Overcoming Hypoxia‐Induced Ferroptosis Resistance via a 19F/1H‐MRI Traceable Core‐Shell Nanostructure

Lipid peroxides accumulation induced ferroptosis is an effective cell death pathway for cancer therapy. However, the hypoxic condition of tumor microenvironment significantly suppresses the efficacy of ferroptosis. Here, we design a novel nanoplatform to overcome hypoxia‐induced ferroptosis resistance. Specifically, we synthesize a novel kind of perfluorocarbon (PFOB)@manganese oxide (MnOx) core‐shell nanoparticles (PM‐CS NPs). Owing to the good carrier of O2 as fuel, PM‐CS NPs can induce higher level of ROS generation, lipid peroxidation and GSH depletion, as well as lower activity of GPX4, compared with MnOx NPs alone. Moreover, the supplement of O2 can relieve tumor hypoxia to break down the storage of intracellular lipid droplets and increase expression of ACSL4 (a symbol for ferroptosis sensitivity). Furthermore, upon stimulus of GSH or acidity, PM‐CS NPs exhibit the “turn on” 19F‐MRI signal and activatable T1/T2‐MRI contrast for correlating with the release of Mn. Finally, PM‐CS NPs exert high cancer inhibition rate for ferroptosis based therapy via synergetic combination of O2‐mediated enhancement of key pathways of ferroptosis. A perfluorocarbon@MnOx core‐shell nanostructure for overcoming the tumor microenvironment hypoxia‐induced ferroptosis resistance via direct delivery of oxygen into the tumor is presented. Using this nanoplatform, activatable 19F‐MRI/1H‐MRI imaging of ferroptosis initiation is also demonstrated.