Introduction

Malignant tumors seriously endanger human health and represent a major public health issue. Clinical treatment strategies have evolved from conventional chemotherapy and radiotherapy to other modalities such as phototherapy and immunotherapy.1,2 However, each monotherapy has inherent limitations chemotherapeutic agents lack tumor specificity, leading to severe systemic toxicity; radiotherapy tends to cause normal tissue damage and radiation resistance; phototherapy is limited by tissue penetration depth; and immunotherapy faces low response rates and immune-related adverse events. The complex tumor microenvironment (TME), characterized by low pH, high glutathione (GSH) concentration, hypoxia, and dense stromal barriers, severely hinders intratumoral drug delivery and penetration while inducing multidrug resistance (MDR), significantly reducing the bioavailability of conventional chemotherapeutic drugs.3,4 Therefore, there is an urgent need to develop intelligent drug delivery systems featuring active tumor targeting, microenvironment-responsive release, and low side effects.

Nanodrug delivery systems (NDDS) encapsulate therapeutic agents within nanoscale carriers.5 NDDS can achieve passive tumor targeting via the enhanced permeability and retention (EPR) effect or active targeting through surface modification with targeting ligands.6,7 NDDS significantly improve the circulation stability of drugs, reduce uptake by normal tissues, and enable controlled or stimuli-responsive release, thereby enhancing therapeutic efficacy while minimizing toxicity.5,8 Compared with conventional formulations, nanocarriers have become an important direction in the field of cancer therapy.

Metal-organic frameworks (MOFs) are porous hybrid materials self-assembled from metal ions or clusters, which coordinate into two- or three-dimensional network crystal structures.9,10 MOFs possess ultrahigh porosity and extremely large surface areas, exceeding 6000 m2/g.11 Compared with traditional drug carriers such as liposomes and polymeric nanoparticles, MOFs exhibit superior drug loading capacity.12 As nanocarriers, MOFs offer unique advantages including pH responsiveness, tunable pore sizes, high efficiency, low toxicity, and lack of side effects.13,14 The controlled host–guest interactions and biodegradability achieved through coordination methods further enhance the attractiveness of MOFs for drug delivery applications.15

ZIF-8, an important subclass of the MOF family and one of the most representative ZIF types, is self-assembled by coordinating Zn2+ with 2-methylimidazole (2-Meim) and can passively target diseased tissues via the EPR effect.16 ZIF-8 exhibits good biocompatibility: Zn2+ is an essential trace element for the human body, and 2-Meim shows good biological tolerance, enabling gradual degradation and metabolic elimination in physiological environments.17 Studies have demonstrated that ZIF-8 is pH-responsive: under normal physiological conditions (pH 7.4), the ZIF-8 structure remains stable, whereas in the acidic tumor microenvironment (pH 5.0–6.5), the Zn2+-imidazolate coordination bonds undergo protonation-induced cleavage, leading to framework disintegration and controlled release of the encapsulated cargo, thereby achieving precise “lysosomal/tumor acidity-triggered” delivery (Figure 1).18 Furthermore, owing to its high specific surface area and abundant interactions such as π-π stacking and hydrogen bonding, ZIF-8 exhibits excellent loading efficiency for a wide range of chemotherapeutic agents, photosensitizers, and genetic drugs.19 The synthesis of ZIF-8 is mild and facile: it can be rapidly synthesized in aqueous or methanol phases at room temperature, and its imidazole-rich surface facilitates covalent or physical modifications, further endowing it with “stealth” and “navigation” capabilities, which represent fundamental approaches to achieving efficient and low-toxicity antitumor therapy. Compared with traditional nanocarriers such as liposomes, polymer nanoparticles, and mesoporous silica, liposomes and polymer systems often exhibit sudden release, while mesoporous silica requires complex surface functionalization to achieve stimulus responsiveness. In contrast, ZIF-8 offers significant advantages: it rapidly disintegrates under acidic conditions, making it more suitable for tumor microenvironment-responsive drug delivery—a property that traditional carriers lack or can achieve only through complex coating processes. Furthermore, its mild aqueous synthesis process and abundant imidazole groups facilitate convenient post-modification with PEG, targeting ligands, or biomimetic membranes, providing a multifunctional platform for active tumor-targeted delivery and controlled release. However, this pH responsiveness also poses stability challenges within endosomes, potentially leading to premature drug release during cellular uptake-a trade-off that must be carefully weighed in formulation design. Compared to other MOFs, such as the MIL and UiO series, ZIF-8 avoids the use of highly toxic heavy metals (such as chromium or zirconium precursors) and exhibits exceptional stability. This makes it one of the most promising MOF carriers for in vivo delivery applications.20 Although previous reviews have summarized the application of MOFs in drug delivery, a systematic performance comparison of ZIF-8 and the rationale behind its use in multimodal synergistic therapy remain insufficiently addressed. This review systematically presents recent advances in ZIF-8 nanoparticles (ZIF-8 NPs) for cancer therapy. First, we summarize the preparation methods of ZIF-8 and its modifications for cancer therapy. Subsequently, we review and discuss the applications of ZIF-8 nanomaterials in cancer treatment, along with potential shortcomings or challenges. On the basis of this review, we aim to maximize the potential of ZIF-8 nanomaterials.

Diagram of ZIF-8 nanoplatform construction, disassembly and multi-modal therapy applications.

Figure 1 The core paradigm of the ZIF-8 nanoplatform for tumor therapy. (A) Synthesis, drug co-loading, and surface functionalization modification of ZIF-8; (B) Structural changes and release mechanisms of ZIF-8 under different pH conditions; (C) Applications of ZIF-8 in nanomedicine delivery systems. (The figure was created in https://BioRender.com).

ZIF-8 Synthesis Method
Room Temperature Stirring Method

Involves mixing solutions of, for example, zinc nitrate (Zn(NO3)2·6H2O) and 2-methylimidazole (2-Hmim) in methanol or water at room temperature, allowing rapid coordination-driven self-assembly to form ZIF-8 nanoparticles. This is the simplest and most commonly used laboratory preparation method. Missaoui employed dimethylformamide (DMF) as the solvent under room-temperature conditions with stirring for approximately 1 hour to obtain hexagonal ZIF-8 nanoparticles with an average particle size of 150 nm.21 Zheng et al encapsulated the anticancer drug doxorubicin (DOX) into ZIF-8 for the treatment of breast cancer (BC). They dissolved 0.2 g of Zn(NO3)2·6H2O in 0.8 g of H2O and added 4 mL of DOX stock solution to the zinc nitrate solution. After stirring for 1 min, a solution containing 2 g of 2-Hmim and 8 g of deionized water (total 10 g) was added dropwise. The reaction mixture was stirred for 15 min, achieving a DOX loading capacity of up to 20%.22 Although this method is highly suitable for rapid screening of drug loading conditions and preliminary in vitro efficacy evaluation, its main limitation lies in the often-overlooked batch-to-batch variations in particle size and size distribution. Such polydispersity can profoundly affect EPR-dependent tumor accumulation, leading to poor in vivo–in vitro correlation.

Solvothermal Method

Involves dissolving Zn(NO3)2·6H2O and 2-Hmim in organic solvents such as methanol or DMF, followed by reaction in a sealed autoclave at elevated temperature (80–150°C) and pressure for several to tens of hours, during which coordination-driven self-assembly yields ZIF-8 crystals. Yang et al dissolved Zn(NO3)2·6H2O in a beaker containing a methanol solution and 2-Hmim in another beaker. Subsequently, the zinc salt solution was poured into the beaker containing 2-Hmim, stirred for 30 min, ultrasonicated for 5 min, and then heated in a 70°C water bath for 20 min to obtain ZIF-8.23 Almutairy et al used this method to synthesize radiolabeled ZIF-8 with a particle size of 198 ± 9.8 nm, a polydispersity index (PDI) of 0.219 ± 0.011, and a hemolysis rate below 5%, indicating good dispersibility and biocompatibility.24 Gao first mixed Zn(NO3)2·6H2O and 2-Hmim in methanol, subjected the mixture to room-temperature ultrasonication to obtain preliminary ZIF-8 nanoparticles, then supplemented the reaction with an additional zinc source, transferred the mixture to a Teflon-lined autoclave, and performed a hydrothermal reaction at 120°C for 2 h. After washing and drying, ZIF-8 with higher crystallinity was obtained.25 This method produces ZIF-8 with high crystallinity and regular morphology, making it suitable for fundamental structural characterization and mechanistic studies. However, the high pressure, high temperature, and prolonged reaction conditions not only consume substantial energy but also are difficult to scale up. Moreover, this method is unsuitable for loading heat-labile biomacromolecules, and the high pressure hinders real-time monitoring of the encapsulation process.

