Solvothermal synthesis is the most commonly used method for obtaining high yields and purity of ZIF-8 (Cravillon et al., 2012). The solvothermal method was initially reported by Park et al., in 2006, and since then, it has become a prominent approach for developing high-quality ZIF-8 (Park et al., 2006). This method is simple and effective, involving the dispersion of zinc salt and 2-methylimidazole in an organic solvent to form a composite solution, which is then heated at a specific temperature. Under the influence of the solvent and heat, the 2-methylimidazole reacts with zinc ions, forming crystal nuclei of ZIF-8. Over time, these nuclei grow until neutral 2-methylimidazole is observed. Currently, the organic solvent commonly used for the synthesis of ZIF-8 include, but are not limited to, methanol (Malekmohammadi et al., 2019), N,N-dimethylformamide (DMF) (Santoso et al., 2021) and N. N-diethylformamide (DEF) (Reif et al., 2019), etc.

In their study, Ahn et al. utilized DMF as the organic solvent and employed the solvothermal method to prepare rhombic ZIF-8 particles with an average size ranging from 150 to 250 μm (Lee et al., 2015). In a separate study conducted by Wiebcke et al., in 2009, methanol was used as the organic solvent to synthesize nano-sized ZIF-8 particles at room temperature (Cravillon et al., 2009). The results showed that the ZIF-8 particles exhibited a regular particle morphology, a narrow size distribution (with an average particle size of approximately 46 nm), and good thermal stability, up to approximately 200 °C. Edit and colleagues utilized acetic acid as a polar solvent to synthesize uniform ZIF-8 particles at room temperature (Santoso et al., 2021). Compared to the ZIF-8 synthesized using DMF, the particles produced through this method had a more uniform distribution and smaller size (with an average particle size of approximately 65 nm). Furthermore, this method effectively enhanced the mesoporosity of the ZIF-8 particles, resulting in a larger pore diameter (2.76 nm), a higher mesopore volume (0.166 cc/g), and a moderate surface area (500 m²/g).

Although solvothermal synthesis is known for producing high-quality ZIF-8, it is worth noting that this approach can be energy-intensive and time-consuming. Additionally, the synthesis process often requires the use of excessive amounts of organic solvents, which can result in significant pollution and potential harm to biosafety (Pan et al., 2022). Many organic solvents are known to be toxic to the human body, which poses a significant challenge for the application of ZIF-8 in tissue engineering, unless careful consideration is given to the removal or avoidance of these solvents. In summary, due to these concerns, solvothermal synthesis may not be suitable for the preparation of ZIF-8 for medical applications.

In addition to solvothermal synthesis, hydrothermal synthesis is another commonly used method to obtain high purity ZIF-8 (Munn et al., 2015; Butova et al., 2017). This aqueous synthesis method effectively addresses the issue of using organic solvents by solely relying on water as the polar solvent, resulting in the formation of well-defined lattice crystals. Furthermore, hydrothermal synthesis offers the advantage of operating at room temperature, eliminating the need for high-temperature conditions and thereby increasing production efficiency (Pan and Lai, 2011; Shi et al., 2011). As a result, hydrothermal synthesis has emerged as an attractive approach for the environmentally friendly and safe production of ZIF-8.

Lai et al. firstly prepared ZIF-8 nanoparticles in aqueous solution (Pan et al., 2011), as shown in Figure 1. The transmission electron microscope images clearly revealed the hexagonal morphology of the synthesized ZIF-8 samples, with an average crystallite size of approximately 70 nm calculated using the Scherrer equation (Figures 1A, B). The X-ray diffraction patterns of the samples exhibited characteristic peaks consistent with published ZIF-8 structure data, confirming the purity of the synthesized ZIF-8 product. Thermal stability testing of the samples in air was conducted, as shown in Figures 1C–E. The color of the samples gradually changed from white to light yellow, and eventually to dark orange as the temperature increased up to 300°C (Figure 1C). However, under SEM observation (Figure 1D), the samples did not show significant changes. Instead, after heating the samples to 400°C for 5 h, their crystals transformed into smaller particles (approximately 25 nm) and the color of the samples returned to white. These results indicated the complete destruction of the ZIF-8 crystal structure and the formation of ZnO based on the XRD patterns. In summary, the hydrothermal synthesis method yielded ZIF-8 with high purity, uniform morphology, and good thermal stability.

