Stimulus-ignited carbon monoxide nanogenerators for cancer therapy: The paradigm shift from lethal toxin to therapeutic agent.

Carbon monoxide (CO)-involving gas therapy, with advantages of high transmembrane diffusivity, multiple pharmacodynamic functions, and non-resistance, holds tremendous potential in cancer therapeutics. However, the main challenges of medicinal CO come from poor tumor targeting and high toxicity. The development of stimuli-responsive CO-releasing molecules (CORMs) enables controlled CO release and reduced gas poisoning. Particularly, advancements in stimulus-ignited nanogenerators built on CORMs create new avenues for precision targeting of malignant tumors and gas-sensitized synergistic therapy. This review initially elucidates the association between CO and tumor progression, and discusses the significance of designing stimulus-ignited CO nanogenerators from the perspective of the dilemma and opportunity of CO treatment. Then, the applications and rationale of CO nanogenerators in spatiotemporally targeted cancer therapy are outlined from different stimulation modalities, highlighting the recent advancements and their primary synergistic effects with other cancer therapeutic paradigms. Finally, the challenges and possibilities of the emerging CO nanogenerators for cancer gas therapy are discussed. This review elucidates the design strategy of stimulus-responsive CO nanogenerators and their synergistic mechanism in precision tumor therapy, which lays down a theoretical framework for the paradigm shift of CO from lethal toxin to therapeutic agent.