Ultrasound and Microwave-Assisted Method

The ultrasound and microwave-assisted method utilizes the rapid and uniform heating of polar molecules (eg, water, methanol) by microwave irradiation to greatly accelerate the nucleation and crystal growth of ZIF-8. Bazzi et al investigated the conversion of zinc oxide (ZnO) to ZIF-8 in different solvent mixtures using ultrasound and microwave assistance (Figure 2), demonstrating that the microwave method can synthesize size-tunable ZIF-8 within minutes (only 40 minutes) with a yield of 92% and excellent adsorption capacity.26 Yao et al employed a stepwise ultrasound-assisted method to synthesize ZIF-8 and studied the regulatory effect of ultrasound on the morphology of ZIF-8. First, 3.75 mmol of Zn(NO3)2·6H2O and 7.5 mmol of 2-Hmim were dissolved in methanol. Under ultrasonic agitation, half of the zinc salt solution was slowly injected into the methanol solution and reacted for 2 min, followed by injection of the remaining half and continued ultrasonication for 10 min to allow full reaction, yielding a milky white suspension of ZIF-8.27 This method features extremely fast reaction rates, uniform heating, high crystallinity, and good controllability over morphology and size, making it suitable for preliminary studies requiring rapid preparation or size screening. However, it also suffers from high equipment costs and typically small reaction volumes.

A schematic of ultrasound and microwave-assisted synthesis of ZIF-8 with adsorption of phosphate.

Figure 2 Schematic of ultrasound and microwave-assisted synthesis of ZIF-8. Reproduced from.26 Licensed under CC BY.

Microfluidic Continuous Synthesis Method

Microfluidic technology, owing to its ability to achieve continuous production, excellent batch-to-batch reproducibility, and precise control over particle size, is considered one of the key technologies for the clinical translation and large-scale production of ZIF-8 nanoparticles. As shown in Figure 3, Gao et al employed microfluidic technology to prepare core-shell structured CUR@ZIF-8-SF-PDA nanoparticles for breast cancer therapy, achieving functionalization through simultaneous loading of curcumin (CUR), silk fibroin, and polydopamine (PDA). This method enabled precise control over the proportions of each component, yielding nanoparticles with a size of approximately 170 nm.28 Compared with the traditional magnetic stirring method, the microfluidic strategy significantly improved the size uniformity and dispersibility of the nanoparticles. Shen et al used a microfluidic continuous-flow mixing chip to achieve precise manipulation of three-phase flow, and the prepared core-shell nanoparticles were superior to those obtained by traditional mixing methods in terms of size uniformity, structural integrity, and drug loading efficiency.29 Carrao et al applied the continuous-flow method for the first time to synthesize ZIF-8 biocomposites. Using a simple microfluidic device composed of Y- and T-shaped mixers, they successfully co-encapsulated bovine serum albumin (BSA) and α1-antitrypsin into ZIF-8, producing size-uniform ZIF-8 particles smaller than 200 nm, meeting the key size requirement for intravenous drug delivery systems.30 Although the nanoparticles prepared by the microfluidic method exhibit high uniformity, low throughput remains a major bottleneck.

Two schematics showing microfluidic mixing for ZIF-8 nanoparticle preparation and CUR release in cancer cells.

Figure 3 Schematic diagram of microfluidic-assisted preparation of ZIF-8. (A) Schematic diagram of rapid mixing-based preparation. (B) Schematic diagram of a microfluidic method for preparing ZIF-8-based nanoparticles.28

Mechanochemical Synthesis Method

The mechanochemical synthesis method utilizes mechanical energy generated by high-frequency impact and friction from milling balls in equipment such as ball mills to replace the solvent environment and external heating required in traditional synthesis, allowing solid-state zinc salts (eg, ZnO) and 2-Hmim to directly undergo coordination reactions to form ZIF-8. This method is therefore also considered a green synthesis approach.31 Tanaka et al first confirmed the mechanochemical dry conversion of ZnO to ZIF-8; after 96 h of ball milling, the specific surface area and micropore volume reached 1480 m2 g−1 and 0.55 cc g−1, respectively, with a yield as high as 80%.32 Balderas et al synthesized ZIF-8 by mechanochemical twin-screw extrusion at a screw speed of 150 rpm, achieving a production rate of 1.3 kg/h. The product exhibited stable hydrogen storage performance at 77 K, with a usable capacity of up to 31.1 g H2 L−1.33 Brekalo demonstrated that in a mechanochemical reaction of basic zinc carbonate and 2-Hmim (1:3) ground in a planetary mill, a large amount of pure ZIF-8 could be formed at room temperature.34 For application scenarios requiring large-scale production but not demanding high monodispersity of nanoparticles, this method is highly attractive.

Spray Drying Method

Wei et al employed spray drying technology to construct hierarchically porous ZIF-8. Using ZIF-8 nanoparticles of different sizes as precursors, they prepared aqueous dispersions and completed spray drying under parameters such as an inlet air temperature of 373 K and a feed rate of 15 mL/min. This successfully achieved efficient encapsulation of DOX, with drug loading and encapsulation efficiency as high as 79%, significantly enhancing the loading capacity and controlled release performance of DOX.35 Fan et al innovatively used a spray deposition method to construct a ZIF-8/polyvinyl alcohol composite separation membrane on a polyvinylidene fluoride fiber substrate. By optimizing the spray process, the ZIF-8 loading was 20–30 wt%, achieving uniform dispersion of ZIF-8 NPs in the coating and effectively solving the agglomeration problem common in traditional coating methods.36 Arora et al combined ultrasound with spray drying technology. First, under ultrasound, a solution containing 2-Hmim was dropped into a zinc-containing solution to synthesize a milky white ZIF-8 solution, which was then spray-dried to obtain the final piperine-loaded ZIF-8 (PIP@ZIF-8) powder with a yield of 38.3%.37 Spray drying is suitable for the post-treatment of heat-tolerant drugs or inorganic nanoparticles and for continuous, large-scale industrial production, and it can directly yield solid powders that are easy to store and transport.

Strategy for Method Selection

For laboratory validation and drug screening, the room-temperature stirring method is the first choice due to its simplicity and speed. However, given the batch-to-batch variability, critical experiments should be validated with replicates. When highly uniform particle size and batch-to-batch stability are required, the microfluidic method is preferred, especially for studies requiring strict in vivo–in vitro correlation or precise targeted delivery. For loading heat-labile biomacromolecules, the solvothermal and spray drying methods should be avoided; the one-pot method under room-temperature stirring or the microfluidic method under mild conditions is preferred. For green chemistry and large-scale industrial production, mechanochemical synthesis and spray drying are the main candidates. Based on the above analysis, the choice of ZIF-8 preparation method should be weighed against specific research objectives. Table 1 summarizes the advantages, disadvantages, and clinical translation potential of different preparation methods.

Table 1 Advantages and Disadvantages of Different Preparation Methods and Their Clinical Translation Potential

Drug Loading Methods of ZIF-8

The drug loading strategy of ZIF-8 directly affects the drug loading efficiency, release behavior, and bioactivity. As shown in Figure 4, Current mainstream methods include the one-pot method (in situ synthesis) and the impregnation method (post-loading), in addition to some hybrid strategies such as “in situ synthesis followed by loading” and “solvent-assisted loading.” The loading mechanisms, applicable drugs, and release kinetic characteristics of different methods vary significantly, requiring rational selection based on drug properties and therapeutic needs.

Two diagrams showing drug loading methods: one-pot process and impregnation method for DOX@ZIF-8 NPs.

Figure 4 Schematic diagram of preparation methods using the one-pot process and impregnation method. (A) One-pot method (B) Immersion method. (The figure was created in https://BioRender.com).

One-Pot Method

The one-pot method is a commonly used approach for drug loading into ZIF-8. It is an innovative method that simultaneously completes ZIF-8 framework synthesis and drug encapsulation in a single reaction system, avoiding the cumbersome process of first synthesizing and then loading drugs as in the impregnation method. In this method, drug molecules are encapsulated in situ within the pores during the coordination nucleation of Zn2+ and 2-Hmim, resulting in increased drug loading and more uniform nanoparticle size, with strong versatility.38,39 Guo et al used the one-pot method to co-encapsulate ICG and Cy5.5 into ZIF-8, preparing dextran-decorated Cy5.5&ICG@ZIF-8-Dex nanoparticles for the treatment of non-small cell lung cancer. These nanoparticles exhibited excellent tumor-targeting ability and photothermal therapeutic efficacy, with fluorescence intensity 40 times that of free Cy5.5, owing to the EPR effect.40 To enhance the therapeutic effect of temozolomide (TMZ) on glioma, Ren designed a tannic acid (TA)-modified ZIF-8 nanoparticle loaded with TMZ. This nanoparticle effectively inhibited the migration and invasion of U251 glioma cells and significantly induced apoptosis by regulating ROS/MMP levels and apoptosis-related protein pathways, demonstrating stronger antitumor activity than free TMZ.41 Research indicates that this method generally achieves high drug loading and encapsulation efficiency.42 The one-pot method is suitable for small-molecule chemotherapeutic drugs, photosensitizers, and some biomacromolecules, but attention should be paid to the synthesis conditions (eg, pH, solvent) that may affect the activity of sensitive drugs.

