Oral Delivery Systems for Gasotransmitters in Therapeutic Applications

Gasotransmitters, including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S), are critically involved in a broad spectrum of physiological and pathological processes, such as vasodilation, neurotransmission, immune modulation, and antioxidant defense. Due to their diverse biological activities, these gasotransmitters have attracted increasing interest as potential therapeutic agents. However, their clinical application remains limited by intrinsic physicochemical challenges, including short half-lives and low targeting specificity, which complicate efficient delivery. In recent years, oral delivery approaches have received growing attention in gasotransmitter-based therapy owing to their noninvasive administration, high patient compliance, and potential for both systemic and localized effects. Polymer-based delivery systems play a pivotal role in the oral administration of gasotransmitters by enabling controlled release, protecting labile molecules from degradation, and enhancing their bioavailability. This Review systematically summarizes recent advances in the oral delivery of NO, CO, and H₂S, with particular emphasis on prodrug design, controlled release systems, carrier engineering, and in vivo release mechanisms. Furthermore, the major technological barriers to clinical translation are critically discussed. Finally, future perspectives are outlined to inform the rational design of optimized oral delivery platforms for therapeutic gases.