Nowadays, this fabrication method of homogeneous, high-quality and safe ZIF-8 has become one of the important indicators of concern. Butova et al. prepared ZIF-8 with a large specific surface area (1,340 m²/g) via hydrothermal synthesis (Butova et al., 2017), and ZIF-8 samples exhibited high capacity in I₂ uptake, which making it possess the ability to selectively adsorb small molecules of drugs. Munn et al. reported a method for the large-scale production of ZIF-8 (Munn et al., 2015), and the surface area of produced ZIF-8 was 1800 m²g⁻¹. More significantly, the lab-scale and pilot-scale of the production method was reached 27 g h⁻¹ and 810 g h⁻¹, respectively, which greatly improved its commercialization ability.

The microwave-assisted method, initially introduced by Bux in 2009 (Bux et al., 2009), is an energy-efficient technology for obtaining ZIF-8. This method offers several advantages, including rapid heating rates, shorter reaction times, and higher selectivity and yield. It operates based on the interaction between electromagnetic waves and charged materials, such as polar molecules in solvents or conductive ions in solids. In comparison to the previous methods mentioned, the microwave-assisted method effectively accelerates the reaction rate and provides control over the shape and size of the ZIF-8 products. Lai et al. and Xing et al. demonstrated the synthesis of regularly rhombohedral and spherical ZIF-8 nanocrystals, respectively, using the microwave-assisted method (Lai et al., 2015; Munn et al., 2015). This method significantly reduced the reaction time compared to solvothermal synthesis. Additionally, Tang and colleagues quickly produced rhombic dodecahedron-shaped ZIF-8 nanocrystals with sizes ranging from 3 to 5 μm using microwave irradiation (Chen and Tang, 2019). The reaction time for this method was shortened to approximately 20 h. Furthermore, Bao et al. combined the advantages of the hydrothermal method with microwave irradiation to prepare ZIF-8 with a high surface area and large micropore volume. They achieved this by using a relatively low ligand to metal ion molar ratio.

For a substance to generate heat under microwave radiation, it is required to have an electric dipole (Kaufmann and Christen, 2002; De la Hoz et al., 2005). When the dipole attempts to reorient itself in response to the alternating electric field, the heating effect in microwave radiation is caused by the part that consists of an electric field, instead of the magnetic field part. This results in the generation of heat through molecular friction. During the synthesis process of ZIF-8 using the microwave-assisted method, the heat generated by dipolar polarization is primarily attributed to the interaction between polar solvent molecules like water, methanol, and ethanol (Van Tran et al., 2020). The frequency range of the oscillating field plays a crucial role in this process. It is important to determine whether the frequency range is appropriate to achieve sufficient interaction between particles. If the frequency range is excessively high, the intermolecular forces may prevent the polar molecules from moving before attempting to follow the field. This can result in inadequate inter-particle interaction. On the other hand, if the frequency range is too low, the polar molecules will have sufficient time to align themselves in phase with the field. Therefore, the microwave-assisted method is more complex compared to the previously mentioned methods, and its successful execution can be challenging in practice. It requires careful consideration of the frequency range to ensure optimal inter-particle interaction and efficient heat generation during the synthesis of ZIF-8.

In addition to solvothermal synthesis, hydrothermal method, and microwave-assisted method, there are several other synthesis routes that can be used to prepare ZIF-8 with high purity. These include sonochemical synthesis (Bui et al., 2022), mechanochemical method (Taheri et al., 2020), dry-gel conversion (Ji et al., 2020) and microfluidic method (Yao et al., 2020),. For instance, Luo et al. demonstrated the sonochemical synthesis of ZIF-8 nanoparticles on the surface of TiO2 nanofibers (Zeng et al., 2016), as depicted in Figure 2A. Ahn et al. achieved high-yield synthesis of ZIF-8 on a 1-L scale by combining sonochemical method with pH-adjusted synthesis conditions using a NaOH solution containing a small amount of triethylamine (Cho et al., 2013). Friščić et al. utilized mechanochemical methods to produce ZIF-8 particles by mixing ZnO and 2-methylimidazole and catalyzing with a small amount of acetic acid (Katsenis et al., 2015), as shown in Figure 2B. Schneider et al. employed the microfluidic method to synthesize ZIF-8 crystals with a wide size range (approximately 300–900 nm) and high specific surface area (around 1700 m²·g^-1) (Kolmykov et al., 2017). These various synthesis routes offer alternative approaches for the preparation of ZIF-8 with high purity, providing flexibility and the opportunity to tailor the properties of the resulting material.

