As the powerhouses of the cell, mitochondria are responsible for generating energy through a series of complex biochemical reactions known as aerobic respiration (Harrington et al., 2023; Qian et al., 2024). For mitochondrial respiration, O₂ is transported from the extracellular environment to the cytoplasm via hemoglobin, then traverses the mitochondrial outer and inner membranes. The inner membrane’s lipid bilayer and specific channels are responsible for facilitating the selective entry of O₂ into the mitochondrial matrix. In this process, O₂ serves as the final electron acceptor in the electron transport chain, facilitating the release of high-energy electrons from nutrients and their conversion into a substantial amount of adenosine triphosphate, which is essential for cellular functions (Borcherding and Brestoff, 2023). Consequently, mitochondria are one of the most O₂-rich organelles within the cell (Peng et al., 2023). Since the Type II PDT mechanism of most photosensitizers relies on the presence of O₂, designing Por-nMOFs that target mitochondria represents an effective strategy to mitigate the limitations imposed by hypoxia. For instance, Gu et al. developed a one-pot synthesis method to incorporate tetrakis (4-carboxyphenyl)porphine (TCPP) into UiO-66, creating a photoactive platform (Figure 2A) (Gong et al., 2020). To alleviate the constraints of hypoxia on the ¹O₂ generation capability of the photosensitizer and to achieve enhanced phototherapeutic efficacy, the authors leveraged the facile surface modification properties of MOFs. This allowed them to functionalize UiO-66-TCPP with both cancer cell-targeting and mitochondria-targeting capabilities. Specifically, they first synthesized phosphonated triphenylphosphonium (TPP) and folic acid (FA) via amide reactions. The phosphate groups were then used to form stable Zr-O-P bonds with the Zr nodes in the UiO-66 framework, thereby achieving the surface functionalization with FA and TPP (Figure 2B). This system ingeniously utilized the structural characteristics of MOFs, which are formed through the coordination of metal clusters with carboxylic acid ligands, to integrate targeting functionalities. Cytotoxicity assays demonstrated that both FA-induced cancer cell targeting and TPP-induced mitochondrial targeting significantly enhanced the phototoxicity of UiO-66-TCPP. The IC₅₀ value of the dual-targeted Por-nMOFs was as low as 0.74 μM, which is four times lower than that of the non-targeted control group (Figure 2C). This study provides a valuable design strategy for mitochondria-targeted Por-nMOFs and effectively demonstrates that mitochondrial targeting may offer new opportunities for the phototherapeutic applications of these materials.

In addition to covalently grafting TPP and folic acid (FA) onto the surface of Zr-nMOFs to achieve dual targeting of cancer cells and mitochondria, researchers have developed a near-infrared (NIR)-light-triggered heterostructure comprising upconversion carbon dots integrated with Por-nMOFs. This system also employs TPP for mitochondrial targeting. Upon NIR irradiation, efficient energy transfer through tight coupling significantly enhances ¹O₂ generation, while TPP-mediated mitochondrial localization amplifies oxidative damage. For example, Zhang et al. synthesized PCN-224 MOF using a conventional solvothermal method (Xiang et al., 2022). They then sonicated, stirred, and freeze-dried the MOF with carbon dots (CDs) prepared via a hydrothermal method using L-ascorbic acid as the carbon source, resulting in the PCDs material. By further stirring and freeze-drying the PCDs with TPP solution, they obtained the TPP-modified PCDTs nanoplatform (Figure 3A). Transmission electron microscope (TEM) images showed that 2 nm-sized CDs were uniformly distributed within the PCN-224 MOF (Figure 3B). The O₂-rich groups on the surface of the CDs imparted a negative surface potential, which neutralized the positive charge of the PCN-224 MOF, making the composite’s potential negative. However, the positive charge introduced by TPP modification restored the composite’s positive potential, as expected (Figure 3C). To demonstrate the effectiveness of CDs as a light energy conversion medium, the authors measured the absorption spectrum of PCN-224 and the emission spectrum of CDs, which showed significant overlap. This result indicated that CDs could effectively achieve fluorescence resonance energy transfer (FRET) to PCN-224 (Figure 3D). Time-resolved photoluminescence (PL) experiments revealed a significant shortening of the PL lifetime of PCDs at 520 nm (Figure 3E), further confirming the energy transfer from CDs to PCN-224. Under 808 nm laser irradiation, the use of singlet oxygen sensor green (SOSG) as a ¹O₂ scavenger showed that PCDs could effectively generate ¹O₂, whereas direct 808 nm laser irradiation of PCN-224 did not produce ¹O₂ (Figure 3F). This result further validated the FRET mechanism in the PCDs structure. Cell viability assays using the CCK-8 method demonstrated that both PCDs and PCDTs exhibited excellent biocompatibility under non-irradiated conditions. However, under 808 nm laser irradiation, they effectively inhibited cancer cell proliferation. With the advantage of targeting mitochondria, PCDTs are highly sensitive to ROS, showed the best inhibitory effect on cancer cell proliferation (Figure 3G).

