The escalating prevalence of antimicrobial resistance (AMR), largely driven by the misuse and overuse of antibiotics, underscores the urgent need to explore alternative non-antibiotic therapeutic strategies. Gas therapy (GT), which utilizes gaseous signaling molecules (GSMs) such as carbon monoxide (CO), nitric oxide (NO), hydrogen sulfide (H2S), oxygen (O2), and hydrogen (H2), has emerged as a promising antimicrobial strategy. These GSMs possess several distinctive advantages, including rapid and unimpeded diffusion into bacterial cells and biofilms, diverse antimicrobial mechanisms—such as reactive species generation, metabolic interference, and immune modulation—and a minimal risk of inducing AMR. This review systematically elucidates the antibacterial and anti-biofilm mechanisms of GSMs, emphasizing their integration with advanced modalities such as photodynamic therapy (PDT), photothermal therapy (PTT), sonodynamic therapy (SDT), and chemodynamic therapy (CDT) to enhance efficacy. We focus on how these strategies enable the precise delivery and controlled release of GSMs, how the released gases synergistically enhance therapeutic efficacy, and how these therapeutic platforms exhibit strong potential in combating infections caused by MDR bacteria and biofilm-associated pathogens. Despite preclinical success, critical barriers—including gas toxicity risks, biofilm penetration limitations, and regulatory hurdles—impede clinical translation. We further discuss future directions, advocating for engineered gas-releasing biomaterials, multimodal synergistic platforms, and artificial intelligence-driven design to optimize therapeutic outcomes. By bridging microbiology, nanotechnology, and clinical practice, this work underscores the potential of GT to redefine infection management in the post-antibiotic era.
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