Impregnation Method

The impregnation method (IM) is one of the most commonly used post-modification or drug loading strategies. It generally refers to the process of loading target molecules into the pores or onto the external surface of pre-synthesized ZIF-8 carriers through physical adsorption, capillary action, and van der Waals forces.43 Padya designed a topical gel delivery system based on Sonidegib (SDG)-modified ZIF-8. First, modified ZIF-8 was synthesized using the one-pot method, followed by loading of 5-fluorouracil (5-FU) via the impregnation method to enhance penetration through the follicular route. SDG simultaneously exerted targeting and therapeutic effects, achieving synergistic enhancement of 5-FU and SDG in basal cell carcinoma.44 Mi designed a folate receptor (FR)-targeting ZIF-8 nanoparticle loaded with baicalin (BAN) (PEG-FA@ZIF-8@BAN). BAN was loaded into the pores of FA-ZIF-8 via the impregnation method, achieving an encapsulation efficiency of 65.83 ± 3.35%. Compared with other BAN nanodelivery systems, PEG-FA@ZIF-8@BAN exhibited higher drug loading efficiency.45 The impregnation method is particularly suitable for drugs sensitive to synthesis conditions, such as proteins, peptides, and nucleic acids, as well as targeting ligands or functional molecules that require post-modification introduction.

Method Comparison

In the one-pot method, drugs are encapsulated within the cage-like framework of ZIF-8, resulting in strong interactions with the framework. In the impregnation method, drugs are mainly adsorbed onto the external surface or pore openings, primarily through physical adsorption, resulting in weaker interactions with the framework.46 Regarding release kinetics, the one-pot method achieves long-term sustained release; drug molecules must slowly diffuse outward through the microporous channels inside ZIF-8, encountering significant steric hindrance and diffusion resistance, leading to a low and constant release rate. In contrast, the impregnation method achieves rapid release, with the release rate mainly limited by the desorption process of drug molecules from the carrier surface, involving fewer limiting factors and resulting in faster release. A study comparing the two methods for Ag(I) ion loading confirmed that one-pot synthesized ZIF-8 exhibited a significantly lower and more constant ion release rate in artificial seawater, whereas ions adsorbed on the surface via the impregnation method were released more quickly.47 For long-term sustained release and precise targeting, the one-pot method is preferred; for rapid action or surface functionalization, the impregnation method may be chosen. Although the one-pot method typically achieves higher drug-loading efficiency, researchers must assess whether encapsulation affects drug bioactivity. In particular, for biomacromolecules such as proteins and nucleic acids, in situ synthesis conditions, such as the presence of Zn2+ or pH changes, may lead to aggregation or loss of function. Furthermore, a higher drug load does not automatically translate to better therapeutic outcomes; for certain drugs that require rapid attainment of peak concentrations to overcome resistance mechanisms, sustained-release may actually be detrimental.

Functionalization Modifications of ZIF-8 Nanocarriers
Biocompatibility Modification

The in vivo application of pristine ZIF-8 is limited by poor stability, non-specific distribution, and immune clearance. Therefore, hierarchical functionalization is required to gradually address these issues: first improving biocompatibility, then conferring active targeting capability, and finally achieving biomimetic stealth.

Polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and polydopamine (PDA) are commonly used modification materials in cancer therapy. Constructing a polymer protective layer on the ZIF-8 surface via physical adsorption or covalent crosslinking is a universal method to balance stability and biocompatibility. Studies have confirmed that PEG modification can effectively enhance the performance of ZIF-8. For example, Peng used PEG-2000 to modify ZIF-8 loaded with hinokiflavone (HF), exhibiting excellent biocompatibility (cell viability >99%) and improving colloidal stability while reducing non-specific adsorption in vivo, which is particularly important for oral administration.48 Similarly, Zhang et al used FA-PEG to modify ZIF-8, effectively preventing nanoparticle aggregation and improving their dispersibility without altering their intrinsic structure.49 PDA itself is an excellent photothermal agent rich in active groups such as catechol and amino groups.50,51 Zhang et al modified the surface of ZIF-8 with PDA, loaded MF-094, and achieved subsequent functionalization with PEG-thiophosphate, synergistically enhancing the tumor targeting and cellular uptake efficiency of the carrier.52 Yin combined chemotherapy and photothermal therapy using PDA-modified methotrexate (MTX)-loaded ZIF-8 NPs, effectively addressing the limitations of monotherapy, avoiding burst drug release, and improving the biocompatibility and near-infrared (NIR) light absorption performance of the nanoparticles.53

Active Targeting Modification

To enhance the accumulation of ZIF-8 nanomedicines in tumors and reduce their systemic toxicity, active targeting surface modification strategies are crucial. Currently, commonly used modifications fall into three categories: small molecule targeting, polysaccharide targeting, and peptide targeting. Folic acid (FA) is the most commonly used small-molecule targeting ligand. The folate receptor (FR) is a glycosylphosphatidylinositol-anchored membrane glycoprotein primarily present on cell surfaces, exhibiting high affinity for FA.54 Studies have shown that FA-modified ZIF-8 remains structurally stable in neutral environments (pH 7.4) with low drug release, reducing toxicity to normal tissues. In the acidic conditions of the tumor microenvironment (pH 5.0), the carrier framework disintegrates, and the drug release efficiency increases threefold compared with physiological conditions, achieving sustained release of curcumin at the target site and enhancing therapeutic efficacy against cervical cancer.55 Li designed an Fe/ZIF-8 carrier co-loading glucose oxidase (GOx), L-arginine, and DOX. In vitro and in vivo experiments confirmed that FA modification endows ZIF-8 NPs with excellent tumor targeting and biocompatibility, greatly increasing drug accumulation at the tumor site and significantly enhancing the synergistic antitumor effect of starvation-like therapy, chemodynamic therapy, nitric oxide gas therapy, and chemotherapy.56

Hyaluronic acid (HA) is a natural polysaccharide that can be metabolized naturally in the human body. Its unique advantage lies in its ability to actively recognize and bind to the CD44 receptor, which is highly expressed on the surface of tumor cells.57,58 Song et al combined the advantages of HA, ZIF-8, and molecularly imprinted polymers (MIPs) for the treatment of prostate cancer. HA played a dual role: not only binding to the CD44 receptor to target prostate cancer cells but also being degradable by hyaluronidase (HAase), which is highly expressed in the tumor microenvironment, achieving dual pH/enzyme responsiveness.59 Li used HA to modify ZIF-8 co-loading ICG and the glycolysis inhibitor cryptotanshinone (CTS). The HA-coated ZIF-8 enhanced the in vitro and in vivo targeting ability of ZIF-8 through both the EPR effect and CD44-mediated active tumor targeting, thereby increasing drug concentration and conferring excellent targeting and synergistic therapeutic capability.60

RGD peptides are short peptide sequences composed of arginine, glycine, and aspartic acid that specifically recognize integrin receptors highly expressed on the surface of cancer cells.61,62 Meng designed a nanodelivery system in which metformin (Met) and glucose oxidase (GOx) were encapsulated in histidine/ZIF-8 (His/ZIF-8) and coated with Arg-Gly-Asp (RGD) peptide (Met/GOx@His/ZIF-8∼RGD). After RGD peptide modification, MDA-MB-231 cancer cells exhibited better cellular uptake compared with non-RGD-modified NPs.63 Kamal investigated the pH responsiveness of the RGD-functionalized nanocarrier GEM⊂RGD@nZIF-8 and its biosafety in healthy zebrafish embryos. RGD not only endowed the nanocarrier with the ability to target cancer cells but also improved its biocompatibility, with an LC50 > 250 μg mL−1 and an embryo survival rate as high as 75% after 96 h.64

In summary, these modifications not only effectively promote drug accumulation at tumor sites and reduce systemic toxicity but also significantly enhance antitumor efficacy by synergizing multiple therapeutic modalities, thereby enriching the application prospects of ZIF-8 in biomedicine and other fields.