In vivo animal experiments also confirmed that PCDs and PCDTs achieved satisfactory tumor volume inhibition under 808 nm laser irradiation (Figure 3H). The tumor weight comparison results were consistent with expectations (Figure 3I). Moreover, even in intratumoral experiments, mitochondrial targeting demonstrated superior antitumor effects. This system leverages the natural porous structure and facile surface modification of Por-nMOFs to achieve a tight integration of well-dispersed, upconverting CDs within the PCN-224 MOF framework. The O₂-rich groups on the CDs and the unsaturated metal sites in the MOF form a stable heterojunction structure, which reduces the distance between the upconversion material and the photosensitizer, facilitating more efficient energy transfer. Both in vitro and in vivo experiments demonstrated the effective FRET process within this framework. Furthermore, the TPP modification endowed the nanoplatform with mitochondrial-targeting properties, and by amplifying oxidative stress within the mitochondria, it achieved enhanced PDT efficacy.

Direct functionalization of Por-nMOFs with mitochondrial-targeting ligands such as TPP is an effective and widely adopted strategy to enhance PDT efficacy. However, these studies also indicate that merely increasing mitochondrial accumulation may be insufficient to overcome the complex challenges posed by the tumor microenvironment, particularly the pervasive hypoxia, which highlights a clear direction for subsequent strategic advancements (Li et al., 2018; Lu et al., 2019; Huang et al., 2021). The hypoxic tumor microenvironment severely compromises the efficiency of Type II PDT (Liang et al., 2023; He and Ma, 2024; Xia et al., 2024). Consequently, researchers have increasingly focused on integrating mitochondrial targeting with “self-oxygenation” or “O₂-supply-enhancing” capabilities. By endowing MOF-based nanoplatforms with the ability to catalytically decompose endogenous H₂O₂ to generate O₂, or to modulate cellular metabolism to reduce O₂ consumption, hypoxia can be alleviated at its source, thereby maximizing the therapeutic potential of mitochondria-targeted PDT. For example, Sun et al. synthesized Sm-TCPP nanosheets via a conventional solvothermal reaction, coordinating TCPP photosensitizer molecules with Sm³⁺ ions (Gao et al., 2020). They then grew Pt nanoparticles in situ on the surface of the Sm-TCPP nanosheets, resulting in the Sm-TCPP-Pt nanosheet material. By leveraging the strong coordination between Sm³⁺ and carboxyl groups, they introduced TPP-PEG-COOH molecules into the Sm-TCPP-Pt platform, yielding a well-dispersed and biocompatible Sm-TCPP-Pt/TPP nanoplatform (Figure 4A). In this system, the Pt NPs function as nanozymes, mimicking the activity of catalase. By catalyzing the decomposition of H₂O₂ into O₂, they increase the intracellular O₂ concentration, thereby enhancing the PDT efficacy of the photosensitizer. TEM images clearly show the 2D nanosheet morphology of Sm-TCPP (Figure 4B). This 2D structure is more favorable for the photosensitizer to interact with O₂ molecules and generate ¹O₂ under light exposure, potentially offering advantages over 3D MOF-based photosensitizers. Additionally, TEM images of Sm-TCPP-Pt confirm the presence of Pt NPs (Figure 4C), and the results indicate that the in situ growth of Pt has a negligible effect on the particle size of Sm-TCPP. To demonstrate the catalase-like activity of the Pt NPs, the authors mixed Sm-TCPP-Pt with H₂O₂ and monitored the absorbance at 240 nm to detect changes in H₂O₂ concentration. The results showed that over time, more bubbles were produced, and the H₂O₂ concentration continuously decreased, confirming the catalytic performance of the Pt NPs (Figure 4D). Next, the authors used 1,3-diphenylisobenzofuran (DPBF) as a ¹O₂ scavenger to assess the ¹O₂ generation capability of the photosensitizer by monitoring the absorbance changes at 426 nm. Under hypoxic conditions, Sm-TCPP-Pt exhibited significantly enhanced ¹O₂ generation compared to Sm-TCPP alone (Figure 4E). This result indicates that the Pt NPs effectively mitigate the limitations imposed by hypoxia on the PDT efficiency of Por-nMOFs. Mitochondrial co-localization experiments demonstrated that FITC-labeled Sm-TCPP-Pt/TPP showed effective fluorescence overlap with a red mitochondrial marker, indicating that TPP successfully mediates the targeting of the Sm-TCPP-Pt/TPP nanoplatform to mitochondria (Figure 4F). At the cellular level, the authors showed that the presence of Pt NPs significantly reduced the levels of hypoxia-inducible factors, indicating their ability to improve the hypoxic environment (Figures 4G,H). Cytotoxicity assays further confirmed that Pt NPs significantly enhanced the cytotoxicity of Sm-TCPP under hypoxic conditions, resulting in a lower IC₅₀ value. Moreover, the mitochondrial targeting modification with TPP further increased the toxicity of the Sm-TCPP photosensitizer, as mitochondria are the primary organelles for H₂O₂ production, facilitating the generation of more O₂ by Pt NPs (Figure 4I). The authors then evaluated the in vivo inhibitory effects of the Sm-TCPP-Pt/TPP nanoplatform on MCF-7 breast cancer cells. The results showed that the Sm-TCPP-Pt/TPP nanoplatform, with the assistance of Pt nanozymes and TPP-mediated mitochondrial targeting, exhibited the most potent inhibition of cancer cell proliferation (Figure 4J). This system not only targets mitochondria using TPP but also utilizes the catalase-mimetic activity of Pt NPs to decompose H₂O₂ and generate O₂, thereby alleviating the hypoxic environment. Under light exposure, this combination effectively suppresses the growth of MCF-7 cancer cells, demonstrating the promising new application prospects of Por-nMOFs in cancer therapy.

