Gasotransmitters in Modern Medicine: Promises and Challenges in the Use of Porous Crystalline Carriers

Abstract

Gas therapy using gasotransmitters is of exponential interest due to the growing recognition of gas signaling molecules that can be involved in multiple therapeutic actions. Finding suitable methods for delivering these molecules is crucial, and porous materials, notably metal-organic frameworks (MOFs), have shown exceptional potential as gas carriers, enabling safe and controlled local delivery. The challenges to translate these MOF therapies to clinical use require not only to validate the mechanisms of action and signaling pathways for the released gas molecules but also get a deep understanding into the MOF rational design, as it requires a combination of features to maximize the therapeutic outcomes. In this perspective, we outline the key criteria for designing suitable MOFs for gas delivery applications and highlight the expanding range of therapeutic opportunities these materials may offer. Readers can use these insights of MOF design and features to develop gasotransmitter therapies with realistic clinic interest.

Keywords: carbon monoxide; gas therapy; gasotransmitters; hydrogen sulfide; metal‐organic frameworks; nitric oxide; porous materials.

Figure 1

Publication trends for gasotransmitters and MOFs as carriers for gas therapy. A) Publication record for the different gasotransmitters since 2000, highlighting NO as the most extensively gasotransmitter studied due to its earlier identification. B) Distribution of publications correlating the gasotransmitter with the most explored therapeutic applications in the last decade. C) Percentage of publications combining MOF with the different gasotransmitters and D) Distribution of publications using gasotransmitter‐loaded MOFs for different applications. Data sourced from SCOPUS (research papers only), covering the last 10 years (2013‐2023), except graph A. More details about the data search in reference.^{[ 27 ]}

Figure 2

Examples of gasotransmitter delivery solutions developed so far (top to down: from the earliest developed to the most recent approaches). Depending on the chemical configuration and type of gas carrier, they can release the gas in the therapeutic site using different triggers.

Figure 3

Different therapeutic gas loading strategies in MOFs. A) Activation process and NO loading on CPO‐27(Ni) via chemisorption, viewed along the crystallographic c‐axis and modeled with balls and sticks. As‐synthesized CPO‐27(Ni) is first dehydrated under vacuum and temperature to free the OMS for NO coordination. Subsequently, NO is introduced and bonds to the Ni sites. Figure reproduced with permission.^{[ 189 ]} Copyright 2021, Wiley‐VCH. B) SO₂ loading on CPO‐27(Ni) at 300 K and 2 bar SO₂ reveals two distinct adsorption sites: one with 100(2)% occupancy corresponding to chemisorbed SO₂, and another with 77.7(19)% occupancy attributed to physisorbed SO₂. In the latter case, the SO₂ molecules occupy the free pore volume without undergoing chemical interactions. Figure reproduced with permission.^{[ 190 ]} Copyright 2024, American Chemical Society. C) Schematic illustrating the encapsulation of the molecular donor MnBr(CO)₅ within a Ti‐MOF though post‐synthetic coordination strategy. Reproduced with permission.^{[ 191 ]} Copyright 2018, Wiley‐VCH.

Figure 4

Key features in MOFs that can lead to enhanced gasotransmitter therapy potential. Properties such as high gas loading capacity, chemical stability, a strong and stable adsorption mechanism, and good biocompatibility should be integrated within a single framework to achieve the best therapeutic outcomes.

Figure 5

Overview of the main challenges in the clinical translation of gasotransmitter MOF carriers. To reach enhanced clinical interest, gas‐loaded MOFs still need to accomplish several challenges related to their design, production and therapeutic mechanism.

Figure 6

Example of a multi‐modal therapy approach using a Mn carbonyl modified PEGylated Fe (III)‐based nanoMOFs (MIL‐100) coated magnetic carbon NPs (MCM@PEG‐CO) as theranostic nanoplatforms for NIR light‐responded CO‐DOX combination therapy toward malignant tumors. A) Magnetic resonance imaging (MRI) images and B) relative T2 signal intensity of MRI at tumor site in mice before injection, after injection and after‐NIR; C) Photoacoustic (PA) images and D) PA intensity of per‐injection and after injection. E) Relative tumor volume monitorization up to 14 days from a HCT116 tumor‐bearing mice after being treated with MCM@PEG‐CO‐DOX+NIR and the respective controls; F) Photographs and weights of tumors following excision under various treatments. Reproduced with permission.^{[ 229 ]} Copyright 2019, Elsevier.