**1. Introduction**

Carbon monoxide (CO) is considered harmful due to its toxic behavior since the last century. It has a tasteless, odorless and colorless nature. Its colorless nature allows CO to remain undetectable even at high concentrations and toxic levels, thus marked as the "silent killer" [1,2]. This poisonous CO behavior is exerted due to the formation of carboxy hemoglobin (COHb) along with oxygen present in the mainstream blood circulation. Haldane and Douglas scientifically explored it the first time through dissociation curves of CO-hemoglobin using a constant percentage of CO along with a variable percentage of oxygen at an atmospheric pressure [3,4]. The ubiquitous enzyme, heme oxygenase (HO) has been investigated in most of the biological species. In the middle of the 19th century, two scientists Tenhunen and Schmidt discovered the intracellular CO production by heme oxygenase with an enzyme being the heme catalyst [5,6]. HO is categorized under two isoforms: HO-1 (HMOX1; gene name), with its capability to remain inducible in all cell functions; and HO-2 (HMOX2; gene name), that is constitutively expressed and substantially contained in vasculature and testes [7,8]. HO-1 is identified as an element exclusively found in spleen and liver [9]; however it might be influenced by varying intensity in most biological tissues. Both HO-1 and HO-2 indicate the rate-determining step, drag-out biliverdin from the heme conversion with the CO release and Iron product associated with a tetra pyrrole ring. Biliverdin using biliverdin reductase transforms into bilirubin while generating ferritin quickly from the Iron segregate (Figure 1) [10]. The released amount of CO attaches with the Iron containing objects due to its higher di ffusion rate and tendency. It tends to make itself bonded with blood in the circulatory system; and ultimately it is exhaled through lungs. CO causes a common sagginess by bringing a ffliction for the mammalians, completely dependent on oxygen for the blood transport system and mitochondrial respiration. Collectively, endogenously generated CO is featured in the physiological role. Generally, a low dose of CO gas endures tremendous benefits and can achieve remarkable therapeutic targets.

**Figure 1.** The intracellular carbon monoxide (CO) production by heme oxygenase (HO) in the mammalian system justifies its biological role.

CO is endogenously produced by either specific enzymes or through gas transmission into a biological system, both types exhibit the physiology and pathophysiology functions through inter- and intra- cellular interactions. The endogenously produced CO also raises their potential as a therapeutic agent. The scientists and researchers are availing this opportunity and spending their time and energies for developing modern drug techniques [11]. Their aim is to explore the modern work with the novelty of this grea<sup>t</sup> strategy.

#### *1.1. CO Biological Scope*

The CO gas is known for its leading role as a molecular messenger in the physiological process for the nervous system [12] and also for following some important therapeutic treatments [2,13]. It has the potential for anti-inflammatory [14], anti-proliferative [15], anti-atherogenic [16], anti-allodynia [17], anti-nociceptive [18], anti-hyperalgesia [17], and anti-apoptotic [19] effects. It is vital for vasodilatory phenomena reducing intraocular pressure [20], immunosuppressive administrated medications [21] and also has the capability to develop the pathological cellular process (Figure 2) [22]. CO also has many advantages for different biological organs: Organ transplantation [2], protection [23] and preservation; heart [24–26]; kidney [23,27–29]; liver [30,31]; lungs [32,33]; pancreatic islet [34] and the small intestine [35]. It is helpful to de-escalate the Ischemia/Reperfusion Injury (IRI) [36], mitigate the myocardial infarction and allograft rejection [37], stimulate the cytoprotective [38], and is also involved in anti-microbial [39] and anti-hypertensive activities [40]. It has a modulated utility for heme-dependent proteins like mitochondrial cytochromes and NADPH [28,41]. Moreover, the intercellular CO production by heme oxygenase has proved itself as a valuable reagen<sup>t</sup> [42]. The pharmaceutical dose through endogenous CO enrichment or exogenous direct transformation is flourishing and will be attracted as a therapeutic interest lately.