In situ O₂ generation via nanozymes represents one of the effective strategies to alleviate tumor hypoxia (Liu et al., 2022; Nan et al., 2022; Xiao et al., 2022; Zhu et al., 2022b). Similarly, integrating O₂-generating functionality into more sophisticated core-shell architectures can further enhance the stability and multifunctionality of nanotherapeutic platforms. For instance, Zhu et al. synthesized oleic acid (OA)-modified upconversion nanoparticles (UCNPs-OA) using conventional methods (Chen et al., 2023b). They then performed ligand exchange to obtain 3,4-dihydroxycinnamic acid (DHCA)-modified UCNPs-DHCA. By mixing these with Zr⁴⁺ ions and TCPP molecules and heating, they prepared a core-shell structured UCNP@MOF material. Subsequently, the UCNP@MOF was mixed with H₂PtCl₆ in an ethanol solution, followed by the addition of NaBH₄, resulting in the formation of UCNP@MOF-Pt nanocomposites. Finally, through the coordination of Zr⁴⁺ ions with TPP-COOH, they obtained a mitochondria-targeting TPP-UCNP@MOF-Pt nanoplatform, which can perform PDT under 980 nm laser irradiation (Figure 5A). TEM results confirmed the core-shell structure of UCNP@MOF-Pt, with clearly visible 2 nm Pt NPs (Figure 5B). As shown in Figure 5C, the absorbance of H₂O₂ at 240 nm decreased over time, indicating a gradual reduction in H₂O₂ concentration. This result confirms the catalytic function of Pt NPs in decomposing H₂O₂ to produce O₂. The O₂ generation curve also verified the catalytic effect of Pt NPs on H₂O₂ (Figure 5D). ¹O₂ phosphorescence (SOP) measurements showed that the self-generated O₂ from the nanoplatform effectively enhanced ¹O₂ production (Figure 5E).

