ROS-Responsive\nand Self-Catalytic Nanocarriers for\na Combination of Chemotherapy and Reinforced Ferroptosis against Breast\nCancer

Ferroptosis\nis an appealing cancer therapy strategy based\non the\nH<sub>2</sub>O<sub>2</sub>-involved Fenton reaction to produce toxic <sup>•</sup>OH for lipid peroxidation. However, intracellular H<sub>2</sub>O<sub>2</sub> is easily consumed and results in a deficient\nFenton reaction. This obstacle can be overcome by traditional chemotherapeutic\ndrugs for H<sub>2</sub>O<sub>2</sub> supplements. Moreover, a recent\nwork illustrated that dihydroartemisinin (DHA) could promote ferroptosis\nagainst tumoral cells, particularly in the presence of ferrous compounds.\nTo achieve combined chemotherapy and ferroptosis, a nanocarrier (<sup>TK</sup>NP<sub>DHA</sub>-Fc) was constructed by using thioketal (TK)-bridged\npaclitaxel prodrug (PEG-TK-PTX) and ferrocene (Fc)-conjugated PEG-Fc,\nwhere DHA was encapsulated by a hydrophobic–hydrophobic interaction.\nUpon cellular uptake, <sup>TK</sup>NP<sub>DHA</sub>-Fc could facilitate\nPTX release through TK breakage under an excess H<sub>2</sub>O<sub>2</sub> microenvironment. Owing to the loss of the hydrophobic PTX\ncomponent, <sup>TK</sup>NP<sub>DHA</sub>-Fc underwent a rapid dissociation\nfor improving DHA to act as a ferroptotic inducer along with Fe supplied\nfrom Fc. Moreover, both the chemotherapy-induced reactive oxygen species\nand the <sup>•</sup>OH produced from reinforced ferroptosis\nfurther stimulated the TK cleavage. The “self-catalytic”\nloop of <sup>TK</sup>NP<sub>DHA</sub>-Fc remarkably improved the antitumor\nperformance in vivo via combined mechanisms, and its tumor inhibition\nrate reached 78.3%. This work highlights the contribution of ROS-responsive\nand self-catalytic nanoplatforms for enhancing the potential of combined\nchemotherapy and ferroptosis for cancer therapy in the future.