment, but its efficacy is limited due to non‐specificity, insufficient hydrogen peroxide (H 2 O 2 ), and excessive glutathione (GSH) within the tumor microenvironment (TME). Here, an intelligent nanoplatform (Fe 3 O 4 @MnO 2 @NO@Au NPs, abbreviated as CD44 FMNA) is reported for the treatment of breast cancer, which is constructed with Fe 3 O 4 nanoparticles (NPs) as the core coated with manganese dioxide (MnO 2 ) nanoshells encapsulating NO donors and gold nanoparticles (Au NPs) within the pores of MnO 2 , followed by the conjugation of targeting ligand anti‐CD44 mAb. The fabricated CD44 FMNA initially remains inactive in normal cells, but after CD44 receptor ‐mediated MDA‐MB‐231 cell‐specific endocytosis, acidic TME can induce the decomposition of the MnO 2 shell to release NO donors, thereby dually depleting the existing GSH in cells and enhancing the Fenton‐like reaction in a cascade manner. The generation of hydroxyl radicals ( · OH) and the dual depletion of GSH can significantly weaken the GSH‐related antioxidant defense system (ADS) within MDA‐MB‐231 cells, accelerating apoptosis and cell death via the mitochondrial pathway. In addition, in vivo studies demonstrate that CD44 FMNA can effectively inhibit tumor growth with good biosafety. Therefore, this nanoplatform may provide an effective therapy for the treatment of breast cancer.