Next, the mitochondrial membrane potential was assessed. The green fluorescence of JC-1 monomers indicated that the mitochondria-targeting TPP-UCNP@MOF-Pt nanoplatform most effectively reduced the mitochondrial membrane potential, causing mitochondrial depolarization (Figure 5F). Cytotoxicity assays demonstrated that, under normoxic conditions, both mitochondrial targeting and the self-O₂-generating capability significantly enhanced PDT efficacy (Figure 5G). Under hypoxic conditions, the advantages of the designed nanoplatform were even more pronounced. The results showed that while UCNP@MOF had weaker PDT efficacy, UCNP@MOF-Pt and TPP-UCNP@MOF-Pt, due to their O₂-generating capabilities, could effectively inhibit cancer cells in a hypoxic environment (Figure 5H). In vivo tumor suppression experiments also aligned with these findings. The TPP-UCNP@MOF-Pt nanoplatform, under 980 nm laser irradiation, achieved the best inhibition of tumor volume (Figure 5I) and weight (Figure 5J). This system, through effective chemical synthesis and coordination, produced a core-shell structured UCNP@MOF composite material. It not only leveraged the advantages of NIR light excitation for porphyrin-based PDT but also utilized its intrinsic O₂-generating function and mitochondrial targeting to provide a novel approach for treating hypoxic tumors.

In addition to using exogenous nanotherapeutics to catalytically generate O₂ and ameliorate the hypoxic microenvironment, modulating intracellular metabolic pathways to reduce O₂ consumption represents another ingenious “O₂-conserving” strategy. For example, Tian et al. first synthesized PCN-224, a MOF formed by the coordination of Zr⁴⁺ with TCPP (Yu et al., 2023). Subsequently, 7ACC2 and doxorubicin (DOX) were physically adsorbed into the pores of PCN-224, forming the 7ACC2/DOX@PCN-224 (AD@P) system. To enhance the stability and drug loading efficiency, a layer of ZIF-8 crystal shell was then grown on the surface of AD@P, resulting in the 7ACC2/DOX@PCN-224@ZIF-8 (AD@PZ) platform (Figure 6A). The authors simplified the synthesis steps and improved drug loading by not removing the free DOX and 7ACC2 from the supernatant before the formation of the ZIF-8 shell, which effectively enhanced the encapsulation of small-molecule drugs. The resulting AD@PZ nanoplatform significantly improved the circulation stability of the drug-loaded PCN-224. Upon reaching the cancer cells, the ZIF-8 shell rapidly degraded under weakly acidic conditions, allowing the controlled release of DOX and 7ACC2. The 2-methylimidazole component of ZIF-8 facilitated lysosomal escape via protonation, enhancing the intracellular delivery of the drugs. As a mitochondrial pyruvate carrier inhibitor, once the 7ACC2 molecule was released, the metabolic activities of the mitochondria will be affected. The released inhibitor not only inhibited the influx of pyruvate into the mitochondria but also effectively blocked the tricarboxylic acid (TCA) cycle, which is fueled by glucose and lactate, thereby disrupting aerobic respiration and alleviating tumor hypoxia (Figure 6B). By targeting the mitochondria, 7ACC2 successfully reduced O₂ consumption within the cells, providing a solid foundation for enhanced PDT under light exposure. Ultimately, this system achieved a synergistic therapeutic effect by combining enhanced PDT induced by the inhibition of mitochondrial respiration and chemotherapy mediated by DOX. The design of the dual-layer MOF@MOF structure in this system offers a new reference for improving the circulation stability of Por-nMOFs, contributing to their preclinical development and application.

Integrating catalytic O₂-generating or metabolism-modulating modules to improve tumor oxygenation has emerged as a pivotal strategy for enhancing the efficacy of mitochondria-targeted PDT. These designs substantially boost ROS generation. Nevertheless, the robust antioxidant defense systems and potential apoptosis resistance mechanisms of tumor cells can still limit the ultimate therapeutic outcomes of PDT (Cheng et al., 2022; Deng et al., 2022; Ren et al., 2025; Wu et al., 2025). These factors prompted researchers to explore synergistic cell-killing pathways beyond conventional apoptosis. To overcome tumor cell tolerance to PDT, recent efforts have focused on combining mitochondria-targeted PDT with mechanisms that induce non-apoptotic forms of cell death. By co-localizing at mitochondria and simultaneously triggering intense oxidative stress, disrupting key antioxidant systems, or releasing specific cytotoxic agents, such strategies can activate more potent cell death programs, such as ferroptosis, enabling efficient eradication of refractory tumors. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, hinges on core redox regulators such as the glutathione (GSH)/glutathione GPX4 axis, making it a compelling therapeutic target across diverse cancer contexts (Ji et al., 2022; Wang et al., 2022; Mao et al., 2023). Mechanistically, ferroptosis is induced by dual perturbations: GSH/GPX4 axis inhibition blocks lipid peroxide detoxification, and dysregulated Fe²⁺ fuels ROS generation via Fenton reactions. The resultant excessive lipid peroxidation disrupts membrane homeostasis and initiates ferroptotic cell death. Recent studies collectively demonstrate that modulating iron homeostasis, suppressing antioxidant defenses, or amplifying lipid peroxidation can effectively trigger ferroptotic cell death in tumors, thereby inhibiting progression and overcoming therapy resistance (He J. et al., 2024; Sun Y. et al., 2024; Guan et al., 2025).

