Dual-Mode Reactive\nOxygen Species-Stimulated Carbon\nMonoxide Release for Synergistic Photodynamic and Gas Tumor Therapy

Controllable carbon monoxide (CO) release simulated by\nlight-generated\nreactive oxygen species (ROS) represents a promising approach for\ncancer therapy but is hampered by low CO release rate and low ROS\ngeneration of conventional photosensitizers in hypoxia tumor microenvironments.\nIn this study, we developed a highly efficient nanoplatform (TPyNO<sub>2</sub>–FeCO NPs) through co-encapsulating organic AIE photosensitizers\n(PSs) and CO prodrug (Fe<sub>3</sub>(CO)<sub>12</sub>), which are\ncapable of light-triggered robust ROS generation and CO release for\nsynergistic photodynamic therapy (PDT) and CO gas therapy. The success\nof this nanoplatform leverages the design of a PS, TPyNO<sub>2</sub>, with exceptional type I and type II ROS generation capabilities,\nachieved through the introduction of the α-photoinduced electron\ntransfer (α-PET) process. With the incorporation of a 4-nitrobenzyl\nunit as a typical PET donor, the intramolecular α-PET process\nnot only suppresses the radiative decay to redirect the excited-state\nenergy to intersystem crossing for more triplet-state formation but\nalso promotes electron separation and transfer processes for radical-type\nROS generation. The resultant TPyNO<sub>2</sub> demonstrates superior\nsinglet oxygen, superoxide anion, and hydroxyl radial generation capabilities\nin the aggregate state. Upon light irradiation, TPyNO<sub>2</sub>–FeCO\nNPs release CO via the type I and type II dual-mode ROS-mediated processes\nin a controlled and targeted manner, overcoming the limitations of\n conventional CO release systems. TPyNO<sub>2</sub>–FeCO NPs\nalso demonstrate a self-accelerating ROS–CO–ROS loop\nas the released CO induces intracellular oxidative stress, depolarizes\nmitochondria membrane potentials, and inhibits ATP production, leading\nto further intracellular ROS generation. Both <i>in vitro</i> and <i>in vivo</i> experiments validated the excellent\nantitumor performance of the combined PDT and CO gas therapy. This\nstudy provides valuable insights into the development of advanced\nPSs and establishes TPyNO<sub>2</sub>–FeCO NPs as promising\nnanoplatforms for safe and effective antitumor applications.