Single Atom Iron‐Doped Graphic‐Phase C 3 N 4 Semiconductor Nanosheets for Augmented Sonodynamic Melanoma Therapy Synergy with Endowed Chemodynamic Effect

Abstract Sonodynamic therapy (SDT) is a non‐invasive therapeutic modality with high tissue‐penetration depth to induce reactive oxygen species (ROS) generation for tumor treatment. However, the clinical translation of SDT is restricted seriously by the lack of high‐performance sonosensitizers. Herein, the distinct single atom iron (Fe)‐doped graphitic‐phase carbon nitride (C 3 N 4 ) semiconductor nanosheets (Fe‐C 3 N 4 NSs) are designed and engineered as chemoreactive sonosensitizers to effectively separate the electrons (e − ) and holes (h + ) pairs, achieving high yields of ROS generation against melanoma upon ultrasound (US) activation. Especially, the single atom Fe doping not only substantially elevates the separation efficiency of the e − ‐h + pairs involved in SDT, but also can serve as high‐performance peroxidase mimetic enzyme to catalyze the Fenton reaction for generating abundant hydroxyl radicals, therefore synergistically augmenting the curative effect mediated by SDT. As verified by density functional theory simulation, the doping of Fe atom significantly promotes the charge redistribution in the C 3 N 4 ‐based NSs, which improves their synergistic SDT/chemodynamic activities. Both the in vitro and in vivo assays demonstrate that Fe‐C 3 N 4 NSs feature an outstanding antitumor effect by aggrandizing the sono‐chemodynamic effect. This work illustrates a unique single‐atom doping strategy for ameliorating the sonosensitizers, and also effectively expands the innovative anticancer‐therapeutic applications of semiconductor‐based inorganic sonosensitizers.