For instance, Peng et al. developed a mitochondria-targeted nanosystem for the co-delivery of a porphyrin-based MOF (PCN-224) and a carbon monoxide-releasing molecule (CORM). The generated ROS and released carbon monoxide (CO) act synergistically to not only promote apoptosis but also sensitize cancer cells to ferroptosis. Firstly, They synthesized an amphiphilic polymer (MR) (Figure 7A) (Yang et al., 2023). This polymer features a mechanism for cleavage in response to ¹O₂ and is functionalized with TPP at its terminus, endowing it with the ability to target mitochondria. These authors then prepared PCN-224 MOFs using a conventional solvothermal method and loaded them with a CO-releasing molecule (CORM) to form PCN-CORM. The resulting PCN-CORM was encapsulated with the MR polymer, yielding MR@PCN-CORM. To mitigate the potential negative impact of the positive charge of TPP on the circulation stability of the nanoplatform, the surface was further modified with HA, resulting in the HA@MR@PCN-CORM nanoplatform (Figure 7B). The prepared HA@MR@PCN-CORM nanoplatform can effectively generate ROS under light irradiation and activate the release of CO, inducing ferroptosis and ultimately achieving enhanced antitumor effects both in vitro and in vivo (Figure 7C). The mechanism involves the light-induced generation of ROS by PCN-224, which can directly induce apoptosis and stimulate the release of CO from CORM-401. The released CO was found to directly affect the biological activity of glutamate-cysteine ligase (GCL) and glutathione synthetase (GS), leading to a reduction in GSH levels, lipid peroxidation, and the induction of ferroptosis (Figure 7D). The authors confirmed the inhibitory effect of the HA@MR@PCN-CORM nanoplatform on 4T1 cancer cell proliferation using the MTT assay (Figure 7E). The MTT assay is a colorimetric method that measures the activity of enzymes in living cells to evaluate cell viability (Wu et al., 2019; Chen et al., 2020; Hu et al., 2020; Yang et al., 2021; Zhao Y. et al., 2021). The measured IC₅₀ value was 0.23 μg/mL, the lowest among all control groups, indicating the highest cytotoxicity. The authors hypothesized that this result was due to the multifunctional design of the nanoplatform, including the tumor-targeting ability of HA, the mitochondrial-targeting capability of the TPP group, and the ROS-responsive cleavability of the thioester (TK) bond, which collectively enhance the photodynamic, gas, and ferroptotic therapeutic effects.

Given that GSH and GPX4 are key markers of ferroptosis, the authors measured their concentrations after treatment. The results showed that the HA@MR@PCN-CORM-treated group had the lowest levels of GSH and GPX4 (Figures 7F,G). Mechanistic validation also indicated that the HA@MR@PCN-CORM nanoplatform inhibited the activity of GCL and GS, key participants in GSH biosynthesis (Figure 7G). After elucidating the mechanism of tumor cell proliferation inhibition, the authors further validated the antitumor effects in animal models. The results demonstrated that, compared to various control groups, the HA@MR@PCN-CORM nanoplatform exhibited the strongest 4T1 cancer cell-killing effect (Figure 7H). In this system, the authors achieved a multifunctionally enhanced antitumor mechanism through the clever design of Por-nMOFs. Targeting mitochondria endowed the nanoplatform with more precise and synergistic antitumor effects. The successful design of this system provides new insights and references for the specific and functional design of Por-nMOFs.

