Disrupting the activity of endogenous gas neurotransmitters: a therapeutic strategy using engineered metal–organic frameworks for cancer

Colorectal cancer represents a significant health challenge globally, with high incidence and mortality rates. Colorectal cancer accounts for approximately 10% of diagnosed cancers and cancer-related deaths worldwide each year. It is the second most common cancer among women and the third most common cancer among men.1 Although chemotherapy drugs such as doxorubicin have been widely used in clinical tumor killing, the efficiency of clinical treatment is low because of their accompanying toxic side effects, such as thrombophlebitis, cardiotoxicity, drug resistance, and renal insufficiency. Therefore, finding drugs that can effectively prevent cancer, have good biosafety, and have minimal side effects on normal parts remains a major issue in oncology research.2 Despite advances in conventional therapies, including chemotherapy, the efficacy of these treatments remains limited owing to their systemic toxicity and the development of drug resistance. In general, the tumor microenvironment (TME) is composed of particular cellular proliferation impairments, energy metabolism impairments, and mitochondrial dysfunction in these tumor cells. Compared with normal tissue, TME exhibits excessive hydrogen peroxide (H2O2) accumulation and oxygen deficiency.3 Cysteine-β-synthases are selectively upregulated in colorectal cancer tissues. The overexpression of cysteine-β-synthase mediates the production of hydrogen sulfide (H2S) in colorectal cancer, leading to significantly higher H2S concentrations in colorectal cancer tissues than in nontumor tissues.3 In recent years, to improve the efficacy of tumor therapy and reduce toxic side effects on normal tissues, several TME-reactive therapy strategies, such as pH-responsive drug release and photodynamic and nanocatalytic therapy, have been developed. This highlights a critical need for innovative approaches that target cancer cells while minimizing side effects. One promising direction is the use of metal–organic frameworks (MOFs), versatile materials known for their tunable structures and biocompatibility. In a work recently published in Advanced Functional Materials, we developed a cutting-edge strategy of employing engineered MOFs to disrupt intracellular iron homeostasis, thereby synergistically inducing ferroptosis with autophagy amplification as a novel approach to cancer therapy.4 The rise of MOFs in medicine: MOFs are crystalline materials of metal ions interconnected by organic ligands to form one-, two-, or three-dimensional structures. The high porosity and surface area of these materials make them excellent candidates for various biomedical applications, including drug delivery, sensing, and separation technologies. In the field of nanomedicine, MOFs possess the following advantages: (1) Due to the relatively weak metal–ligand coordination bonds, they are easily biodegradable; (2) they exhibit high porosity and large pores, facilitating efficient loading of cargo; and (3) they are easily adaptable, allowing for the encapsulation or modification of various cargos. Consequently, MOFs have been extensively utilized in medical applications.5 Recent innovations have extended their use to the field of oncology, where MOFs are engineered to catalyze intracellular chemical reactions that can promote cancer cell death. MOF materials are a type of porous material formed by coordination bonds between metal ions or metal clusters and organic ligands. MOF materials have attracted widespread attention because of their ultrahigh specific surface area, adjustable pore size, and functionalized structure. On the basis of their composition, structure, and functional characteristics, MOF materials can be classified in the following ways: (1) Classified by the type of metal center: (i) Transition metal MOF: using transition metals such as iron, copper, zinc, etc., as the metal center. These types of MOFs typically exhibit good stability and diverse catalytic activities. (ii) Main group metal MOFs, such as aluminum, magnesium, and other metals as centers, typically exhibit high chemical stability and are commonly used for gas adsorption and separation. (ii) Rare earth metal MOFs: MOFs with rare earth elements such as yttrium, scandium, and cerium as metal centers have excellent optical and magnetic properties. (2) Classified by the type of organic ligand: (i) Carboxylic acid-ligand MOF: This type of MOF uses organic ligands with carboxylic acid groups, which typically have good thermal and chemical stability and are commonly used for gas storage and separation. (ii) Imidazole-based MOFs: MOFs with imidazole or its derivatives as ligands typically exhibit good catalytic performance and electrochemical