From canes to pills: the evolution of carbon monoxide therapeutics

Carbon monoxide (CO) has gained increasing attention as an endogenous gasotransmitter with potential therapeutic relevance. In preclinical studies, including acute lung injury, sepsis, transplantation, inflammatory bowel, and cardiovascular diseases, CO has shown anti-inflammatory, anti-apoptotic, vasodilatory, and cytoprotective properties, suggesting its application in treating a wide range of diseases associated with cellular stress. CO impairs blood oxygen transport when systemic exposure occurs, but it is safe when blood oxygen transport is not compromised. Consequently, treatment modalities benefit from local rather than systemic CO delivery to open the therapeutic window of this physiological gasotransmitter. This review, therefore, focuses on local drug delivery strategies for generating and delivering CO, and on solutions and perspectives for various applications that leverage CO's anti-inflammatory and cytoprotective effects with an enhanced safety profile. We present the use of CO-releasing molecules (CORMs) and their incorporation into advanced drug delivery devices to control local CO exposure. Special emphasis is placed on drug vehicles featuring controlled on-target delivery, dosing, and biocompatibility. Therefore, we identify key principles and remaining obstacles in CO delivery technologies, which confluences in strategies that reduce the risk for pharmaceutical development and clinical application for safe, controlled, and targeted therapies.