Rational Molecular Design of Efficient Heavy‐Atom‐Free Photosensitizers for Cancer Photodynamic Therapy

Photodynamic therapy has emerged as a promising modality for treatment of cancer due to its minimal invasiveness and high selectivity. However, development of advanced photosensitizers (PSs) for clinical translation of photodynamic therapy remains challenging. To overcome the limitations of common photosensitizers containing heavy atoms, we herein developed highly effective heavy‐atom‐free photosensitizers based on strong donor‐π‐acceptor‐type structures (PTZ‐CN and PXZ‐CN) for bioimaging and photodynamic ablation of cancer. These PSs exhibited bright fluorescence emission with a large Stokes shift as well as considerable reactive oxygen generation capability under specific conditions. Notably, PTZ‐CN could produce reactive oxygen species more efficiently than Ru(bpy)32+ (commercial PS) with an approximately 2.2‐fold via type I and type II photochemical mechanisms. In addition, their stable nanoparticles were easily formed by self‐assembly in an aqueous solution without employing a polymer. More importantly, PTZ‐CN/PXZ‐CN exhibited bright fluorescence and excellent photodynamic performance with negligible dark cytotoxicity toward HeLa cells. This study demonstrates the promising potential of donor‐π‐acceptor‐type molecule‐based PSs in fluorescence image‐guided photodynamic therapy. Donor–π‐acceptor–type‐based heavy‐atom‐free photosensitizers (PTZ‐CN and PXZ‐CN) were developed using malononitrile as the electron acceptor and functionalized phenothiazine/phenoxazine as the electron donor. Both PTZ‐CN and PXZ‐CN exhibit bright fluorescence and excellent ROS generation and hold great potential as photosensitizers for fluorescence imaging‐guided photodynamic therapy.