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 <i>in vitro</i> and <i>in vivo</i> 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.