Combination of starvation therapy and bio-chemotherapy based on MOF

To start with, MOF can mediate the use of starvation therapy in combination with traditional chemotherapy (Fig. 2). For example, Chen et al. synthesized RHI-DOX-GOD@ZIF-90 MOF-based NPs by encapsulating the near-infrared fluorescent dye RhI and the anticancer drug adriamycin (DOX) within the framework of an MOF material, ZIF-90, then loading GOD onto the surface of ZIF-90 (Ref. Reference Chen48). Remarkably, RHI-DOX-GOD@ZIF-90 NPs are exclusively broken down in cancer cells due to their exceptional ATP-detection sensitivity and selectivity as well as the increased ATP level in cancer cells compared to normal cells. After degrading materials within cancer cells, RhI is released to provide significant NIR emission, achieving controlled drug delivery. Subsequently, DOX and GOD are released to kill cancer cells through chemicals and starvation mechanisms. Interestingly, Ke et al. also opt for synergistic starvation and chemotherapy using GOD and DOX. NP bioreactor RGD-mGZD was obtained by embedding GOD and DOX in tumour-targeting ligand (RGD)-modified red blood cell membranes (RBCm) camouflaged with metal-organic framework ZIF-8 (Ref. Reference Ke49). With its remarkable bio-interfacial properties, RGD-mGZD not only improves blood retention time through immune evasion properties, but also selectively targets tumour sites by specifically recognizing overexpressed integrin receptors on the tumour cell membranes. Once the bioreactor reaches the desired area, GOD rapidly depletes glucose and oxygen from the tumour, starving cancer cells and initiating potent starvation therapy. More importantly, the study reveals that the deterioration of the acidic microenvironment in the tumour region induces the breakdown of MOF structures, which triggers the release of DOX and enhances the effectiveness of chemotherapy. Similarly, Zhang et al. also developed an erythrocyte membrane (EM)-encapsulated MOF biomimetic nanoreactor, TGZ@em, which likewise chose ZIF-8 that decomposes under acidic condition but stabilizes under physiological condition as a nanocarrier to encapsulate GOx and the prodrug tirapazamine (TPZ) for starvation-activated colon cancer treatment (Ref. Reference Zhang50). Based on the bionic properties of EM, TGZ@em can effectively accumulate in tumour tissues with immune escape and prolong blood circulation. Afterwards, GOx in the nanoreactor effectively consumes endogenous glucose and O₂ to starve tumour cells. Meanwhile, the aggravation of the hypoxic microenvironment within the tumour induced by the nanoreactor can convert the prodrug TPZ released by the nanoreactor in the acidic ‘lysostaphin/inclusion bodies’ environment into highly cytotoxic free radicals, which can enhance the chemotherapeutic effect of TPZ. In brief, all three nanomedicines have been demonstrated to achieve good synergistic therapeutic effects of chemotherapy and starvation therapy through in vivo and in vitro experiments.

Figure 2. (By FigDraw) (A) The types of bio-chemotherapy. (B) MOF-based nanoplatforms mediated starvation therapy combined with physical therapy to kill tumour cells.

Note: MOF, multifunctional metal-organic framework; CDT, chemodynamical therapy.