In fact, the size and morphology of ZIF-8 can vary depending on the specific preparation processes employed. For instance, Lee et al. conducted a study comparing the morphology and structure of ZIF-8 crystals using seven different synthesis methods (Lee et al., 2015), as illustrated in Figure 2C. The results revealed that while the BET surface areas of the samples fell within the range of 1,250–1,600 m²·g⁻¹, but there were noticeable differences in the size of the crystals, ranging from several nanometers to hundreds of micrometers. Among these methods, sonochemical synthesis was capable of producing relatively homogeneous crystals. However, the unstable reaction conditions associated with this method can limit the purity of the crystals, making it challenging to achieve large-scale production. On the other hand, mechanochemical methods allow for large-scale synthesis of ZIF-8, but they may not guarantee uniformity of nanoparticles and can even result in the collapse of the crystal structure. Electrochemical methods, on the other hand, can yield ZIF-8 crystal particles with high crystallinity and relatively good properties. However, one challenge is the difficulty of separating ZIF-8 particles from the solution.

Overall, each of these techniques has its own advantages, limitations, and appropriate applications. When selecting a synthesis method for ZIF-8 based on performance requirements, it is important to consider factors such as size, shape, surface properties, strength, and thermal stability of the synthetic materials. For instance, if the goal is to investigate the effects and applications of ZIF-8 in tissue engineering, hydrothermal method may be suitable due to potential toxicity or compatibility issues. Moreover, in addition to the aforementioned approaches, researchers are actively exploring and developing new synthetic methods for the preparation of green and high-quality ZIF-8 and its derivatives. These efforts are guided by both theoretical principles and practical considerations. Examples of such emerging methods include electrochemical synthesis and ionothermal synthesis. By continuously exploring and refining synthetic routes, scientists aim to enhance the efficiency, sustainability, and control over the synthesis process, ultimately enabling the production of ZIF-8 and its derivatives with desired properties for a wide range of applications.

ZIF-8 belongs to the class of porous materials constructed from 2-methylimidazole coordinated to Zn²⁺. While the porous structure of ZIF-8 shares similarities with zeolites, it has distinct characteristics in terms of pore size, shape, and absorptivity. Typically, the thermal stability of MOFs is lower compared to most inorganic microporous materials, primarily due to the presence of organic linkers (Kumar et al., 2017). However, ZIF-8 stands out by exhibiting relatively high thermal stability, which may be attributed to its unique crystal growth mode. Therefore, it is crucial to investigate the growth mechanism of ZIF-8 crystals to deepen our understanding of its essence and improve control over particle size. Based on previous research, there is a consensus that the formation of ZIF-8 involves two main processes: nucleation and crystal growth.

The nucleation of ZIF-8 is primarily attributed to homogeneous nucleation, which is commonly used to explain the crystallization behavior of nanocrystalline structures formed by the connection of nitrogen or oxygen atoms to metal tetrahedral nodes (Cravillon et al., 2011). In the reaction system, the excess 2-methylimidazole undergoes protonation and then coordinates with the zinc ion, leading to the formation of a crystal nucleus (Cravillon et al., 2009). This nucleation process occurs spontaneously as it reduces the free energy of the system under conditions of concentration supersaturation. Subsequently, the growth of ZIF-8 in the solution proceeds through the diffusion and subsequent binding of small monomers on the crystal surface. Under conditions of concentration supersaturation, the nanocrystalline nucleus experiences rapid growth, resulting in the formation of ZIF-8 nanoparticles. As the solution saturation decreases, the neutral 2-methylimidazole combines with the positively charged ZIF-8, leading to the termination of the reaction. Therefore, the growth of the crystal nucleus surface is dependent on the level of reagent supersaturation.

The regulation and control of ZIF-8 particle size can be summarized into two aspects: the regulation of reaction parameters, the introduction of surfactants and crystal regulators.

