*1.10. Solubility*

For making CORM acceptable as a pharmaceutical drug in the mammalian biological system, solubility is one of the most prominent factors where the researcher can evaluate the proficiency of the product. Solubility estimates how much CORMs and CORMats are convenient for the practical demonstration. CORM-2 is soluble in DMSO, olive oil and PEG [95,112], while CORM-3 contributes to the water compatibility with a weak acidic nature (pH = 3) [26,37]. Specifically, CORM-A1 possesses the water solubility and stability but it breaks-down immediately after liberating the CO under acidic condition (pH = 11) [87]. CORM-ALF186 can a fford the disintegration in the water system and is unstable at an aerobic condition [113] and ALF062 is soluble in methanol and DMSO, while it remains unstable in the air [98,113]. Furthermore, CORM-1 has the compatibility with DMSO and ethanol [114].

Although the CORMs motif is good for releasing the CO moiety, but the tissue selectivity and targeting sites dilemma has reduced its overall biological performance and hence lost its therapeutic significance. Most importantly, the toxicity of organometallic complexes is handled very poorly, so to reduce the toxicity and increase its reactivity, it requires an exploration of all the alternative strategies. Therefore, the researchers have moved from CORMs to CORMats.

#### **2. Research on New CO Transport Materials**

As discussed, the MCCs are the admissible and professional class of (soluble) CORMs; however, it has been imperative to examine their probable shortcomings. In fact, a small number of organometallic compounds can be manipulated for pharmaceutical agents predominantly caused by the side-reaction of metals with biological chemical compounds, (e.g., nucleophilic or even electrophilic side chains of proteins) together with the toxicity of several heavy metals. Water-soluble CORMs are approaching the entire body organism and it could accelerate the toxicity against healthy tissues. The spatial and acceptable releasing rate of it into biological tissues/cells is still the utmost challenge. Furthermore, the CO-releasing activity inevitably accumulates a metal and co-ligand fragment, probably takes part in the biological activity as well. This residue (i-CORMs) can be managed through the insoluble framework. On the basis of abovementioned issues and challenges, new and compatible CO transport materials and strategies are emerging in order to ge<sup>t</sup> rid of the CO lethal gas dilemma and to convert it into a valuable clinical agent. CORM-1 [115], CORM-2 [116,117], CORM-3 [118] and CORM-A1 [87] have been tested in various disease models to observe their therapeutic e ffects and to obtain its surprisingly outcomes in typical clinical conditions [2,119]. CORM-3 has good cure-ability for inflammatory disorders like rheumatoid arthritis, osteoarthritis and collagen-induced arthritis (CIA) [97,120,121]. CORM-A1 provides ameliorated course in experimental auto-immune uveoretinitis (EAU) [122], while CORM-2 attenuates the tumor proliferation [123] and a considerable enhancement the coagulation and slow-down of the fibrinolytic bleeding [117,124] and improves survival in the liver injury a ffected by cecal ligation and perforation (CLP) [116,125]. CORM-3, CORM-2 and ALF-062 corroborates with antimicrobial functions [98,126–131]. The CO is encouraging the proliferation of endothelial cells, progenitor cells and regulatory T-cells [34,132,133]. There is still more interrogation required for further improvement to employ practical knowledge. So, the development of the solid CO precursor in tandem with peculiar trigger for releasing the enclosed CO gas commodity is an imperative research motive. To date, due to the unavailability of a safe delivery system for CORM; none of those prescribed formulations could have been employed in humans as a direct dose for respective damaged tissues or disease. Although a few scientific proposals have been presented in that scenario for making CORMs as a clinically viable project, but none of them exhibits the secure transportation material system for the patient's right choice. All that discussion pursued that the nanoscale and macromolecular carrier system could be exploited to obtain a selected tissue enrichment and proposed mechanism strategy for CORMs delivery (Scheme 3) [134,135].

**Scheme 3.** Various organometallics MCCs incorporate with numerous conjugate systems to produce carbonylation complexes, i.e., CORMats for therapeutic CO release upon trigging.

The clinical trials on CORMs proved that CORMs exhibited the important biological applications, but after CORMs, the degradation metal residue (i-CORMs) also caused toxicity unfortunately [136]. The prohibited i-CORMs activity containment is a big challenge for the researchers. To reduce toxicity and capture the i-CORMs toxic moiety, scientists have explored a strategy known as CORMats. In this strategy, firstly, CO is entrapped inside the CORMats through specific administration, and then upon certain conditions the captured CO is escaped out. Several scaffolds and conjugated formulations have been introduced in this scope and it is still under investigation by compatible conjugate CORM's such as Ruthenium-MCC (Ru-MCC) and Manganese-MCCs (Mn-MCC) by different nano-transporting services such as Iron MOFs [137,138], peptide [139–144], micellization [55,59,145], protein [121,146–149], vitamins [150–153], co-polymer systems [47,154–156], nanofiber gel [142], inorganic hybrid scaffolds [157–160] and metallodendrimers [161] (Figure 5). The intrinsic toxicity control of i-CORMats is the top priority for each developed system.

**Figure 5.** The CO-releasing administration with different conjugate and encapsulate strategies.