The “PDT + gas therapy” strategy has opened a new avenue for synergistic cancer treatment (Xie et al., 2025; Zhang S. et al., 2025; Gao et al., 2026; Peng et al., 2026). Likewise, leveraging the intrinsic multi-enzyme-like activities of nanomaterials to disrupt cellular redox homeostasis represents another powerful approach for inducing potent cytotoxicity. For example, Yang et al. reported a nanozyme-functionalized MOF (termed PyroFPSH) that exhibits glutathione peroxidase- and catalase-mimicking activities. This system effectively depletes intracellular glutathione, generates ROS, and co-delivers a mitochondria-depolarizing agent, thereby overcoming apoptosis resistance in cancer cells. Firstly, They synthesized PCN-224 MOFs using a conventional solvothermal method and loaded them with Fe elements and the small molecule sulfasalazine (SAS) via the MOF’s pores (Lv et al., 2024). The surface of the MOFs was then modified with HA, resulting in the formation of the HA@SAS@FeMOF (PyroFPSH) nanoplatform (Figure 8A) (Lv et al., 2024). Subsequent experimental results demonstrated that PyroFPSH, upon entering the cells, releases Fe elements. Fe³⁺ ions can react with intracellular GSH, reducing GSH concentrations and forming Fe²⁺ ions. These Fe²⁺ ions can further react with H₂O₂ in the cells, generating highly reactive OH. Additionally, the released SAS molecules target the mitochondria, causing mitochondrial depolarization, which prevents further O₂ consumption and energy production for cellular metabolism. Thus, the designed PyroFPSH system achieves a multifunctional and synergistically enhanced mechanism (Figure 8B). On one hand, SAS molecules reduce the consumption of O₂ by mitochondria, while Fe³⁺ ions lower intracellular GSH levels, disrupting the cellular redox balance. On the other hand, light-activated porphyrins generate ¹O₂, and Fe²⁺ ions react with H₂O₂ to produce OH. The combination of these mechanisms makes PyroFPSH a highly effective mitochondria-targeting photosensitizing nanoplatform.

Multienzyme-mimetic nanoplatforms can simultaneously disrupt redox homeostasis through multiple mechanisms. Combining this “ROS storm” strategy with photothermal effects further amplifies mitochondrial damage. For instance, Feng et al. developed a Zr/Co-porphyrin-based MOF theranostic agent (denoted ZTCIPA) (Figure 9) (Zhao et al., 2025). The authors demonstrated that under 808 nm laser irradiation, ZTCIPA generates both photothermal heat and ¹O₂. Moreover, the localized hyperthermia accelerates Co²⁺-mediated catalysis of endogenous hydrogen peroxide in cancer cells, producing highly reactive OH. Together with ¹O₂, these species orchestrate a potent “ROS storm” that severely damages mitochondria, leading to effective suppression of cancer cell proliferation.

The “ROS storm” strategy has dramatically enhanced therapeutic lethality. Beyond leveraging exogenous effector molecules, optimizing the intracellular spatial distribution of photosensitizers to simultaneously attack multiple organelles can also induce lethal synergistic effects. For example, Luo et al. developed a dual-organelle–targeting platform (ALA/Hf-MOL) that concurrently targets mitochondria and lysosomes (Luo et al., 2023). This system enables in situ synthesis of protoporphyrin IX (PpIX) from 5-aminolevulinic acid (ALA) within mitochondria, while the MOF-based photosensitizer is retained in lysosomes. Upon light irradiation, both organelles are synchronously damaged, resulting in synergistically amplified PDT efficacy (Figure 10A). The authors found that ALA release from the platform was pH-independent but significantly enhanced with increasing phosphate concentration (Figure 10B). Although ALA/Hf-MOL and Hf-MOL exhibited comparable ROS generation capacities, phototoxicity assays under 630 nm irradiation revealed that the IC₅₀ value of the ALA/Hf-MOL group was 2.7-fold lower than that of the Hf-MOL group, demonstrating markedly improved phototherapeutic efficacy after ALA loading (Figure 10C). This enhancement stems from the intracellular conversion of ALA into PpIX, which itself acts as an additional photosensitizer (Figure 10D). To validate the dual-organelle targeting effect, the authors examined mitochondrial and lysosomal depolarization. As shown in Figures 10E,F, the ALA/Hf-MOL group exhibited the most pronounced decrease in organelle-specific fluorescence just 2 min post-irradiation compared to all control groups, confirming its superior capacity to disrupt both mitochondria and lysosomes. Subsequent in vivo experiments further demonstrated that the ALA/Hf-MOL group achieved the strongest tumor growth suppression (Figure 10G). Additionally, co-staining of intratumoral mitochondria and lysosomes revealed the most significant reduction in both organelles in the ALA/Hf-MOL-treated group (Figure 10H). By simultaneously compromising two critical organelles, lysosomes and mitochondria, this system achieves highly effective inhibition of cancer cell proliferation through synergistic action. This work provides valuable preclinical insights for the development and application of porphyrin-based MOF materials in cancer therapy.