Fenton response (Fig. 3) based therapy (FBT) is an important pathway for CDT in recent years (Ref. Reference Ranji-Burachaloo51) and the process of utilizing GOx for starvation therapy happens to enhance FBT. For instance, Ranji-Burachaloo et al. prepared novel NPs, GOx&Hb@ZIF-8, by encapsulating GOx and haemoglobin Hb in pH-sensitive ZIF-8 NPs (Ref. Reference Ranji-Burachaloo51). In the micro acidic environment of cancer cells, GOx is released, which consumes D-glucose and O₂ and produces gluconic acid and H₂O₂, respectively, to achieve starvation therapy. And the produced gluconic acid increases the acidity of the TME, leading to complete destruction of the NPs and increasing the release of Hb and GOx. In the presence of endogenous and produced H₂O₂, Fe²⁺ from the haeme group of haemoglobin is also released, undergoing the Fenton reaction, and producing ⋅OH. Reactive free radicals represented by ⋅OH can rapidly oxidize surrounding biomolecules in biological systems to treat cancer cells (Refs Reference Ghattavi and Nezamzadeh-Ejhieh52, Reference Mirsalari and Nezamzadeh-Ejhieh53, Reference Ghattavi and Nezamzadeh-Ejhieh54, Reference Rezaei and Nezamzadeh-Ejhieha55). The in vitro experiments demonstrated the cytotoxicity of this novel NP at very low concentrations (<2 μg/ml) against HeLa cervical cancer cell line and MCF-7 breast cancer cell line. Similarly, Zhou et al. developed a multifunctional nanoplatform, MGaV for efficient CDT and anti-angiogenesis, which was constructed using the bioconjugation of GOD and anti-vascular endothelial growth factor receptor-2 (anti-VEGFR2) on top of a peroxidase-mimicking Fe-MOF (Ref. Reference Zhou56). GOD catalyses intratumoural glucose decomposition and triggers tumour starvation, while providing abundant H₂O₂ as a substrate, which undergoes the Fenton reaction catalysed by Fe-MOF, generating enough highly ⋅OH to enhance CDT, instantly attacking the tumour vascular endothelium, and destroying existing blood vessels, while the anti-VEGFR2 directs the nano-heterotrophs to target the blood vessels and block the VEGF-VEGFR2 linkage to prevent angiogenesis. Results of in vitro and in vivo studies showed that the nanoplatform led to apoptosis and vascular disruption of tumour cells and promoted tumour regression. Apart from that, Wan et al. designed a cancer cell membrane-covered cascade nanoreactor, NMIL-100@GOx@C, based on Fe-metallic-organic skeleton and glucose oxidase modification, which used Fe-based MOF (NMIL-100) as a Fe source for FBT and a carrier for loading GOx, while it was encapsulated on the cancer cell membrane (Ref. Reference Wan57). The nanoreactors, benefiting from the homologous targeting and immune escape ability of the cell membrane, are more inclined to accumulate at the tumour site and are efficiently internalized by cancer cells. Once internalized, NMIL-100@GOx@C generates the following cascade of reactions: (i) high levels of glutathione (GSH) at the tumour site reduce Fe³⁺ in NMIL-100 to Fe²⁺, leading to structural collapse of NMIL-100 and complete release of Fe; (ii) GOx catalyses the oxidation of glucose to generate gluconic acid and H₂O₂, which depletes glucose at the tumour site, cutting off the nutrient supply for starvation therapy; (iii) Fe²⁺ undergoes a Fenton reaction with the H₂O₂ generated from the first two reactions to produce ⋅OH, leading to FBT treatment. In this way, this cancer cell membrane-camouflaged nanoreactor could achieve enhanced synergistic effects of tumour-targeted FBT and starvation therapy, thereby effectively inhibiting tumour growth in a more efficient and safer manner. Interestingly, Gao and Song et al. proposed a new strategy for the synthesis of porphyrin-based metal-organic compounds using Cu₂O nano-cubes and Cu-TCPP nanosheets as a Cu source. These were utilized as a nanoplatform to prepare multifunctional nanomedicines by sequential loading and functionalization (Cu₂O/Cu-TCPP/(Pt-Au)/FA) (Ref. Reference Gao58). Among them, Cu⁺ originating from the reduction of Cu²⁺ by Cu₂O or GSH can trigger the Fenton reaction to generate ⋅OH for effective CDT. Then, Pt NPs with catalase (CAT) mimetic activity can catalyse the conversion of H₂O₂ to O₂ in tumour cells, modulating the hypoxic atmosphere of the tumour and enhancing the O₂-dependent glucose oxidation reaction. In addition, gold NPs with GOx mimetic activity can accelerate glucose consumption and cut off the nutrient supply for inducing starvation therapy while generating additional H₂O₂. And folic acid (FA) is incorporated to enhance drug targeting. This study demonstrates that multifunctional Cu₂O/Cu-TCPP/(Pt-Au)/FA nanomedicines exhibit high specificity, significant activity, and negligible systemic toxicity. Importantly, they enable synergistic tumour starvation therapy with CDT, as evidenced by in vitro experiments.