**Figure 2.** The coagulation and fibrinolysis scope of CO-releasing materials (CORMats).

#### *1.2. CO Therapeutic Ways*

Mainly, there are two ways to insert the CO molecules as a therapeutic agen<sup>t</sup> inside the human body, i.e., direct and indirect CO insertion. The direct inhalation has not been preferred, owing to its rise in the COHb level above 10% and lack of tissue selectivity (Figure 3). Moreover, it provides a direct interaction of the CO and lungs only while detainment of CO is also observed in this method. These limitations don't allow CO to approach other biological organisms for therapy. To overcome these problems, researchers have developed an alternate strategy called "Exogenous Endeavor" for obtaining the required therapeutic actions. In the early 19th century, researchers also recognized the toxic gas NO as the nitro drug having therapeutic impacts. The nitric medications are well demonstrated as nitric oxide-releasing molecules (NORMs), and that established their well reputation afterward CORMs cogitation [43].

**Figure 3.** The carboxy hemoglobin (COHb) percentage is increasing in the direct CO inhalation beyond the therapeutic zone (~10%) during the mainstream blood circulation. (This information is based on data reported in reference [44,45]).

#### *1.3. Why Exogenous Endeavor is Required?*

The CO-releasing fragment is basically an exogenous endeavor that has opened up the paths for therapeutic treatments (Figure 4). The exogenous stakeholder CO, makes space for searching the affected sites, reaches at the diseased tissue site and makes conflict/collusion with the selected tissues for the destruction of damaged organs or/and diseased cells. If required, the CO-releasing rate can be regulated and modified according to specs. To disintegrate CORMs and CORMats into CO and metal residue, numerous activators are being administratively applied for controlling the CO liberation rate that has already been experienced in Photo-CORMs and Photo-CORMats through Ultra Violet (UV), Visible and NIR light with on/off switching facility [11,46–50]. The photon energy also has a utility to extract CO from its parent organometallic ligand. The main advantage of CO's exogenous interactions with the mammalian organism is that it reduces the CO moiety to be directly induced into blood streams for maintaining the COHb under allowable serum levels (up to 10%). Without an endogenous CO administration, it is quite challenging to ge<sup>t</sup> productive outcomes.

**Figure 4.** The feasibility analysis of the CO direct and indirect inhalation shows their different biological observance inside a human body.

#### *1.4. Clinical Translations*

In spite of its hazardous nature, a controlled CO direct inhalation has some therapeutic benefits as well. A clinical trial of controlled CO dosage was conducted on healthy volunteers for temporary paralysis of intestines known as Post-Operative Ileus (POI), and usually every patient is engaged in this POI after surgery of the abdomen. This clinical study revealed that serious POI complications could be significantly reduced if the CO dose (~250 ppm) is inhaled before and after the colon surgery (ClinicalTrials.gov identifier: NCT01050712). Another CO clinical translation test also shows a transplantation protection when the CO–saturated medium is provided for harvesting islets as it protects the cell from chronic pancreatitis (ClinicalTrials.gov identifier: NCT02567240).

This valuable intensive information about the CO therapeutic analysis plays a vital role for all the researchers' attention. Although there are few unfavorable emblems associated with releasing CO moiety, but recent outcomes of therapeutic potential helps to promote CO as preclinical stems [13]. This novel idea was initiated through clinical and pre-clinical trials for either the direct inhaled therapy [13] or oral intake of CO-releasing substances including CORMs or CORMats, which is a modern result of the professional chemistry enterprise [51].

#### *1.5. Challenges and Demanding Features of CORMs and CORMats*

Although CORMs and CORMats have a tremendous therapeutic utility but it also possesses some sort of following limitations for releasing the embedded CO.


The abovementioned fundamentals have been discussed as a prescribed domain while exploring the CO discharge. Considering the CO gas as a therapy treatment based on CORMs and CORMats are easier to control by the transportation of gas molecules rather than the direct CO gas intake. Moreover, the rapid diffusion of these small molecules limits their ability to concentrate in specific tissues. Many challenges also arise during movability of the CO gas molecules by these strategies. Both the carbonyl transition metal and all its degradation products are biologically toxic in nature. Hence, it is difficult to manage the CO discharge with respective biological tissues. Particularly, the release of the CO molecules from CORMs also participates in depositing heavy metal ions inside the human body, which could be harmful for biological organisms.