This review systematically explores Por-nMOFs as multifunctional nanoplatforms for enhancing synergistic antitumor strategies in PDT, SDT, and RDT through mitochondrial targeting. These Por-nMOFs, owing to their high porosity, tunable chemical structures, and intrinsic photosensitizing properties, serve as ideal carriers or active components for photo/sono/radio-sensitizers. By modifying with mitochondrial-targeting ligands such as triphenylphosphonium, these nanoplatforms can specifically accumulate in the mitochondria of tumor cells, the cellular powerhouses closely linked to ROS-mediated cell death pathways. In PDT, under NIR or visible light excitation, MOFs generate ¹O₂, and mitochondrial targeting not only increases the local ROS concentration at the subcellular level but also alleviates tumor hypoxia, a major bottleneck of PDT, by interfering with the respiratory chain or producing O₂, thereby significantly amplifying therapeutic efficacy. In SDT, ultrasound-activated porphyrin MOFs also produce ¹O₂, and combining mitochondrial targeting with strategies like calcium overload or GSH depletion synergistically amplifies oxidative stress, enhancing sonodynamic killing efficiency. In RDT, the incorporation of high atomic number metals enables porphyrin MOFs to efficiently absorb X-rays, generating ·OH and ¹O₂ via the RT-RDT mechanism; meanwhile, loading dual gas donors and triggering their release under X-ray irradiation can induce mitochondrial dysfunction, radiosensitizing tumors and achieving synergy between gas therapy and RDT. In summary, Por-nMOFs, through the precise integration of mitochondrial targeting with multiple energy excitation modes (light, ultrasound, X-rays) and auxiliary strategies (hypoxia modulation, oxidative stress amplification, gas therapy), construct efficient, multi-layered nanoplatforms for tumor treatment, demonstrating significant potential for clinical translation.

Despite the notable advantages of Por-nMOFs in enhancing PDT, SDT, and RDT via mitochondrial targeting, their further development and clinical translation face several challenges. First, the contradiction between physiological stability and biodegradability is prominent: Notably, MOF biodegradation is often accompanied by metal ion release (e.g., Hf⁴⁺, Zr⁴⁺), which can induce oxidative stress, inflammatory responses, or organ damage through long-term accumulation in vivo, posing a major obstacle to biocompatibility. Although coatings like ZIF-8 or polymer modifications can improve stability, they may affect drug loading/release kinetics or biodegradability. Second, balancing targeting efficiency and systemic toxicity requires optimization: cationic targeting ligands like TPP, while effective for mitochondrial accumulation, can cause nonspecific adsorption, aggregation, and rapid clearance in systemic circulation, potentially inducing toxicity to normal cell mitochondria. Moreover, TPP may exhibit off-target mitochondrial effects towards some normal cells (e.g., cardiomyocytes, neurons) with high membrane potential, leading to unintended accumulation and disruption of normal mitochondrial function, which may trigger cardiotoxicity or neurotoxicity. Existing “stealth” strategies (hyaluronic acid coating) improve pharmacokinetics but still need enhancement in triggered exposure efficiency within the tumor microenvironment. In terms of pharmacokinetics and long-term clearance, current Por-nMOF systems often suffer from poor blood circulation stability and rapid reticuloendothelial system clearance, resulting in low tumor accumulation efficiency. Meanwhile, the long-term clearance pathways of MOF degradation products, including metal ions and ligand fragments, remain unclear, and their potential long-term biological effects have not been fully evaluated.

In addition, therapeutic efficacy is limited by the complexity of the tumor microenvironment: although O₂-generating nanozymes or respiratory inhibitors are integrated to alleviate hypoxia, insufficient H₂O₂ supply in tumors, pH-dependent catalytic efficiency (MnO₂ deactivation in acidic environments), and metabolic heterogeneity among cell types may lead to unstable O₂ enhancement effects. Furthermore, the construction and regulation of multimodal synergistic therapies remain complex: integrating MOFs with UCNPs, CDs, or other nanozymes often involves complicated synthesis steps, poor structural homogeneity, and insufficient energy transfer efficiency; additionally, precise spatiotemporal control over the release sequence of multiple therapeutic components to maximize synergy is still poorly understood. Finally, research on the impact on the immune microenvironment and long-term antitumor mechanisms is insufficient: current studies focus primarily on direct cell killing, while the ICD induced by porphyrin MOF-mediated PDT/SDT/RDT and its synergistic potential with immunotherapy remains underexplored, limiting their ability to combat metastasis and recurrence.

