ROS-Responsive and Self-Catalytic Nanocarriers for a Combination of Chemotherapy and Reinforced Ferroptosis against Breast Cancer

Ferroptosis is an appealing cancer therapy strategy based on the H₂O₂-involved Fenton reaction to produce toxic ^•OH for lipid peroxidation. However, intracellular H₂O₂ is easily consumed and results in a deficient Fenton reaction. This obstacle can be overcome by traditional chemotherapeutic drugs for H₂O₂ supplements. Moreover, a recent work illustrated that dihydroartemisinin (DHA) could promote ferroptosis against tumoral cells, particularly in the presence of ferrous compounds. To achieve combined chemotherapy and ferroptosis, a nanocarrier (^TKNP_DHA-Fc) was constructed by using thioketal (TK)-bridged paclitaxel prodrug (PEG-TK-PTX) and ferrocene (Fc)-conjugated PEG-Fc, where DHA was encapsulated by a hydrophobic-hydrophobic interaction. Upon cellular uptake, ^TKNP_DHA-Fc could facilitate PTX release through TK breakage under an excess H₂O₂ microenvironment. Owing to the loss of the hydrophobic PTX component, ^TKNP_DHA-Fc underwent a rapid dissociation for improving DHA to act as a ferroptotic inducer along with Fe supplied from Fc. Moreover, both the chemotherapy-induced reactive oxygen species and the ^•OH produced from reinforced ferroptosis further stimulated the TK cleavage. The "self-catalytic" loop of ^TKNP_DHA-Fc remarkably improved the antitumor performance in vivo via combined mechanisms, and its tumor inhibition rate reached 78.3%. This work highlights the contribution of ROS-responsive and self-catalytic nanoplatforms for enhancing the potential of combined chemotherapy and ferroptosis for cancer therapy in the future.