Cell Membrane Modification

In recent years, cell membrane modification has been widely applied in targeted tumor therapy, as it can both facilitate immune evasion and actively target tumors, leading to accumulation at tumor sites.65,66 Commonly used cell membranes include cancer cell membranes, red blood cell membranes, and macrophage membranes. As a natural barrier, the cell membrane endows nanomedicines with “homologous cell mimicking” properties, granting them the ability for “long in vivo circulation,” evading immune recognition, reducing foreign body rejection, and simultaneously improving the structural stability of nanoparticles in vivo.67,68

Qiao constructed red blood cell membrane-camouflaged ZIF-8 co-loading DOX and the type I transforming growth factor β receptor inhibitor. This significantly enhanced tumor enrichment and deep distribution of DOX, restored ROS production capacity and cytotoxicity of DOX under hypoxic conditions, and achieved synergistic collagen clearance and hypoxia relief by modulating the tumor microenvironment, providing a new strategy for chemotherapy sensitization in solid tumors.69 Yang et al used a hybrid membrane composed of Hepa1-6 hepatoma cell membrane and red blood cell membrane for modification, achieving a dual mechanism of “top-down inhibition of cholesterol synthesis + bottom-up degradation of existing cholesterol.” Combined with sonodynamic therapy (SDT), this approach achieved a tumor inhibition rate of 90% in a liver cancer model, significantly downregulating the expression of the anti-apoptotic protein Bcl-2 and upregulating the pro-apoptotic protein Bax.70

The application of 4T1 cancer cell membranes in ZIF-8 primarily exploits their two major biomimetic properties—homologous targeting and immune evasion—to achieve precise therapy for breast cancer. Zhao constructed ZIF-8 NPs loaded with 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) and Ce6, coated with 4T1 cancer cell membranes. The cell membrane synergized with the pH-responsive properties of ZIF-8, achieving release rates of DMDD and Ce6 of 62.9% and 71.2%, respectively, within 6 h in the acidic tumor environment. The tumor apoptosis rate reached 58.27%, and the tumor inhibition rate was significantly higher than that of single treatment groups.71 Li similarly designed 4T1 membrane-coated ZIF-8 NPs loaded with GOx and the autophagy inhibitor chloroquine. Utilizing the synergistic effect of ZIF-8-induced autophagy and its inhibition strategy, the nanoparticles were preferentially taken up by tumor cells. The phagocytosis rate by RAW264.7 macrophages was significantly reduced, while no significant targeting was observed toward heterologous tumor cells such as HeLa and MCF-7 or normal H9c2 cardiomyocytes, providing a new approach for combined cancer starvation therapy and autophagy regulation.72

Macrophage membrane-modified ZIF-8 leverages the inflammatory tropism and immunomodulatory functions of macrophages, demonstrating unique application advantages in tumor therapy. Zhang constructed copper-doped ZIF-8 NPs coated with genetically engineered M1 macrophage membranes overexpressing CCR2, co-delivering the targeted drug β-lapachone and the hypoxia-activated prodrug TH-302. Through CCR2 binding to CCL2, tumor targeting was achieved, and pro-tumor macrophage infiltration was reduced. The synergistic ROS burst induced immunogenic cell death of tumor cells, reversing the immunosuppressive microenvironment induced by incomplete radiofrequency ablation.73 Yang et al expressed HER2 antibodies on macrophage membranes, endowing the nanoparticles with the ability to actively recognize and bind HER2-overexpressing breast cancer cells. Through antibody-dependent cell-mediated cytotoxicity and photothermal effects, they reversed the immunosuppressive microenvironment and enhanced antitumor immune responses.74

Cell membrane-camouflaged ZIF-8 nanoplatforms, by integrating the drug-loading advantages of metal-organic frameworks with the biomimetic functions of natural cell membranes, provide a versatile strategy for tumor-targeted therapy. As shown in Table 2, researchers have recently developed various cell membrane-modified ZIF-8 systems that achieve the integration of immune evasion, homologous targeting, pH-responsive drug release, and multimodal synergistic therapy. These biomimetic nanosystems not only significantly enhance drug accumulation and deep penetration at tumor sites but also effectively overcome the delivery barriers and drug resistance issues of traditional nanomedicines by modulating the tumor microenvironment.

Table 2 Applications of Nanocarriers with Different Cell Membrane Modifications in Tumor Targeted Therapy

A comprehensive comparison of various modification strategies shows that PEGylation is the most basic “invisible” modification, suitable for nearly all ZIF-8 systems, but it lacks active targeting capability; Modifications with small-molecule or polysaccharide ligands, such as FA and HA, confer active targeting but are limited by the heterogeneity of target receptor expression; RGD peptide modification targets the integrin pathway and is versatile across various solid tumors, but multivalent presentation may increase the risk of immunogenicity; Cell membrane coating represents the most biomimetic strategy, combining both immune evasion and homologous targeting functions, but the process is complex and standardizing membrane sources is difficult. Researchers should rationally select single or combined modification strategies based on the molecular characteristics of the target tumor and clinical application scenarios, rather than blindly stacking functional layers.

Application of ZIF-8 Nanoparticles in Tumor Therapy
Synergistic Chemotherapy

Chemotherapy is one of the core modalities of current clinical tumor therapy. It involves oral or intravenous administration of chemical drugs that travel through the bloodstream to the entire body, launching a “non-selective” attack on cancer cells. The core principle is to interfere with the proliferation of cancer cells, affecting their DNA, RNA, or protein synthesis, ultimately leading to cancer cell death.87,88 However, the lack of selectivity often leads to severe toxic side effects, such as nausea, vomiting, hair loss, and even cardiotoxicity and nephrotoxicity, which are the roots of its disadvantages and side effects.89–91 The introduction of the ZIF-8 nanodelivery system offers a new approach to improving the therapeutic index of chemotherapeutic drugs. Currently, chemotherapeutic drugs loaded into ZIF-8 are mainly classified into three categories: 5-FU, DOX, and PTX, enabling precise pH-responsive release, targeting of tumor cells, increasing drug loading, and causing almost no damage to normal cells.

Synergistic 5-FU Therapy

5-FU is a first-line drug for treating solid tumors such as colorectal cancer, breast cancer, and head and neck cancer. ZIF-8 can precisely address the shortcomings of 5-FU, including its short half-life, high toxicity, and poor tumor targeting.92,93 Padya et al used ZIF-8 to load 5-FU and coated the surface with SDG. 5-FU disrupts DNA/RNA synthesis to kill tumor cells, while SDG blocks the Hedgehog signaling pathway, fundamentally inhibiting cancer stem cells and tumor growth. One carrier simultaneously delivers two drugs, overcoming resistance to monotherapy and producing synergistic effects while inhibiting key signaling pathways and exerting cytotoxic attacks.44 Gorish et al integrated machine learning to optimize process parameters and constructed Lignin@GO@ZIF-8 for the co-delivery of 5-FU and Met for prostate cancer therapy. This carrier exhibited low toxicity to normal prostate epithelial cells but demonstrated potent killing effects on LNCaP prostate cancer cells, reducing cell viability to 18 ± 3% at 72 h. The mechanism involves 5-FU inhibiting DNA synthesis, metformin interfering with cellular metabolism, and the carrier’s own antitumor effects, achieving multi-pathway synergistic cancer inhibition.94 Hao et al found that in the 5-FU@ZIF-8 nanodelivery system, the drug loading of 5-FU could reach 271.41 ± 21.94 mg/g. In oral squamous cell carcinoma (OSCC), it exerted antitumor effects by downregulating proliferation genes and upregulating apoptosis pathways. ZIF-8 dissolved in acetic acid buffer, and acetic acid, as a lipid synthesis precursor in OSCC, together with tumor microenvironment acidification, constitutes a dual target for 5-FU targeted delivery, providing a new mechanism for OSCC chemotherapy.95 To address resistance to single chemotherapeutic drugs, researchers co-encapsulated MTX and 5-FU in ZIF-8 for sequential delivery in breast cancer therapy. The ZIF-8 shell was loaded with MTX, and the mesoporous silica core was loaded with 5-FU. In the tumor microenvironment, MTX was released first, followed by 5-FU, aligning with the synergistic mechanism of “MTX pretreatment enhancing 5-FU target binding.” In vitro cell experiments showed that the IC50 of Fu-MSN@MTX-NMOF against MCF-7 cells decreased from 51.54 μg/mL to 14.34 μg/mL with increasing incubation time (24 h to 72 h), confirming the synergistic effect of sequential release.96