Figure 3. (By FigDraw) Mechanism of tumour cell killing with ⋅OH produced by the Fenton reaction.

Autophagy is a self-protection mechanism exerted by tumour cells under starvation stress, in which tumours phagocytose degraded and inactivated proteins, organelles and fragmented nuclei, etc. This mechanism is also a critical factor that reduces the efficacy of starvation therapy (Ref. Reference Yao59). Interestingly, studies have shown that over-activated autophagy not only improves the effectiveness of starvation therapy, but also leads to autophagic death. Yao et al. designed Cur@MOF-GOx/HA, a nano-enzyme that treats tumours by inducing autophagy hyperactivation (Ref. Reference Yao59). When the nano-enzymes were internalized by the tumour cells, the HA shell of the nano-enzymes was degraded by the HAase. Then, exposure to GOx triggers starvation while activating self-protective autophagy to resist the starvation treatment. Moreover, GOx successively catalysed the generation of H₂O₂ gluconic acid from glucose to feed the MOF-mediated Fenton reaction, while releasing a powerful autophagy inducer, curcumin (Cur), which converted GOx-induced pro-survival autophagy into pro-death autophagy, leading to autophagic death. Both in vivo and in vitro experiments showed that the nano-enzymes could manipulate tumour cells to produce cytotoxic ROS and autophagic cell death.

Interestingly, Wu et al. successfully synthesized a nanoreactor, MOF-Pt(IV)@GOx, which can synchronously perform iron oxidation, starvation therapy, and chemotherapy via a synergistic cascade reaction (Ref. Reference Wu60). High concentrations of GSH in the TME can decompose the MOF-Pt(IV)@GOx nanoreactor by reducing Fe(III) in the MOF centre and Pt(IV) in the grafted prodrug, resulting in the simultaneous release of Fe(II), cisplatin and GOx. Fe(II) is responsible for the generation of highly toxic ROS via the Fenton reaction, in which the required H₂O₂ is produced by GOx-catalysed glucose oxidation and cisplatin-mediated activation of NADPH oxidase (NOX). Glucose oxidation not only cuts off the glucose supply, starving the cancer cells, but also provides the acidic environment needed for the Fenton reaction. Moreover, cisplatin creates Pt-DNA adducts, hindering both DNA replication and transcription. Similarly, Li et al. have developed a Fe-doped ZIF-8 (Fe/Z) nano-delivery system, denoted as GLDFe/Z-FA, featuring synergistic effects and FA receptor targeting. This system involves the co-loading of GOx, L-arginine and DOX (Ref. Reference Li61). Notably, Fe/Z not only facilitates efficient loading of therapeutic agents but also provides protection for GOx from degradation by substances in the physiological environment, while FA imparts drug targeting capabilities. When the nano-systems are successfully internalized by tumour cells and disintegrate in the micro-acidic environment of the tumour, loaded drug molecules are released, triggering a cascade reaction. First, GOx consumes glucose to produce H⁺ and H₂O₂ in cancer cells, disrupting energy and nutrient supply and providing a substrate for the subsequent production of ⋅OH. Second, H₂O₂ catalyses the Fenton reaction to generate ⋅OH, leading to tumour CDT. Third, L-arginine is oxidized to produce NO, which serves as an intracellular signalling molecule at low concentrations and inducing cancer cell death at high concentrations. Both in vitro and in vivo experiments have shown that GLDFe/Z-FA can lead to glutathione peroxidase 4 (Gpx4) inactivation and lipid ROS accumulation, which ultimately results in mitochondrial dysfunction, cellular Fe death and nutrient-poor cancer cell death. Other than that, Liu et al. initially synthesized MOF(Fe) (NH2-MIL-101(Fe)) using 2-aminoterephthalic acid (BDC) and FeCl₃, and then covalently modified the outer surface of MOF(Fe) with GOx to create MOF(Fe)-GOx. Afterwards, the drug CPT was loaded into the channels of MOF(Fe) to obtain CPT @MOF(Fe)-GOx (Ref. Reference Liu62), which can simultaneously deliver GOx, Fe³⁺ and drugs capable of starvation/ROS-mediated/chemotherapy in a cascade manner. Once the prepared CPT@MOF(Fe)-GOx particles enter the cancer cells, GOx catalyses glucose in the cytoplasm to gluconic acid (H⁺) and H₂O₂. The depletion of glucose starves cancer cells for starvation therapy. Next, the particles were degraded in the H⁺-enhanced acidic environment to release CPT and Fe³⁺ for tumour chemotherapy. Finally, the H₂O₂ produced in the initial step of the reaction is catalysed by Fe³⁺-activated ROS-mediated therapy into ⋅OH, inducing cancer cells death for CDT. Both in vitro and in vivo experiments demonstrated the outstanding therapeutic efficacy of CPT@MOF(Fe)-Gox, confirming the effectiveness of the cascade response in enabling starvation/ROS-mediated/chemotherapy.

