Carbon monoxide gas molecules: Therapeutic mechanisms in radiation-induced lung injury

Radiation therapy (RT) remains an essential treatment modality for lung cancer, yet its effectiveness is frequently hindered by radiation-induced lung injury (RILI), a common outcome of modern therapeutic regimens. With the aim of addressing this challenge, a novel nanocomposite, Au@mSiO₂@Mn(CO)₅Br (ASMB), was synthesized with Au@mSiO₂ as the carrier and Mn(CO)₅Br as the functional component. The gold nanorods (Au rods) core generates reactive oxygen species (ROS) under X-ray irradiation, which then activates Mn(CO)₅Br to release carbon monoxide (CO) locally within the lung during radiotherapy. The released CO then diffuses to surrounding tissues, inhibiting the excessive accumulation of ROS, thereby preventing damage to normal cells caused by ROS generated in a short period of time. Meanwhile, the released manganese ions (Mnⁿ⁺) catalyze the conversion of hydrogen peroxide (H₂O₂) in the microenvironment into oxygen (O₂). In vitro experiments demonstrated that the release of CO markedly attenuated radiation-induced ROS production, thereby inhibiting the activation of the NLRP3 inflammasome and reducing the levels of inflammatory cytokines and pyroptosis-related proteins. Moreover, it downregulated the expression of fibrosis-associated proteins, including TGF-β1 and α-SMA. Additionally, CO facilitated DNA damage repair, thereby mitigating radiation-induced tissue injury. In the RILI model, the ASMB NPs-treated lungs exhibited notably reduced pulmonary edema, congestion, and inflammatory cell infiltration, primarily by inhibiting NLRP3 inflammasome-dependent pyroptosis and reducing levels of inflammation and fibrosis markers. The release of O₂ further mitigates local tissue hypoxia, enhancing the effectiveness of radiotherapy. Overall, ASMB NPs provide a promising alternative for the treatment of RILI and a potential therapeutic strategy to improve the efficacy of radiotherapy.