Synergistic DOX Therapy

DOX is a broad-spectrum anticancer drug, but its clinical application is limited by cardiotoxicity, non-specific distribution, and multidrug resistance.97,98 Studies have shown that π-π stacking, hydrogen bonding, and electrostatic interactions exist between DOX and the ZIF-8 framework, which not only enable efficient loading but also help maintain the structural integrity of DOX during circulation.99 Hu et al assembled ZIF-8 with DOX and MnCO into ZIF-8@MnCO@DOX NPs. The combination of metal ions and chemotherapy induced a strong oxidative reaction through Fenton-like reactions, significantly enhancing the radiation sensitivity of HCC cells and activating the cGAS-STING pathway, thereby catalyzing a potent antitumor immune response (Figure 5).100 To synchronously ablate tumors with chemotherapy and chemodynamic therapy (CDT), an innovative DOX-loaded ZIF-8/SrSe nanozyme was used. The ferroptosis inhibitor Fer-1 partially restored cell viability, and the apoptosis inhibitor ZVAD-FMK also partially restored viability, indicating the simultaneous induction of apoptosis and ferroptosis. Annexin V/PI staining showed that the ZIF-8/SrSe@DOX group had the highest apoptosis rate (38.6%), significantly higher than the DOX group (16.7%) and the ZIF-8/SrSe group (35.1%). By pairing DOX with Fenton reactants, GSH was consumed, and ferroptosis and apoptosis were induced, confirming the feasibility of synergistic apoptosis and ferroptosis induced by chemotherapy and CDT.101 Wu et al first constructed a DOX-Fe3O4@ZIF-8 core-shell structure for osteosarcoma therapy, possessing dual advantages of magnetic targeting and pH-responsive release. In vivo experiments showed that the tumor inhibition rate in the DOX-Fe3O4@ZIF-8 + magnetic field group was as high as 83.22%, much higher than that of the free DOX group (41.63%) and the Fe3O4@ZIF-8 group without a magnetic field (61.88%), demonstrating that magnetic targeting significantly enhanced the chemotherapeutic effect. The toxicity of the Fe3O4@ZIF-8 group to the heart and liver was significantly lower than that of the free DOX group, addressing the cardiotoxicity issue in DOX clinical application.102 Wei constructed Cu/ZIF-8@GOx-DOX@HA, in which DOX not only achieved pH-responsive release but also benefited from H2O2 generated by GOx consuming glucose and Cu2+-mediated GSH consumption and Fenton reactions, forming a starvation/oxidation/chemotherapy triple synergistic delivery system to address the insufficient H2O2 in CDT.103

Workflow showing nanoparticle formation, injection and immune signaling leading to tumor suppression.

Figure 5 Schematic diagram of ZIF-8@MnCO@DOX (ZMD NPs) for hepatocellular carcinoma treatment and activation of the cGAS-STING pathway.100 Copyright 2025 Springer Nature.

Synergistic PTX Therapy

Paclitaxel (PTX), the third most commonly used chemotherapeutic drug, can also be combined with the ZIF-8 delivery system for precise therapy. PTX was the first natural-source plant anticancer drug approved by the US FDA. It promotes tubulin polymerization and inhibits microtubule depolymerization, thereby arresting mitosis at the G2/M phase and ultimately inducing cancer cell apoptosis.104 However, the limited solubility and high toxicity of PTX present challenges and limitations in its application for cancer therapy.105 To address this issue, Zhao delivered PTX to target liver cancer cells, successfully achieving controlled release of PTX within liver cancer cells. In vitro experiments confirmed that this formulation selectively induced apoptosis in liver cancer cells, upregulated TNF-α, and induced ROS, while exhibiting low toxicity to normal hepatocytes.106 Geng et al further studied the co-loading of PTX and propranolol (PRN) in ZIF-8. PTX and Zn2+ released from ZIF-8 induce autophagy (pro-survival effect), while PRN, as an autophagy inhibitor, blocks autophagic flux, converting the pro-survival effect of autophagy into a pro-death effect. Simultaneously, this system significantly increases intracellular ROS levels, further inducing apoptosis, representing an innovative strategy for sensitizing chemotherapy by regulating autophagy.107 Combining chemotherapy with phototherapy can greatly enhance tumor growth inhibition. Lu et al self-assembled ZIF-8 with ICG and Tax into ZIF-8@ICG@Tax. ICG efficiently converted light energy into heat under 808 nm laser irradiation, with a photothermal conversion efficiency of 54.3%. This not only directly killed tumor cells through local hyperthermia but also significantly enhanced the uptake of nanoparticles by tumor cells, further amplifying the chemotherapeutic effect. ZIF-8@ICG@Tax combined with NIR irradiation effectively inhibited tumor growth, raising the tumor site temperature to 51.3°C, achieving significant antitumor efficacy while reducing the hepatorenal toxicity of Tax through encapsulation.108

Synergistic Therapy with Other Chemotherapeutic Drugs

In addition to the three major categories of chemotherapeutic drugs mentioned above, ZIF-8 carriers are also frequently combined with carboplatin (CP), cisplatin (CDDP), and other chemotherapeutic agents. For CP delivery, Ganapathy constructed CP-loaded ZIF-8 nanoparticles for breast cancer therapy. Cytotoxicity experiments showed that the IC50 of CP@ZIF-8 against MCF-7 breast cancer cells was 15.01 ± 3.03 µg/mL, significantly better than that of free CP (34.98 ± 4.25 µg/mL), confirming that ZIF-8 can effectively enhance the anti-proliferative activity and apoptosis-inducing ability of carboplatin.109 Dashti et al further designed ZIF-8-coated chitosan-poly(N-isopropylacrylamide) (CS-PNIPAAm) core-shell nanoparticles for the co-delivery of CP and DOX, exhibiting dual pH/temperature responsiveness and demonstrating significant synergistic killing effects in MCF-7 and MDA-MB-231 breast cancer cells.110 For platinum-resistant ovarian cancer (PROC), Lin et al developed an epigenetic metal-organic framework nanoagonist (CMZ-Pt-SA@HA) using Mn-ZIF-8 as the core, co-loading CDDP and the histone deacetylase inhibitor SAHA. This system overcomes the triple defense mechanisms of PROC through multiple pathways: SAHA epigenetically downregulates resistance proteins, CaO2 triggers calcium overload and oxygen release, and Mn2+/Zn2+ enhance oxidative stress and STING signaling, demonstrating potent therapeutic efficacy in both subcutaneous and patient-derived xenograft models.111 Zhang et al also designed a bimetallic nanoplatform based on ZIF-8 loaded with the cisplatin prodrug Pt(IV). The study found that the mechanism of action of Pt(IV) differs from that of traditional cisplatin; it can bind to the inositol moiety of the cellular messenger IP3, interfering with IP3-mediated cell communication and downregulating cytoplasmic Ca2+ concentration and downstream signaling, thereby inhibiting tumor cell proliferation and invasion. Meanwhile, Zn2+ released from ZIF-8 reduces ATP biosynthesis, further limiting cell communication, achieving a unique dual mechanism of action.112

Synergistic Photothermal Therapy

Photothermal therapy (PTT) utilizes photothermal agents to absorb NIR radiation and convert it into localized hyperthermia, thereby directly ablating tumor cells and inducing ICD.113 The pH responsiveness of ZIF-8, combined with the photothermal effect generated by NIR irradiation, further promotes drug release, achieving a pH/NIR dual-responsive drug delivery system that enhances treatment precision and efficacy. The combined modality exhibits significantly better antitumor effects than monotherapy.108,114 Photothermal agents are classified into organic and inorganic types. Organic materials have developed rapidly in recent years, with their greatest advantage being good biocompatibility and degradability, reducing the risk of long-term toxicity.115 ICG, as a representative organic small molecule, is an FDA-approved near-infrared dye for clinical use, possessing both photothermal and photodynamic therapeutic effects and enabling fluorescence imaging.116 This section focuses on the tumor-killing effects of ICG and gold nanomaterials via thermal effects.

