Unsaturated phospholipid modified FeOCl nanosheets for enhancing tumor ferroptosis

Iron-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation plays key roles in ferroptosis, which has been an attractive strategy to kill tumor cells. However, the rapid annihilation of hydroxyl radicals (•OH) produced by Fenton reaction has become a major obstacle to induce lipid peroxidation in cells. In this paper, we developed a nano delivery system of unsaturated phospholipid (Lip) and polyacrylic acid (PAA) functionalized FeOCl nanosheets (FeOCl@PAA-Lip). In this system, •OH produced by Fenton reaction between FeOCl nanosheets and endogenous H 2 O 2 of tumor cells attacks Lip on the nanosheets in situ to initiate the lipid peroxidation chain reaction, which not only realizes free radical conversion but also achieves the amplification of ROS and lipid peroxides, thus enhancing tumor ferroptosis. The in vitro and in vivo results confirmed that FeOCl@PAA-Lip nanosheets exhibited specific tumor cell-killing effect, good biocompatibility, long circulation time, low side effects, high tumor targeting and excellent tumor inhibition rate (73%). The Lip functionalization strategy offers a paradigm of enhancing ferroptosis treatment by conversion of •OH/phospholipid radical/lipid peroxyl radical and strengthening lipid peroxidation.