The
upregulation of dihydroorotate dehydrogenase (DHODH) redox
systems inside tumor cells provides a powerful shelter against lipid
peroxidation (LPO), impeding ferroptosis-induced antitumor responses.
To solve this issue, we report a strategy to block redox systems and
enhance ferroptotic cancer cell death based on a layered double hydroxide
(LDH) nanoplatform (siR/IONs@LDH) co-loaded with ferroptosis agent
iron oxide nanoparticles (IONs) and the DHODH inhibitor (siR). siR/IONs@LDH
is able to simultaneously release IONs and siR in a pH-responsive
manner, efficiently generate toxic reactive oxygen species (ROS) via an Fe2+-mediated Fenton reaction, and synergistically
induce cancer cell death upon the acceleration of LPO accumulation. In vivo therapeutic evaluations demonstrate that this nanomedicine
has excellent performance for tumor growth inhibition without any
detectable side effects. This work thus provides a new insight into
nanomaterial-mediated tumor ferroptosis therapy.