Photodynamic therapy (PDT) is a non-invasive treatment modality against a range of cancers and nonmalignant diseases, however one must be aware of the risk of causing phototoxic reactions after treatment. We herein report a bioinspired design of next-generation photosensitizers (PSs) that not only effectively produce ROS but undergo fast metabolism after treatment to overcome undesirable side effects. We constructed a series of b -pyrrolic ring-opening secochlorins, termed beidaphyrin ( BP ), beidapholactone ( BPL ), and their zinc(II) derivatives ( ZnBP and ZnBPL ), featuring intense near-infrared absorption and effective O 2 photosensitization. Irradiation of ZnBPL led to a non-cytotoxic, metabolizable beidaphodiacetamide ( ZnBPD ) via in situ generated O 2 •- but not 1 O 2 , as revealed by mechanistic studies including time-resolved absorption, kinetics, and isotope labeling. Furthermore, water-soluble ZnBPL showed an effective therapeutic outcome, fast metabolism, and negligible phototoxic reactions.