ICG and DSF were co-loaded into ZIF-8, and the surface was modified with HA/PEG-grafted-polyglutamic acid (HPG), improving the solubility of DSF. In vitro experiments showed that ID@ZIF-8@HPG was better taken up by tumor cells, thereby achieving excellent photothermal and photodynamic properties.117 ICG encapsulated within the ZIF-8 framework and modified with CeO2 nanozymes formed a bimetallic catalytic system with Zn2+ released from ZIF-8 and Ce3+/Ce4+ from CeO2. The local hyperthermia (~52.5°C) generated by the photothermal effect of ICG further accelerated the kinetics of hydroxyl radical generation, creating a photothermal-enhanced ROS storm that efficiently ablated tumors, achieving deep synergy between PTT and CDT. Moreover, NIR-II imaging guided precise surgical resection of breast cancer, avoiding residual recurrence.118 As shown in Figure 6, Chen et al introduced silk fibroin as a biological template, screened the MCF-7 breast cancer-specific peptide AR, and modified it onto the surface of ZIF-8@ICG/DOX, achieving triple combination therapy of PTT, PDT, and chemotherapy. Under 808 nm laser irradiation, the local hyperthermia generated by ICG not only directly killed tumor cells but also promoted the intratumoral penetration of DOX. In vivo experiments demonstrated that AR-ZS/ID-P NPs significantly inhibited tumor growth.119 Integrating radiosensitization and photothermal therapy strategies, the efficient photothermal conversion of ICG increased tumor blood supply and oxygenation, overcoming radiotherapy resistance caused by hypoxia. Feng et al encapsulated rapamycin and ICG in ZIF-8. In vitro experiments proved that RIZM NPs arrested the cell cycle in the G1 phase, preventing DNA replication and cell entry into the S phase, thereby enhancing radiosensitivity. In vivo efficacy experiments showed a radiosensitization enhancement ratio of 1.22 for RIZM NPs, indicating significant radiosensitizing effects.120

AR-ZS/ID-P nanoparticle prep for breast cancer therapy using NIR laser and peptide guidance.

Figure 6 Schematic diagram of AR-ZS/ID-P nanoparticle preparation and targeted peptide-guided photothermal and photodynamic therapy for breast cancer.119 (A–C) The silk fibroin (SF) was prepared and added to the 2-HmIm aqueous solution to serve as a bio-template (A), followed by the addition of the anticancer drug DOX, the photosensitizer ICG (B), and then the Zn(NO3)2·6H2O aqueous solution to form drug-loaded ZIF-8 nanoparticles (termed ZS/ID NPs) by one-pot process (C). (D) A PEI coating strategy was introduced to ZS/ID NPs (termed ZS/ID-P NPs) to improve the stability of nanoparticles and provide rich binding sites for MCF-7 breast tumor-targeting peptides. (E) The MCF-7 breast tumor-targeting peptide AR was linked with ZS/ID-P NPs (termed AR-ZS/ID-P NPs) under the action of EDC/NHS crosslinkers. (F) AR-ZS/ID-P NPs injected into the caudal vein of mice were guided to tumor by the AR peptide, allowing the NPs to selectively accumulate within the tumor. Then, in response to the acidic environment in cancer cells, AR-ZS/ID-P NPs were dissolved. Thus, DOX and ICG were released from the AR-ZS/ID-P NPs into cancer cells, leading to cancer cell death with the help of an additional 808 nm laser. Licensed under CC BY.

Inorganic photothermal agents are primarily based on gold-based nanomaterials, which offer high photothermal conversion efficiency, stable chemical properties, and ease of surface modification.121,122 To address the limitation of PTT-triggered protective autophagy in tumor cells, FA-modified gold nanoparticles (GNPs) loaded with the autophagy inhibitor bafilomycin were coated with ZIF-8. The ZIF-8 coating significantly enhanced the stability of the GNPs with minimal impact on their photothermal performance, achieving synergy between autophagy regulation and PTT.123 Huang et al constructed a core-shell structure with a gold nanorod (AuNR) core and a ZIF-8 shell (Au@ZIF-8) loaded with DOX. The Au@ZIF-8 exhibited a photothermal conversion efficiency as high as 22%, with concentration- and time-dependent photothermal heating characteristics. Benefiting from the synergistic effect of PTT and chemotherapy, Au@ZIF-8/DOX efficiently accumulated at the tumor site through high permeability and the EPR effect. The combined chemo-photothermal therapy group achieved the best tumor inhibition effect, with half of the tumors eliminated and no tumor recurrence, significantly outperforming single-modality treatment groups.124 Li et al used ZIF-8 as a carrier to co-load gold nanorods (GNRs), artesunate, and dequalinium chloride, achieving synergy between PTT and mitochondria-targeted chemotherapy. Artesunate and dequalinium chloride disrupted mitochondrial membrane potential, induced ROS generation, and triggered mitochondria-mediated apoptosis. The photothermal effect of GNRs further amplified this effect, enabling synergistic chemo-photothermal killing and demonstrating excellent in vitro and in vivo therapeutic effects against non-small cell lung cancer.125 Sood et al used ZIF-8 as a sacrificial template to synthesize gold half-shell nanoparticles with strong near-infrared absorption via a one-pot method for photothermal ablation of breast cancer. The photothermal conversion efficiency was approximately 37%, and animal experiments showed a disease-free survival rate of 75%. Half-shell-mediated photothermal therapy not only eliminated primary tumors but also significantly inhibited tumor metastasis to vital organs, improving survival rates.126

Synergistic Photodynamic Therapy

Photodynamic therapy (PDT) is a minimally invasive, highly selective tumor treatment modality whose core mechanism relies on three elements: a photosensitizer, a specific wavelength of light source, and molecular oxygen.127,128 Hypoxia is a common characteristic of solid tumors and a major factor severely limiting the efficacy of conventional PDT.129 ZIF-8, through the incorporation of photosensitizers and metal ions such as Co2+ and Fe2+, effectively consumes GSH, amplifies oxidative damage effects, catalyzes the production of highly toxic hydroxyl radicals from H2O2, and complements the ROS generated by PDT,130,131 achieving multimodal synergistic enhancement of PDT with chemodynamic therapy, ion toxicity, and even chemotherapy. This section focuses on the chemical killing of cells through the interaction of photosensitizers and oxygen to produce singlet oxygen and other ROS.

Ce6 and IR780 are two representative and widely studied near-infrared photosensitizers. Ce6 focuses on improving the efficiency and targeting of PDT,132 while IR780 has become a star molecule for combined PTT/PDT therapy due to its unique photophysical properties.133 Ce6 was loaded into ZIF-8, and the outer layer was coated with disulfide bond-containing polydopamine (ssPDA). In a high-GSH tumor environment, the ssPDA layer breaks and consumes GSH, while ZIF-8 acid-dissociates to release Ce6. Under 660 nm laser excitation, Ce6 generates ROS, inducing tumor cell apoptosis, thereby achieving synergy between PDT and ferroptosis (Figure 7).131 Li co-loaded Ce6 and the chemotherapeutic drug DSF into ZIF-8, along with CuO2. Upon release, DSF, Ce6, and Cu2+, H2O2, O2 from CuO2 decomposition were simultaneously released. DSF chelated with Cu2+ to form the CuET complex, killing cancer cells by disrupting the ubiquitin-proteasome system and inducing oxidative stress, enhancing DSF chemotherapy. Cu2+ catalyzed Fenton-like reactions to achieve CDT, while O2 alleviated hypoxia and assisted Ce6 in producing singlet oxygen under laser to enhance PDT, and GSH consumption amplified oxidative stress, achieving triple synergy of chemotherapy, CDT, and PDT.134 Yang constructed Ce6-DNAzyme@ZIF-8@PEG nanoparticles, integrating a miR-21 dual-cycle signal amplification imaging system with GPX4-DNAzyme-mediated gene editing to enhance PDT therapy. The loading efficiencies of GPX4-DNAzyme and Ce6 reached 10 wt% and 26 wt%, respectively. Through Ce6-mediated PDT and GPX4-DNAzyme gene editing, the dual mechanism enhanced therapeutic efficiency, achieving highly sensitive miR-21 imaging and PDT therapy for breast cancer.135

An infographic showing GPX4 decreases and LPO, FerroOrange and MDA rise with laser in treated cells.

Figure 7 Results of Ce6@ZIF-8@ssPDA NPs stimulated ferroptosis activation against HNCs. (A and B) PCR and Western blot results of GPX4 expression. (C–F) Representative CLSM images and quantitative results of LPO and FerroOrange. (G and H) GSH/GSSG ratio and MDA expression of HN6 cells after treatment of different groups.*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.131 Licensed under CC BY.