To address these challenges, future research should advance from material design, biomedical engineering, to clinical translation. Regarding stability and biocompatibility, novel “smart” coatings or hybrid structures can be developed: for example, designing pH- or enzyme-responsive polymer shells that remain stable in circulation but degrade at the tumor site to expose targeting ligands, enabling precise delivery; simultaneously, exploring more stable MOF materials or developing self-sacrificial coatings (ZIF-8) could balance stability with controlled release. For mitigating metal ion release toxicity, surface modification with chelating ligands or incorporation of metal ion scavenging components into MOF frameworks can be considered to reduce free metal-ion accumulation in vivo. To enhance targeting specificity and safety, multi-stage targeting strategies should be pursued: for instance, co-modifying MOF surfaces with tumor-targeting molecules and organelle-targeting ligands to enhance tumor accumulation via EPR effect and active targeting, followed by improved subcellular localization through mitochondrial targeting; moreover, developing new mitochondrial-targeting groups or utilizing mitochondrial-specific signals (membrane potential) to trigger drug release may reduce systemic toxicity. To optimize long-term clearance and pharmacokinetics, modifying MOFs with hydrophilic, non-immunogenic polymers (e.g., PEG derivatives, zwitterionic polymers) can extend blood circulation time. Meanwhile, designing MOFs with biodegradable backbones that can be completely degraded into metabolizable small molecules and non-toxic metal ions will promote long-term clearance and reduce chronic toxicity.

For optimizing tumor microenvironment modulation, more efficient catalytic systems need to be designed: for example, constructing bimetallic MOFs (Zr/Co, Fe/Cu) to synergistically enhance Fenton-like reactions and photocatalytic performance, or developing self-O₂-supplying and self-amplifying ROS-generating nanozymes for sustained H₂O₂ and O₂ supply; concurrently, combining metabolic regulation (simultaneous inhibition of glycolysis and oxidative phosphorylation) or calcium overload strategies could dismantle tumor defenses through multiple pathways. To simplify multifunctional integration and precise control, “all-in-one” MOF designs should be advanced: for example, embedding upconversion CDs, nanozymes, and targeting ligands directly into the MOF or pores via one-pot synthesis to shorten synthetic routes and ensure uniform dispersion; leveraging the spatiotemporal differences of external stimuli (light, ultrasound, X-rays) to program the sequential activation of different therapeutic modes, such as triggering PDT with NIR light to generate ROS first, followed by X-ray-activated gas release to enhance RDT. Finally, research on immune synergistic therapy and long-term efficacy should be expanded: co-loading porphyrin MOFs with immune adjuvants and combining them with immune checkpoint inhibitors (anti-CTLA-4 antibodies) can induce ICD through SDT/PDT to release tumor antigens, simultaneously activating dendritic cells and T cells to establish systemic antitumor immune memory; additionally, utilizing the modifiability of MOFs to load reporter genes or contrast agents could enable real-time imaging monitoring of the treatment process, promoting theranostics.

For the clinical translation of Por-nMOFs, three key issues need to be solved: safety, scalability, and dosing. In terms of safety, a comprehensive preclinical system should be established, including acute/chronic toxicity tests, long-term organ function monitoring, and immunogenicity evaluations. Special attention should be paid to the potential off-target effects of TPP and metal ion release toxicity, and the corresponding mitigation strategies (chelation modification, targeted ligand optimization, etc.) must be verified in large animal models. Regarding scalability, current laboratory-scale synthesis methods are difficult to meet clinical demand. Therefore, developing scalable synthesis technologies with low cost and good reproducibility is essential. In terms of dosing, personalized dosing methods considering patient characteristics, tumor type, and size should be developed. Moreover, the pharmacokinetic properties of Por-nMOFs in different patients need to be clarified to avoid adverse reactions induced by individual differences. Additionally, as novel nanomedicines, Por-nMOFs must comply with regulatory medical guidelines and criteria for safety and efficacy to accelerate the clinical translation process. In conclusion, with the integration of materials science, nanotechnology, and tumor biology, Por-nMOFs are poised to evolve into intelligent, personalized, multimodal synergistic platforms for tumor therapy, ultimately achieving clinical translation.