properties. (iii) Sulfonic acid-ligand MOF: an organic ligand that uses sulfonic acid groups and has strong acidity and is commonly used in acid-catalyzed reactions.6 (3) Classified by pore structure: (i) Microporous MOF with a pore size of less than 2 nm, suitable for gas separation and storage, such as hydrogen, methane, etc. (ii) Mesoporous MOF with a pore size between 2–50 nm, suitable for adsorption and catalysis of larger molecules. (iii) Macroporous MOFs, with pore sizes greater than 50 nm, are commonly used for the adsorption and separation of biomolecules. (4) Classified by function: (i) Catalytic MOF: This type of MOF is specifically used for catalytic reactions, typically with metal centers or ligands that exhibit catalytic activity. (ii) Gas adsorption and separation MOF: This method is used for the adsorption and separation of specific gases, such as carbon dioxide, hydrogen, and methane. (iii) Fluorescent MOF: This method is used for sensing or imaging through the luminescent properties of metals or ligands.7 Mechanism of iron homeostasis disruption by MOFs: Fenton-based nanocatalytic therapy is a promising treatment method for cancer. The current situation of using peroxygenase nanocatalysts to treat cancer involves Fenton or Fenton-like reactions in tumor tissue, converting H2O2 with lower reactivity in the TME into highly cytotoxic reactive oxygen species (ROS) with tumor-inhibiting ability.8 Iron-based MOFs are three-dimensional structures formed by organic ligands through coordination bonds and self-assembly of central metal ions. Owing to their greater specificity, they are used for nanocatalytic tumor therapy because of their high surface area and porosity, which are conducive to catalytic chemical reactions.9 Iron plays a pivotal role in cell survival and proliferation, making it a critical target in cancer therapy. Engineered MOFs, particularly iron-based MOFs, exploit this vulnerability by disrupting iron homeostasis within cancer cells. This disruption is achieved through the nanocatalytic activity of the MOFs, which facilitates the Fenton reaction to produce lethal levels of ROS, thereby inducing oxidative stress and cell death. It converts less reactive endogenous H2O2 into the most harmful hydroxyl radical (·OH) in a low-acidity TME via a Fenton-like reaction or an intratumoral Fenton process.10 Synergistic cancer therapy: nanocatalysis and ferroptosis: The MOFs discussed in this article are designed for nanocatalytic therapy in cases where autophagy amplification promotes ferroptosis. Ferroptosis represents a distinct form of cell death from apoptosis and necrosis and is characterized by the accumulation of iron-dependent ROS. Under mild conditions, thiamine pyrophosphate (TPP) is used to etch the MOF NH2-MIL-88B(Fe), creating an open cavity structure to enhance its capacity to adsorb and catalyze H2O2.4 The possible mechanism for etching the MOF is that TPP is initially adsorbed onto most of the MOF surface to shield these areas from the etching agent. Subsequently, TPP, a mild organic acid, slowly releases protons, which etch the unprotected or preferentially etched surfaces of the MOF by breaking coordination bonds. This approach thus generates a unique etched structure in MOFs. Then, chitosan oligosaccharides (COSs) were modified onto the surface of the open cavity MOF by TPP, resulting in the novel nanoplatform COS@MOF. MOFs, particularly the COS@MOF complexes, enhance this process by manipulating autophagy, a cellular degradation pathway, to degrade the iron storage protein ferritin, thereby increasing the amount of intracellular free iron and promoting the generation of ROS (Figure 1). Typically, ROS levels are important for effective nanocatalytic therapy. The introduction of natural COS@MOF increased the concentration of ROS within the tumor. After etching COS@MOF, the elevated Fe2+/Fe3+ ratio within the tumor can trigger in situ reactions with hydrogen sulfide, bolstering the Fe2+/Fe3+ cycle and enhancing the efficiency of catalytic therapy. The buildup of ROS from nanocatalytic therapy triggers intracellular lipid peroxidation, resulting in eventual ferroptosis. Therefore, COS@MOF serves two critical functions: first, it etches MOFs to create unique structures that enhance catalytic performance; second, COS induces the autophagy of ferritin, which increases intracellular iron levels and thereby enhances ferroptosis.4Figure 1: Schematic diagram of an engineered MOF with increased autophagy to strengthen ferroptosis for nanocatalytic tumor therapy.COS@MOF increases the autophagy of intracellular ferritin, releasing stored iron ions, which leads to iron overload and further fosters ferroptosis. Additionally, iron ions can respond in situ to H2S in tumors to enhance the Fe2+/Fe3+ cycle and improve the efficiency of catalytic therapy. ROS