IR780 was conjugated with atovaquone (ATO) and co-loaded with DOX into ZIF-8. After release in the acidic tumor microenvironment, ATO and Zn2+ interfered with mitochondrial electron transport and glycolysis, respectively, leading to energy depletion, thereby inhibiting the activity of P-glycoprotein and HSP70, thus reversing tumor resistance to chemotherapy and PDT.136 IR780 generates ROS for PDT and heat for PTT upon laser irradiation. Meanwhile, GOx catalyzes glucose decomposition, consuming ATP and downregulating the expression of heat shock protein 90 (HSP90), thereby sensitizing cancer cells to hyperthermia and significantly enhancing the synergistic therapeutic effect of PDT/PTT.137 Gao et al developed a multiple myeloma cell membrane-coated ZIF-8 nanocarrier (D/INPs@CM) co-loading IR780 and DOX. Under NIR laser, the photothermal effect of D/INPs was positively correlated with concentration and laser power. IR-780 provided the carrier with efficient photothermal conversion and photodynamic activity. This study achieved, for the first time, efficient accumulation of IR780 in multiple myeloma lesions and synergistic chemo-phototherapy, laying the foundation for combined photo-chemotherapy of other bone marrow-derived hematological tumors.86

In addition to the above-mentioned star molecules, verteporfin, a benzoporphyrin derivative, is a photosensitizer that also plays an important role in PDT. When activated by a specific wavelength of light in vivo, it generates ROS, thereby destroying target tissues.138 Yu et al constructed ZIF-8@Ver-M1M nanophotosensitizers. Under laser irradiation, ROS were effectively generated. Live/dead staining showed that the proportion of dead cells in the ZIF-8@Ver-M1M group was much higher than that in the free verteporfin and uncoated ZIF-8@Ver groups, further confirming the synergistic PDT killing effect of macrophage membrane modification and laser irradiation.139 Furthermore, the emergence of new nanophotosensitizers has injected new vitality into PDT. Cu-Cy NPs are a novel nanophotosensitizer that can be excited by multiple energy sources to generate ROS and possess Fenton-like activity. Li et al applied Cu-Cy NPs to the treatment of cutaneous squamous cell carcinoma (cSCC). The copper ions triggered Fenton-like reactions and depleted GSH to exert CDT effects, while under UV light, O2 was generated to achieve PDT effects. The synergy between the two significantly inhibited cSCC cell proliferation and induced apoptosis, fully leveraging the “photosensitizer + enzymatic” dual characteristics to achieve natural synergy between CDT and PDT, overcoming the limitations of traditional photosensitizer monotherapy.140

Synergistic Gene Therapy

Gene therapy is a widely studied alternative treatment method that involves introducing therapeutic genes into cancer cells or tissues to cause cell death or slow cancer growth.141 Co-delivery of drugs and genes using nanoparticles can produce synergistic effects on tumors and promote cellular uptake through endocytosis.142 ZIF-8, as a novel non-viral gene vector, offers advantages such as high loading capacity, pH responsiveness, and ease of functionalization, providing a new approach for gene therapy.

Li constructed carbon quantum dot (CD)-modified ZIF-8@CDs co-loading DOX and survivin-siRNA. ZIF-8@CDs catalyzed the production of hydroxyl radicals from H2O2 in the tumor microenvironment while consuming GSH. The siRNA silenced the anti-apoptotic gene survivin, reversing drug resistance, while DOX directly killed cells. The synergistic effect resulted in an apoptosis rate of 49%, achieving significant synergy among chemodynamic therapy, chemotherapy, and gene therapy.143 An IR780 derivative (PTA), 2-Hmim, siRNA, and Zn2+ self-assembled into siRNA@PT-ZIF-8. The siRNA silenced the heat shock protein HSP70, enhancing tumor sensitivity to mild photothermal therapy and significantly improving antitumor efficacy, overcoming the limitations of short blood circulation half-life and weak stability of free genes, achieving synergistic gene and photothermal therapy.144 Plasmid DNA containing the p53 tumor suppressor gene was loaded into ZIF-8 to express normal proteins upon cell entry. ZIF-8-PEI as a p53 gene delivery vector exhibited good transfection efficiency and higher cell death-inducing ability in HeLa and MDA-MB-231 cells. The introduction of PEI not only increased plasmid loading but also enhanced the endosomal escape capability of the nanoparticles, improving gene therapy efficacy.145 DOX and PD-L1 siRNA were loaded into ZIF-8 to synthesize RNA-DOX@ZIF-8 (RDZ). RDZ was uniformly mixed with catechol-modified chitosan to prepare a multifunctional hydrogel. siPD-L1 silenced PD-L1 in tumors, activating CD8+ T cells and releasing granzyme B, thereby activating an antitumor immune response, achieving synergistic local chemotherapy and gene therapy against tumors.146 Hu et al co-loaded DOX and MDR1-siRNA into ZIF-8. In vitro experimental results showed that the fluorescence intensity of DOX in the nucleus was dose- and time-dependent on MDR1 silencing efficiency. siMDR1 efficiently silenced MDR1, reducing drug efflux and synergizing with nuclear enrichment, reducing the IC50 by 5.2-fold compared with free drug.147 Saeinasab et al constructed Apt-PEG-siRNA@ZIF-8. SNHG15 is an oncogenic lncRNA highly expressed in prostate cancer. Targeted delivery of SNHG15 siRNA to PC-3 cells prolonged its systemic circulation time and promoted siRNA release to silence SNHG15 expression without affecting its host gene SNORA9, avoiding interference with the host gene.148

Synergistic Immunotherapy

PD-1/PD-L1 antibodies are commonly used immune checkpoint inhibitors that attack tumors by reactivating exhausted T cells and are among the most widely applied immunotherapies in clinical practice.149,150 However, systemic administration may lead to non-specific immune activation, causing severe immune-related adverse events.151 ZIF-8 carriers have been extensively explored for the targeted delivery of immunotherapeutic agents. ZIF-8 can specifically degrade under the weakly acidic conditions of the tumor microenvironment, achieving controlled release and intratumoral accumulation of PD-1/PD-L1 antibodies or other inhibitors, thereby significantly reducing the immunotoxicity associated with systemic exposure while enhancing therapeutic efficacy.152

As shown in Figure 8, Li et al prepared mitoxantrone-loaded ZIF-8 nanoparticles (MIT@ZIF-8). The Zn2+-mediated pyroptosis-inducing function amplified the ICD effect induced by MIT, significantly enhancing calreticulin exposure and HMGB1 release, thereby activating CD8+ cytotoxic T cells and reducing the proportion of regulatory T cells. This converted immunologically “cold” prostate cancer into “hot” tumors and significantly sensitized them to anti-CTLA-4 immune checkpoint inhibitors.153 ZIF-8 synergized with the DNA methyltransferase inhibitor decitabine (DCT), oxaliplatin (OXA), and imiquimod (R837) to induce pyroptosis in melanoma cells. DCT upregulated the key pyroptosis protein GSDME, OXA activated the caspase-3-GSDME pathway to induce tumor cell pyroptosis, and R837, as a TLR7 agonist, amplified the pyroptosis-mediated immunogenic cell death effect, promoting the release of damage-associated molecular patterns (DAMPs) such as ATP, CRT, and HMGB1, activating dendritic cell maturation and CD8+ T cell infiltration, achieving local and systemic antitumor immunity.154 Peng et al used ZIF-8 to load polyphyllin II (PPII), with the surface coated with mesenchymal stem cell membranes for mitochondrial targeting. In the tumor microenvironment, PPII was released, inducing ferroptosis in HCC cells. Mitochondrial stress released endogenous mtDNA, which specifically activated the cGAS-STING pathway in synergy with Zn2+. This drove dendritic cell maturation, polarization of tumor-associated macrophages from M2 to M1, enhanced CD8+/CD4+ T cell infiltration, and inhibited Tregs, reversing immunosuppression.155 Long et al transformed ZIF-8 from an inert carrier into a multifunctional mitochondrial synchronizer. HA/ZGA co-delivered GOx and 5-ALA, simultaneously blocking glucose supply and mitochondrial energy metabolism through the triple mechanism of Zn2+/GOx/5-ALA, synergistically eliminating cancer stemness, reversing PD-L1/CD44 co-expression, and triggering cytotoxic T lymphocyte (CTL) infiltration.156 Yan utilized the Cu2+ valence cycle-mediated Fenton-like reaction and the photosensitizer P18-mediated PDT to generate ROS, further amplifying pyroptosis and immunogenic cell death, significantly enhancing antitumor immune responses and inhibiting melanoma growth, providing a new approach for MOF-released Zn2+ to regulate cell death pathways and activate antitumor immunity.157 Liang et al achieved efficient encapsulation of the CAR gene in ZIF-8, targeted delivery to TAMs, and efficient intracellular transfection, constructing CAR-macrophages (CAR-M) in situ. Co-delivery of IFN-γ and the CAR gene maintained the specific tumor killing and phagocytic activity of CAR-M while activating adaptive immunity, achieving up to 95.54% tumor growth inhibition in a prostate cancer mouse model.158 αPD-1 antibody-conjugated ZIF-8 nanoparticles released hyaluronidase and DCT in the acidic TME, degrading the matrix and promoting CCL5 secretion, forming a self-reinforcing TIL infiltration cycle. In immunodeficient mice, TIL infiltration increased 12-fold, achieving tumor eradication and metastasis inhibition in immunocompetent models.159 ZIF-8 co-loaded the chemotherapeutic drug DOX, the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan (1MT), and the immune adjuvant CpG, achieving synergistic chemotherapy and immunotherapy. In a 4T1 tumor-bearing model, the tumor inhibition rate reached 85.6%, with reduced drug toxicity, providing a safe and efficient new strategy for chemo-immunotherapy.160 Su et al constructed PDA/(CPT+1-MT)@ZIF-8 (PCMZ) nanoparticles. In vitro and in vivo experiments showed that PCMZ NPs effectively inhibited tumor growth, induced ICD in tumor cells, promoted dendritic cell maturation, inhibited the IDO pathway, and ultimately differentiated T cells into cytotoxic T cells and helper T cells, thereby effectively activating antitumor immune responses.161

MIT@ZIF-8 nanoparticles boost chemo-immunotherapy via pyroptosis and immune activation.

