FeIII-Doped Two-Dimensional C3N4 Nanofusiform: A New O2-Evolving and Mitochondria-Targeting Photodynamic Agent for MRI and Enhanced Antitumor Therapy

Local hypoxia in tumors, as well as the short lifetime and limited action region of 1O2, are undesirable impediments for photodynamic therapy (PDT), leading to a greatly reduced effectiveness. To overcome these adversities, a mitochondria‐targeting, H2O2‐activatable, and O2‐evolving PDT nanoplatform is developed based on FeIII‐doped two‐dimensional C3N4 nanofusiform for highly selective and efficient cancer treatment. The ultrahigh surface area of 2D nanosheets enhances the photosensitizer (PS) loading capacity and the doping of FeIII leads to peroxidase mimetics with excellent catalytic performance towards H2O2 in cancer cells to generate O2. As such tumor hypoxia can be overcome and the PDT efficacy is improved, whilst at the same time endowing the PDT theranostic agent with an effective T 1‐weighted in vivo magnetic resonance imaging (MRI) ability. Conjugation with a mitochondria‐targeting agent could further increase the sensitivity of cancer cells to 1O2 by enhanced mitochondria dysfunction. In vitro and in vivo anticancer studies demonstrate an outstanding therapeutic effectiveness of the developed PDT agent, leading to almost complete destruction of mouse cervical tumor. This development offers an attractive theranostic agent for in vivo MRI and synergistic photodynamic therapy toward clinical applications. Highly selective and efficient cancer treatment can be achieved by overcoming photodynamic therapy (PDT) shortcomings, such as hypoxia, short lifetimes, and limited action region of 1O2. A mitochondria‐targeting, H2O2‐activatable, and O2‐evolving PDT nanoplatform is developed based on a FeIII‐doped, two‐dimensional C3N4 nanofusiform. This development offers an attractive theranostic agent for in vivo MRI and enhanced photodynamic therapy towards clinical applications.