accumulation induced by nanocatalysis in lipid peroxidation in cells ultimately leads to ferroptosis. Created with Adobe Illustrator 2024. COS: Chitosan oligosaccharide; H2O2: hydrogen peroxide; H2S: hydrogen sulfide; ·OH: hydroxyl radical; MOF: metal–organic framework; ROS: reactive oxygen species.According to our previous report,4in vitro and in vivo evidence corroborates the therapeutic efficacy of COS@MOF in promoting cancer cell death by increasing ROS generation and ferroptosis. Cell viability assays, toxicity assays, fluorescence staining, transcriptome sequencing, and immunoblotting were employed to validate the therapeutic effects. Experiments performed on colorectal cancer cell lines and mouse models demonstrated significant tumor growth inhibition. These findings underscore the potential of this approach to deliver a dual assault on cancer cells by integrating nanocatalysis with targeted therapy strategies. Challenges: Although the research findings are highly promising, challenges persist in the clinical translation of MOF-based treatment strategies. These challenges include ensuring the stability and biocompatibility of COS@MOF within human systems, controlling the release of active substances, and preventing off-target effects that could harm healthy tissues. Additionally, the scalability of the synthesis of uniform COS@MOF nanoparticles presents another significant obstacle. Despite significant advancements in drug delivery via MOF-based nanocarriers, their therapeutic applications are still in the early stages. COS@MOF is derived from therapeutic ligands. Active metal ions, or their combinations, have evolved into therapeutic agents that significantly advance the treatment of various diseases. In recent years, significant research advancements in the biomedical field have been achieved. However, significant challenges remain: (1) The biosafety of MOF remains a concern. (2) The stability of MOFs within biological systems is suboptimal. (3) The conditions of synthesis are not conducive. (4) Their metabolic pathways are unclear. (5) The structure and pharmacology of MOFs require refinement. (6) Strategies for the large-scale production of MOFs are limited. (7) Most methods for target modification are cumbersome and complex. These challenges significantly impede the clinical translation of MOF.10 Some researchers contend that the MOF represents a potential drug delivery system; however, large-scale production and widespread use require overcoming several challenges. The primary challenge involves expanding the production scale in an energy-efficient and environmentally sustainable manner. The prevailing preparation method, solvothermal synthesis, requires harsh conditions or employs toxic solvents. A secondary challenge entails developing more efficacious formulations for clinically relevant drugs, given that existing research is confined to a limited number of model drugs.11 In addition, further research is needed on the drug release kinetics of the MOF to ensure its effective release of the loaded drug. Further research is needed on the surface modification of MOF.12 Future perspectives: Current research efforts are anticipated to concentrate on enhancing the design and functionality of MOFs, aiming to increase their therapeutic effectiveness and selectivity. Advanced engineering techniques, including the integration of targeted ligands or stimulus-responsive release mechanisms, can further refine the delivery of MOF-based therapeutic approaches. Additionally, exploring the synergies between MOFs and other therapeutic modalities, such as immunotherapy or radiotherapy, could offer comprehensive strategies in the fight against cancer. MOF-based delivery systems boast inherent advantages, including biodegradability, high porosity, tunable composition, flexible modification, and controlled release. Although the clinical deployment of MOFs remains a distant prospect, recent advancements in their fabrication, drug encapsulation, imaging, and drug delivery applications suggest that these endeavors are indeed worthwhile. Conclusion: The innovative use of engineered MOFs to disrupt iron homeostasis offers a transformative approach to cancer treatment. By enhancing ROS production and inducing ferroptosis via synergistic autophagy processes, COS@MOF effectively inhibits tumor growth through synergistic nanocatalytic therapy and ferroptosis, as demonstrated by in vivo and in vitro experimental results. This study presents an alternative yet promising MOF engineering approach for efficient synergistic nanocatalysis/iron collapse therapy in colorectal tumor treatment. These new materials are anticipated to overcome significant limitations in current cancer treatments. As research progresses, engineered MOFs have the potential for more effective and targeted cancer therapies.