CO

Carbon monoxide (CO) is a "prototypical exerkine" produced by heme oxygenase 1 (HO-1) that functions to reduce inflammatory responses in activated macrophages PMID 39641407. By inhibiting the peripheral NLRP3 inflammasome signaling pathway alongside Irisin, exercise-induced CO contributes to the mitigation of neuroinflammation and offers potential protective effects against the progression of Alzheimer's disease PMID 39641407.

• Anti-inflammatory Signaling: CO helps inhibit the NLRP3 inflammasome signaling pathway and hence reduces inflammatory responses in activated macrophages PMID 39641407.

CO is considered a "prototypical exerkine" because its production is upregulated in response to physical activity. Exercise activates the Nrf2 pathway, which in turn induces the expression of HO-1 leading to increased systemic levels of CO to mediate beneficial physiological adaptations PMID 39641407PMID 37247469.

• Neuroprotection: By alleviating peripheral NLRP3 inflammasome signaling, exercise-induced CO may help slow the progression of neurodegenerative conditions like Alzheimer's disease PMID 39641407.

1. Oncology and Cancer Immunotherapy

• CO is emerging as a potent agent in multimodal cancer therapies. Recent studies demonstrate its ability to enhance immunotherapy or overcome resistance to checkpoint blockades by reprogramming the tumor microenvironment PMID 39442888PMID 41205705. CO can beintegrated alongside nanoplatforms for synergistic photodynamic and photothermal therapies, where it helps induce immunogenic cell death and suppress heat shock proteins that typically protect cancer cells PMID 40915292PMID 40279848PMID 39543646. Furthermore, CO has been shown to induce ferroptosis (a type of cell death) to treat bone metastases PMID 41080723.

2. Neuroprotection and Stroke Recovery

• Novel nanomodulators releasing CO have shown promise in penetrating the blood-brain barrier to drive both neuroprotection and neurogenesis in stroke models PMID 41104983. Additionally, CO-releasing molecules (CORMs) have been found to promote oligodendrogenesis and cognitive recovery in traumatic brain injury PMID 39862180 and offer potential therapeutic targets for Parkinson's disease by modulating oxidative stress PMID 40713247PMID 39895106.

3. Inflammation, Sepsis, and Organ Transplantation

• CO attenuates ischemia-reperfusion injury in kidney and heart transplants, potentially expanding the pool of usable donor organs PMID 40869142PMID 39013278PMID 34525329. In sepsis models, CO nanogenerators have been shown to scavenge inflammatory mediators, reduce cytokine storms, and inhibit macrophage activation PMID 38883313PMID 39880317. It also shows potential in treating inflammatory bowel diseases by restoring immune homeostasis PMID 37843108PMID 39925143.

4. Metabolic Disorders and Wound Healing

• Therapeutic CO delivery is showing efficacy in metabolic regulation. Oral administration of CORMs has been observed to combat obesity by modulating the gut microbiome PMID 38608580 and ameliorating metabolic dysfunction-associated steatohepatitis (MASH) PMID 39163766. In regenerative medicine, CO-releasing microneedles and hydrogels are being developed to accelerate the healing of infected diabetic wounds by promoting angiogenesis and fibroblast migration PMID 39573876PMID 38292600.

5. Advanced Delivery Systems

• To mitigate systemic toxicity, current research emphasizes the development of controllable delivery systems rather than gas inhalation. These include:
• Nano-delivery systems: Utilizing Near-Infrared (NIR) imaging for guided release PMID 41560795.
• CORMs: Metal-based or organic molecules that release CO in response to specific stimuli like light, ultrasound, or reactive oxygen species PMID 38515608PMID 40585853.
• Oral formulations: "CO in a pill" strategies using prodrugs for targeted gastrointestinal delivery PMID 34481027.