Dual-Mode Reactive Oxygen Species-Stimulated Carbon Monoxide Release for Synergistic Photodynamic and Gas Tumor Therapy

Controllable carbon monoxide (CO) release simulated by light-generated reactive oxygen species (ROS) represents a promising approach for cancer therapy but is hampered by low CO release rate and low ROS generation of conventional photosensitizers in hypoxia tumor microenvironments. In this study, we developed a highly efficient nanoplatform (TPyNO₂–FeCO NPs) through co-encapsulating organic AIE photosensitizers (PSs) and CO prodrug (Fe₃(CO)₁₂), which are capable of light-triggered robust ROS generation and CO release for synergistic photodynamic therapy (PDT) and CO gas therapy. The success of this nanoplatform leverages the design of a PS, TPyNO₂, with exceptional type I and type II ROS generation capabilities, achieved through the introduction of the α-photoinduced electron transfer (α-PET) process. With the incorporation of a 4-nitrobenzyl unit as a typical PET donor, the intramolecular α-PET process not only suppresses the radiative decay to redirect the excited-state energy to intersystem crossing for more triplet-state formation but also promotes electron separation and transfer processes for radical-type ROS generation. The resultant TPyNO₂ demonstrates superior singlet oxygen, superoxide anion, and hydroxyl radial generation capabilities in the aggregate state. Upon light irradiation, TPyNO₂–FeCO NPs release CO via the type I and type II dual-mode ROS-mediated processes in a controlled and targeted manner, overcoming the limitations of conventional CO release systems. TPyNO₂–FeCO NPs also demonstrate a self-accelerating ROS–CO–ROS loop as the released CO induces intracellular oxidative stress, depolarizes mitochondria membrane potentials, and inhibits ATP production, leading to further intracellular ROS generation. Both in vitro and in vivo experiments validated the excellent antitumor performance of the combined PDT and CO gas therapy. This study provides valuable insights into the development of advanced PSs and establishes TPyNO₂–FeCO NPs as promising nanoplatforms for safe and effective antitumor applications.