Figure 8 (a) Schematic of the design and synthesis of MIT@ZIF-8 nanoparticles for enhanced chemo-immunotherapy. (b) MIT@ZIF-8 effectively amplifies ICD through increased tumor uptake of MIT and pyroptosis triggered by Zn2+ ions, augmenting chemo-immunotherapy for both immunologically “hot” and “cold” cancers and sensitizing prostate cancer to anti-CTLA-4 immunotherapy.153 Licensed under CC BY.

As a drug delivery carrier, ZIF-8 exhibits unique advantages in combination therapy, synergizing with chemotherapy, photodynamic therapy, photothermal therapy, immunotherapy, and gene therapy to achieve multimodal combination antitumor effects. To systematically summarize the design strategies and key findings of ZIF-8 in different synergistic therapy approaches, Table 3 summarizes representative applications.

Table 3 Research Progress on ZIF-8-Based Nanoparticle Formulations for Synergistic Cancer Therapy

The pH-responsive properties of ZIF-8 enable a temporal coordination strategy of “modifying the microenvironment first, followed by targeted attack”; this differs from traditional combination therapies where individual drugs distribute independently. The coencapsulation strategy ensures that different therapeutic agents arrive simultaneously at the target cells, thereby initiating all treatment signals concurrently and maximizing the synergistic cytotoxic effect. The superior efficacy of multimodal collaborative cancer therapy compared to single-agent therapies can be attributed to its complementary anti-tumor mechanisms, mitigation of the limitations inherent in monotherapy, reversal of multidrug resistance, reduction of off-target systemic toxicity, and remodeling of the immunosuppressive tumor microenvironment. The localized hyperthermia generated by photothermal therapy not only directly ablates tumors but also alleviates hypoxia by enhancing blood perfusion and oxygenation levels, thereby increasing the sensitivity of radiotherapy and photodynamic therapy; conversely, the ROS produced by photodynamic or chemodynamic therapies can consume antioxidant molecules such as glutathione, further amplifying the oxidative damage induced by chemotherapeutic agents, effectively reducing the probability of cross-resistance; furthermore, the combined activation of multiple cell death pathways—apoptosis, ferroptosis, and pyroptosis can block compensatory survival pathways in tumors, ultimately overcoming drug resistance.

Challenges and Future Prospects

Despite the numerous breakthrough advances achieved with ZIF-8-based nanodrug delivery systems in fundamental research, their translation to clinical practice remains fraught with significant challenges. At present, most studies are still confined to cellular and murine models, with insufficient evidence regarding safety profiles and in vivo fate evaluation for clinical translation. The cytotoxicity of ZIF-8 is primarily attributed to intracellular accumulation of Zn2+ ions, with smaller particles exhibiting higher toxicity, potentially inducing necrotic cell death via oxidative stress. Furthermore, premature degradation under physiological conditions may lead to premature drug leakage and even provoke an immunosuppressive microenvironment. Critical data required by regulatory agencies—including Zn2+ metabolic kinetics, degradation product distribution, and chronic toxicity—remain largely unavailable.169 In terms of delivery efficiency, the actual efficacy of the conventional EPR effect in human tumors is considerably lower than that observed in animal models.170 The high interstitial pressure, dense extracellular matrix (ECM), and antioxidant systems within the tumor microenvironment severely impede deep penetration of nanoparticles and compromise therapeutic efficacy. Thus, designing ZIF-8 nanocarriers capable of deep tumor penetration represents a critical direction for future research. From a manufacturing standpoint, although scale-up processes such as microfluidics and mechanochemistry have been explored, ton-scale production compliant with GMP has yet to be achieved, and reproducibility, batch-to-batch consistency, and stability remain difficult to ensure.

To overcome these obstacles, future efforts should focus on further enhancing targeting precision and minimizing off-target effects through the design of pH/redox dual-responsive systems, which could facilitate ECM barrier penetration, enable deep tumor delivery, and achieve precisely controlled Zn2+ release. The adoption of green and efficient manufacturing techniques—such as microwave-assisted synthesis and mechanochemical approaches—coupled with the establishment of standardized GMP-compliant synthesis and characterization protocols, will be pivotal for industrial translation. Concurrently, the development of stable formulation strategies is essential to ensure reliability during clinical application.

Conclusion

As a nanomaterial, ZIF-8 has demonstrated tremendous potential. It is not limited to specific tumor types but can serve as a multifunctional targeted carrier, with highly tunable optimal applications. Depending on the loaded drug and the conjugated targeting ligand, this carrier can be customized to match the unique characteristics of various malignant tumors. In the field of combination therapy, the ZIF-8 carrier has successfully integrated photothermal therapy, photodynamic therapy, chemodynamic therapy, and chemoradiotherapy into a single nanocarrier system. Synergistic therapies can simultaneously target different sites and pathways; for example, chemotherapeutic drugs kill rapidly proliferating cells, while PTT/PDT can ablate drug-resistant “cold tumor” regions. The two approaches complement each other, reducing the likelihood of recurrence. Multimodal synergistic therapy overcomes the limitations of monotherapy and, through complementary mechanisms, microenvironment remodeling, synchronized drug release, and systemic immune activation, achieves a qualitative rather than merely quantitative improvement in therapeutic efficacy; this establishes ZIF-8’s status as a highly promising anticancer drug delivery platform.

Overall, ZIF-8 demonstrates significant technical advantages in improving drug targeting, enhancing therapeutic efficacy, and reducing systemic off-target toxicity. With the continued advancement of materials engineering and translational nanomedicine, ZIF-8 holds broad prospects in the field of clinical translation and is expected to evolve into a universal nanoplatform for precision oncology and combination immunotherapy, ultimately providing a safe, highly effective, and controllable therapeutic tool for the treatment of malignant tumors.

Abbreviations

TME, Tumor microenvironment; GSH, Glutathione; MDR, multidrug resistance; NDDS, Nanodrug delivery systems; EPR, enhanced permeability and retention; MOFs, Metal-organic frameworks; ZIF-8, Zeolitic imidazolate framework-8; 2-Meim, 2-methylimidazole; DMF, dimethylformamide; PTT, Photothermal therapy; DOX, doxorubicin; PDI, Polydispersity index; CUR, Curcumin; PDA, Polydopamine; BSA, Bovine serum albumin; TMZ, Temozolomide; TA, Tannic acid; IM, Impregnation method; 5-FU, 5-fluorouracil; FR, folate receptor; PEG, Polyethylene glycol; PVP, Polyvinylpyrrolidone; NIR, Near-infrared; MTX, Methotrexate; FA, Folic acid; GOx, Glucose oxidase; HA, Hyaluronic acid; OSCC, Oral squamous cell carcinoma; DMDD, 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione; CDT, Chemodynamic therapy; PTX, Paclitaxel; PDT, Photodynamic therapy; ICD, Immunogenic cell death.

Data Sharing Statement

No new data were collected, and no new ethical approval was required.

Consent for Publication

Informed consent for publication was received from all participants.

Acknowledgments

Thanks to all the authors for their help and contributions to this paper.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was supported by the Hunan Provincial Natural Science Foundation (Grant No.: 2025JJ60912), the Hunan Provincial Department of Education Research Project (Grant No.: 24A0277), the National Undergraduate Innovation and Entrepreneurship Research Program (Grant No.: 202210541070), and the National Key Research and Development Program (Grant No.: 2022YFD1801101).

Disclosure

The authors declare that they have no competing interests.

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