The immune checkpoint protein indoleamine 2,3-dioxygenase (IDO), which is highly expressed in tumours, inhibits the proliferation of effector T cells by catalysing the generation of kynurenine (Kyn) from tryptophan (Trp) and induces the expansion of T regulatory (Treg) cells, thus becoming an attractive immunotherapeutic target for alleviating the immunosuppressive microenvironment (Ref. Reference Dai63). For example, Dai et al. constructed a pH/ROS dual-sensitive degradable MOF nanoreactor nano-system (denoted as PCP-Mn-DTA@Gox@1-MT) for tumour starvation/CDT/IDO blockade immunotherapy (Ref. Reference Dai63). The nano-system is rapidly decomposed in tumour cells triggered by abundant ROS and acidic environment to form polyethylene glycol imine(PEI)-coupled cationic nuclei, which significantly improves the depth of penetration and phagocytosis of the system into the tumours. Apart from this, the nano-system are further converted into highly toxic hydroxyl radicals (⋅OH) through Mn²⁺ mediated Fenton-like reactions. And the IDO-specific competitive inhibitor, 1-methyltryptophan (1-MT), contained within the nano-system can effectively alleviate immune evasion. By in vivo and in vitro experiments, the PCP-Mn-DTA@Gox@1-MT nano-system effectively inhibited tumour growth and metastasis with these mechanisms. Differently, Zheng et al. achieved immunotherapy from the perspective of tumour-associated macrophages (TAMs) (Ref. Reference Zheng64). They synthesized ROS-responsive degradable Fe-MOF using 2,2′-[propane-2,2-diylbis(thio)] diacetic acid (TK-COOH) as a ROS-sensitizing agent. Subsequently, GOx as an exogenous H₂O₂ supplier and starvation inducer and perfluorocarbon (PFC) as an oxygen supplier were co-loaded into Fe-MOF. Finally, the tumour-targeting molecule HA was introduced onto the surface of the loaded Fe-MOF to obtain the functional nano-system (HFNP@Gox@PFC) (Ref. Reference Zheng64). The nano-system offers several advantages: (i) it can specifically aggregate at tumour sites via the HA receptor-ligand-mediated targeted endocytosis pathway; (ii) its uptake by tumour cells can be catabolized in response to ROS in the tumour cell cytosol, leading to the release of PFC, GOx and Fe²⁺; (iii) PFC provides O₂ and promotes the initiation of GOx-mediated catalytic reactions, while GOx can react competitively with intracellular glucose and O₂ to starve tumours and produce abundant H₂O₂, which further facilitates its disassembly, drug release and oxidative tumour killing; (iv) cascade amplification of CDT by Fe²⁺ reaction with H₂O₂ induces effective tumour damage; (v) the ROS generated from the above reaction further enhance the tumour immune response by re-inducing TAMs through the activation of the nuclear factor NF-κB and mitogen-activated protein K signalling pathways, resulting in a better tumour therapeutic effect. In vitro and in vivo studies have shown that the nano-system combines starvation, CDT and immunotherapy with good stability, biocompatibility and anti-tumour effects.

