**5. Concluding Remarks**

CO is generally infamous for its toxicity, but a controlled dose of CO shows useful biological impacts. The CO's detail analysis exhibits endogenous production by heme oxygenase and explores the therapeutic scope. This scientific study not only confirms the endogenous generation of CO, which has important potential in pathological tissues but also guarantees exogenously released CO's therapeutic impacts. Therefore, the challenges for the pharmaceutical drug chemists have always been and are continuing still, for the development of a risk-free and more convenient strategy to deliver therapeutic CO dosage. The CO administration with biological system suggests their therapeutic potential. This CO administration relies on MCCs for CO liberation. Thus, CORMats were developed by MCCs with different conjugate/scaffold systems. The CORMats have been covalently assembled with different nanomaterial including polymers, silica nanoparticles, proteins cages, vitamins, metallodendrimer, micelles, nanodiamond and nanofiber gel (peptide amphiphilic) or even incorporated with magnetic nanoparticles (maghemite), tablets, non-woven, or either MOFs for following features: To enhance sustainability and stability; to approach the special cellular tissues/organs; to reduce the toxicity; to attain the EPR- effect; or to permit special triggers facilities. CORM has the capability to deliver the CO to tissues and cells in vivo, in-fact constitute the most appropriate scheme to accomplish the therapeutic outcomes. This proof-of-concept refers to the medicinal chemists to endeavor modern CORMats furnished with ADME (CORMats characteristics: Administration, Distribution, Metabolism, Excretion), prerequisite for the clinical utility. As a prodrug, these developed mechanisms are highly dependent on in vivo performance. It has been worth mentioning that many pharmaceutical materials were also claimed to be non-toxic such as smectite clay that might be transformed into CORMats for promising therapeutic benefits. Probably crystalline smectite clays are the best choice for the CORMats development due to its con-comitant administration. Additionally, their layered structure exfoliations and cation exchange capacity (CEC) have been encouraging for developing the new class of CORMats. Furthermore, it is mandatory to investigate the metal residues (remaining fragments) after CO liberation, if any side e ffect of newly developed materials is reported should try to minimize it by modern carrier designs. The aim of the controlled CO delivery managemen<sup>t</sup> was sponsored by tissue selection and distribution. The CORMats activation with di fferent triggers did not permit to develop "universal" CORMats for every disease model. The method of CORMs/CORMats trigger or even CO activation is used to disintegrate the MCCs through photo, thermal, enzyme, pH, oxidation and solvent trigger CORMs/CORMats bearing ligand exchange strategies. These CORMs/CORMats strategies are promising candidates of the therapeutic potential and deserve exclusive attention for thorough therapeutic investigations.

The toxicity of the CO precursor is still a big challenge for the researchers. The CORMs/CORMats toxicity was in-action during and after the CO release with depleted metal residues abbreviated as i-CORMs/CORMats. The fast CO release helps to study the ion-channel path, while the slow release favors tissue targets. It is mandatory that CORMs/i-CORMs and CORMats/i-CORMats (before/after CO release) should not be participating in any toxic activity. Otherwise it will not be possible to prescribe for patients; as the safety of human organs is the utmost priority.

The above discussion confirms that CORMs and CORMats are accountable for the CO-produce being the active ingredient. It should be noted that CORMats did not technically modify specific receptors but only provided a transport and discharge services for the CO gas. Therefore, the therapeutic impacts of CORMats under physiological conditions to employ CO preferentially and professionally against damaged biological tissues/organism must prevail and ensure the quick release of loaded CO upon trigger.

**Author Contributions:** Conceptualization, W.Z. and Y.W. (Yanyan Wang); Methodology, Y.W. (Yanyan Wang), M.F., Y.H. and W.Z.; Writing —Original Draft Preparation, M.F., H.S., Y.H., N.M., K.N. and Y.W. (Yanyan Wang); Writing —Review and Editing, Y.H., N.M., Y.W. (Ya Wu), W.D., R.L., K.N., W.Z. and M.F.; Supervision, Z.G. and W.Z.; Project Administration, W.Z. and Z.G.

**Funding:** This research was supported by the gran<sup>t</sup> from National Natural Science Foundation of China (21771122, 21571121), the 111 Project (B14041), the Program for Chang Jiang Scholars and Innovative Research Team in University (IRT\_14R33), Key Research and Development Project of Shaanxi Science and Technology Department (2017SF-064).

**Acknowledgments:** This work was performed within the "211 Project" of Ministry of Education (MOE) China at the Key Laboratory of Applied Surface and Colloid Chemistry with the support of China Scholarship Council program at Shaanxi Normal University, Xi'an, China.

**Conflicts of Interest:** The authors declare that there is no conflict of interests regarding the publication of the paper.
