Harnessing gasotransmitters for orthopaedic infection therapy: Mechanisms and advanced delivery platforms.

Orthopaedic infections are increasingly prevalent in the aging population, posing a significant clinical and economic burden. Despite progress in antimicrobial therapies, challenges such as antibiotic resistance and superbug emergence persist. Gas therapy has emerged as a promising strategy for managing orthopaedic infections. Classical gasotransmitters-including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S)-exhibit antibacterial and immunomodulatory effects at controlled concentrations, though improper dosing may induce adverse effects. This review critically examines the dual mechanisms through which gasotransmitters combat infection while promoting orthopaedic regeneration. We also survey advanced delivery platforms-such as smart scaffolds, nano-reservoirs, and on-demand release systems-engineered for targeted gasotransmitter delivery to infected bone tissue. Finally, we discuss current limitations and future prospects, aiming to inspire novel biomaterial designs for targeted therapeutic delivery and to advance gas therapy as a viable option for orthopaedic infection treatment.