From the above synergistic treatment of starvation therapy with various biochemical therapies we can see that starvation therapy plays an important role and mutually reinforces with various therapies in terms of therapeutic mechanisms. However, there is no specific synergistic treatment programme that has a clear advantage.

Combination of starvation therapy and physiotherapy based on MOF

Physical therapy mainly includes PDT, PTT and sonodynamic therapy (SDT) (Fig. 4).

Figure 4. (By FigDraw) (A) The types of physiotherapy. (B) MOF-based nanoplatforms mediated starvation therapy combined with physical therapy to kill tumour cells.

Note: MOF, multifunctional metal-organic framework; PDT, photodynamic therapy; PTT, photothermal therapy; SDT, sonodynamic therapy.

Starvation therapy + PDT. In 2017, Li et al. used porphyrin-based Zr-MOF, PCN-224, as a nano-sensitizer (PS) and as a carrier loaded with both GOx and CAT. Finally, PCN-224 loaded with GOx and CAT was further coated with a cancer cell membrane to obtain a cancer cell membrane camouflaged tandem bioreactor mem@catalase@GOx@PCN-224 (mCGP), which was used for tumour-targeted starvation therapy and PDT (Ref. Reference Li65). According to the study, mCGP will preferentially accumulate in tumour tissues and selectively internalize into cancer cells due to the immune escape and isotype targeting ability of cancer cell membranes. Besides, CAT not only regulates the hypoxic microenvironment of tumours by catalysing the catabolism of endogenous H₂O₂, but also reduces O₂ consumption for glucose catabolism by GOx. In addition, the produced O₂ catalysed by PCN-224 also promotes the production of highly toxic single-linear state oxygen (¹O₂), which will further enhance the therapeutic efficiency by synergizing starvation therapy and PDT. And in 2021, Liu et al. synthesized MOF core-shell nano-assemblies using poly(D,L-lactic-glycolic acid) (PLGA) and Fe³⁺, in which GOx and trichloroethane (Ce6) were introduced, to construct a MOF-based targeted nanoreactor, PTFCG@MH, with hyaluronic acid deposited on the surface HA-stabilized MnO₂ (Ref. Reference Liu66). Because of its surface shape, the nanoreactor can target tumour cells specifically. Upon absorption, it initiates a series of processes that modulate the TME. Firstly, GOx depletes glucose, hindering ATP synthesis. Subsequently, MnO₂ catalyses the generated H₂O₂ to produce O₂, alleviating hypoxia and reducing photodynamic sensitization of tumours. Concurrently, MnO₂ effectively depletes GSH to prevent the tumour from establishing an antioxidant defence. These two nano-systems have been demonstrated to exhibit a robust synergistic therapeutic effect involving PDT and starvation therapy, effectively inhibiting tumour growth without significant side effects.

Starvation therapy + PTT. In addition to PDT, the MOF nanoplatform also enables synergistic treatment with PTT and starvation therapy. For example, Gao and Shi with their team developed a MOF-based biomimetic nanoreactor, GOx-ICG@ZIF@CM, for tumour therapy by simultaneous inhibition of intracellular protective proteins and defence systems (Ref. Reference Gao67). To be specific, GOx and the photothermic agent indocyanine green (ICG) were loaded into MOFs, which were further camouflaged with homotypic cancer cell membranes for tumour targeting. Nanoreactor-mediated hyperthermia down-regulated intracellular CAT and MCT, while the starvation effect of GOx could effectively inhibit the expression of heat shock protein 90 (HSP90, a defence protein protecting intracellular proteins from thermal inactivation), further exacerbating the thermal vulnerability of intracellular CAT and MCT. These mechanisms ultimately synergistically inhibit the intracellular defence system, trigger cellular acidic stress and oxidative stress, activate the apoptotic cascade response and induce tumour apoptosis. This work explores the protective role of MOF against heat-inactivated enzymes for the first time, with the realization of synergistic treatment with starvation therapy and PTT. Later in 2021, Zhu et al. obtained a biomimetic multifunctional nanoreactor, ZGAM, by coating EM onto MOF-based molecular sieve imidazole skeleton-8 (ZIF-8) containing gold nanorods and GOx (Ref. Reference Zhu68). By camouflaging its surface with a red blood cell membrane, this nanoreactor can effectively accumulate in tumour tissue after intravenous injection without being recognized by the immune system. The gold NPs can trigger a photothermal effect when irradiated with near-infrared light, while the released GOx effectively consumes endogenous glucose, limiting the energy supply to tumour cells. Significantly, the expression of HSPs in tumour cells is inhibited in the absence of ATP and thereby the efficacy of PTT is enhanced. In vivo studies have shown that ZGAM has a significant therapeutic effect on HCT116 hormonal mice. Interestingly, Cheng et al. designed a biomimetic functional nanoplatform, PCoA@M, using macrophage membrane as a carrier in 2022 (Ref. Reference Cheng69). In this nanoplatform, polydopamine (PDA) was used as the core and Co-MOF as the shell layer to construct the multiphase structure, after which the precursor for H₂S release, Anethole Trithione (ADT), was loaded into the pores of the MOF and the interstices of the heterostructures by a one-pot method. Finally, modification of macrophage membranes improves probe biocompatibility, reduces phagocytosis of the nanoplatform by immune cells, and achieves target recognition on tumour cells. The study found that after degradation of Co-MOF in the acidic TME, free Co²⁺ downregulated the expression of HSP90, which inhibited the heat resistance of HSP and enhanced the effect of PTT. In addition, a high concentration of H₂S was released from the premedicine to kill the tumour. ADT also significantly alters the level of reduced coenzyme I (NADH) at the tumour site, affecting the NADH/flavin adenine dinucleotide (FAD) balance, which results in impaired ATP synthesis in the tumour cells and a reduction in the energy supply to the cells to achieve starvation therapy. In vivo experiments have demonstrated that the application of this nanoplatform can effectively enhance targeted PTT, synergistic gas starvation therapy and inhibit lung cancer cell metastasis.

Starvation therapy + SDT. SDT is also an important physical therapy for tumours and has recently been applied in synergy with starvation therapy. For instance, Bao et al. developed a MOF-based biomimetic nanocomposite-PPGE NCs for loading PCN-224 NPs and GOx as acoustic sensitizers (Ref. Reference Bao70). Among them, platinum nanoparticles (Pt NPs) on PCN-224 facilitated the catalytic conversion of overexpressed H₂O₂ to oxygen at the tumour site, combined with ultrasound (US) irradiation to generate highly toxic ROS via SDT. Simultaneously, GOx can effectively reduce the glucose content at the tumour site and locally generated additional H₂O₂ can be further utilized by Pt NPs and through a cascade reaction to regenerate O₂, which in turn enhances SDT, thereby realizing the combined treatment of starvation therapy with SDT. In addition, the EM artefacts on the surface of PCN-224 carriers could enhance their biocompatibility. In vitro and in vivo studies have shown that PPGE NCS can result in an increase in apoptosis and a decrease in the proliferation rate of tumour cells. Interestingly, Zhou et al. reported that they constructed adaptive acoustic-sensitive platelet (PLT) cassettes to mediate the cascade delivery engineering of porphyrin MOF nanostructures loaded with the selective amino acid transporter protein blocker α-methyl-DL-tryptophan (α-MT) and overlaid with MnO₂ unblocking layers to obtain new integrated bio-nanoplatforms (denoted as αMM@PLT) (Ref. Reference Zhou71). When αMM@PLT reaches the tumour site, US stimulates ROS production from porphyrin MOFs loaded with PLTs, leading to morphology changes of PLTs and release of NPs. Subsequently, the outer MnO₂ layer is broken down by excess GSH in the TME, which triggers the release of encapsulated α-MT, thereby preventing glutamine addition and interfering with glutamine metabolism. The research revealed that US stimulation mediated the transformation of de-extended pseudopods of circulating PLT into dendritic PLT and thrombus formation, effectively blocking the blood supply to the tumour. Simultaneously, MnO₂-induced depletion of intracellular glutathione and α-MT-induced lack of raw materials for glutathione synthesis resulted in a significant increase in the sensitivity of stereotactic US treatment of tumours to achieve a synergistic treatment with SDT and starvation therapy.

According to Table 1, it can be observed that the experiments in which starvation therapy was synergistically treated with PTT generally achieved better tumour suppression rates, which may be attributed to the fact that the two are mutually reinforcing in terms of therapeutic mechanisms. In contrast, the effect of starvation therapy with PDT or SDT that mutually promotes each other in the mechanism may not be obvious, which leads to the fact that its efficacy may not be as desirable as that of the former.

Diversified therapy with starvation therapy as one of the adjuvant therapies based on MOF

MOF can also provide diversified therapies, which means that starvation therapy, biochemistry therapy and physical therapy can be realized simultaneously on a single nanoplatform (Fig. 5). Currently, Yin et al. developed an MOF-based cascade biomimetic therapeutic nanoplatform, C1@M@C2G, by utilizing Fe-based porphyrin MOF wrapped with bis(2-carbocyclooxy-35,6-trichlorophenyl) oxalate (CPPO), GOD and further encapsulated with a cancer cell membrane on the outside, which could simultaneously realize chemical light-induced photodynamic therapy, Fenton-responsive CDT-based and GOD-mediated starvation therapy to synergistically enhance cancer treatment (Ref. Reference Yin72). The cancer cell membrane encapsulated on the NPs enables the nanoplatform to accumulate at the tumour site in a targeted manner. Local glucose is then consumed by GOD-catalysed oxidation reaction to activate starvation therapy, while the produced gluconic acid and H₂O₂ can cause a significant decrease in the pH of the TME. Subsequently, additional elevated H₂O₂ undergoes a low pH-accelerated Fenton reaction, converting it into OH for CDT. Meanwhile, some other hydrogen peroxide can react with CPPO to form a high-energy state that excites the porphyrin photosensitizer, leading to in situ generation of ¹O₂ for PDT. Moreover, the nanoplatform featuring CAT activity continuously generates O₂, effectively mitigating tumour hypoxia, thus enhancing the catalytic effect of GOD and the therapeutic efficacy of PDT to achieve diversified combined therapy. Recently, Wang et al. developed a multifunctional therapeutic platform integrating CDT, radiation therapy, starvation therapy, gas therapy, magnetic resonance imaging and chemotherapy, D-Arg/GOX/TPZ@MOF (Fe)-PDA/Fe³⁺/FA-BSA (Ref. Reference Wang73). The obtained NPs demonstrated the capability to undergo a Fenton reaction, utilizing Fe³⁺ to produce reactive oxygen species for CDT. Additionally, GOD effectively depleted glucose, the energy source for starvation therapy, while D-Arg produced NO to alleviate tumour hypoxia and promote radio-sensitization. Apart from that, these combined therapies, along with TPZ, down-regulated hypoxia-inducible factor, vascular endothelial growth factor, platelet endothelial cell adhesion molecule-1 and Ki67, up-regulated histone γ-H2AX expression, as well as reduce non-targeted side-effects on healthy tissues. More importantly, the NPs exhibited T1-weighted MRI contrast properties, enabling rapid and efficient MRI imaging, while maintaining an optimal effective X-ray dose. The results of the in vitro and in vivo studies suggest that the NPs can control tumour volume to a greater extent and reduce damage to healthy cells through diversified combined therapy.

Figure 5. (By FigDraw) MOF-based nanoplatforms mediated diversified therapies to kill tumour cells.

Note: MOF, multifunctional metal-organic framework.

According to Table 1, it is evident that the tumour inhibition rate of diversified therapies including starvation therapy mediated by MOF nanoplatforms is not high, which may indicate that although multiple therapeutic overlays can be achieved at the same time by MOF, their efficacy may not necessarily be significantly enhanced.