• Adjustment of reaction parameters

Adjusting reaction parameters, such as reaction time, temperature, mixing speed, and feeding ratio, is a direct and effective way to influence the characteristics of ZIF-8 powder. Choi et al. observed that the average size of ZIF-8 decreased from 155 to 35 nm as the reaction temperature increased from 120°C to 180°C (Choi et al., 2015). Similarly, Langner et al. found that the average size of ZIF-8 decreased from 78 nm to 26 nm as the synthesis temperature increased from −15°C–60°C (Tsai and Langner, 2016). These results indicate that higher reaction temperatures lead to smaller ZIF-8 grains due to increased nucleation and limited grain growth caused by the consumption of 2-methylimidazole. In addition to synthesis temperature, adjusting the charging ratio or changing the material composition can also control the particle size. Beh et al. found that increasing the concentration of Zn²⁺ enhanced the nucleation rate and suppressed nuclei growth, resulting in smaller ZIF-8 particles (Beh et al., 2018). Conversely, increasing both Zn²⁺ and 2-methylimidazole concentrations simultaneously enhanced nucleation and nuclei growth, leading to larger particle sizes. Schneider et al. investigated the effect of different zinc salts on size and morphology and found that the reactivity of the zinc salts influenced the particle size and morphology of ZIF-8 (Schejn et al., 2014). For example, the use of highly reactive zinc salts such as Zn(NO₃)₂, ZnSO₄, and Zn(ClO₄)₂ resulted in the formation of fine ZIF-8 particles with diameters of approximately 50–200 nm. Moderately active zinc salts like ZnCl₂ yielded particles with sizes ranging from approximately 350–650 nm. Low-reactive zinc salts led to the generation of micro-sized crystals. In fact, the reaction parameters mentioned earlier are interconnected, as the growth process of ZIF-8 involves two stages: nucleation and growth. By controlling factors such as reaction time or 2-methylimidazole concentration, it is possible to achieve smaller particle sizes at lower reaction temperatures. For instance, Beh et al. successfully prepared fine ZIF-8 particles with a mean size of approximately 60 nm by controlling the reaction time at a low temperature of 5 °C (Schejn et al., 2014). Therefore, it is worth considering the formulation of a specific combination strategy to obtain nanoparticles of the desired size.

• Introduction of surfactants agent and crystal regulator

Surfactants play a crucial role in controlling the size and morphology of nanoparticles due to their unique amphoteric molecular structure, with one end being hydrophilic and the other end being hydrophobic (Zhang and Marchant, 1996). In general, the hydrophobic end, being non-polar, inhibits crystal growth through steric effects, while the hydrophilic end with polarity often leads to high surface tension, reducing the surfactant’s adsorption capacity and affecting particle morphology (Zhu et al., 2017). As a result, surfactants can be used as blocking agents for ZIF-8 to regulate its particle size. For example, Chen et al. utilized non-ionic surfactants, specifically triblock copolymers P123 and F127, to prepare ZIF-8 particles with sizes below 104 nm and a high BET surface area of 1,599 m²g⁻¹ under microwave irradiation (Xing et al., 2014).

Another commonly used method to control the particle size of ZIF-8 is through the use of crystallization regulators. These regulators control the nucleation process of nanoparticles by introducing crystallization inhibitors or promoters into the reaction system, thereby precisely controlling the particle size of ZIF-8. One commonly used crystallization promoter is triethylamine (TEA), which enhances the nucleation rate of ZIF-8 by accelerating the deprotonation process of 2-methylimidazole, leading to the formation of fine ZIF-8 particles. Various studies have shown that the particle size of ZIF-8 decreases with an increase in the content of TEA. On the other hand, monodentate ligands like 1-methylimidazole, formate, and n-butylamine are often used as crystallization inhibitors to assist in ZIF-8 synthesis. These ligands help adjust the proton balance during the nucleation and growth of ZIF-8 crystals. For instance, Wiebcke et al. synthesized ZIF-8 particles with a size of 10 nm by adjusting the crystal inhibitor (Cravillon et al., 2011).

Traditional drug treatments often face challenges related to drug specificity, a narrow window of efficacy, adverse pharmacokinetic profiles, and potential side effects (Edwards and Aronson, 2000; Huggins et al., 2012). In this regard, nanoparticle therapy aims to maximize the loading of drug molecules, thereby avoiding premature drug release and achieving more effective treatment when reaching damaged tissue sites. ZIF-8, in particular, offers advantages in this context due to its high surface area and pore volume, which enable higher drug loadings. Furthermore, ZIF-8 exhibits good degradation performance and stability in aqueous solutions, allowing for controlled and sustained release of drugs, and ultimately leading to long-lasting therapeutic effects.

In tissue regeneration treatments, the required drug functions typically include antibacterial, anti-inflammatory, and regeneration-promoting properties. To prevent premature drug leakage before reaching the target location, the most effective approach is to encapsulate drugs during the synthesis process of ZIF-8. Zhu et al. utilized ZIF-8 to encapsulate biological cascade enzymes and combined them with antisense oligonucleotides (ASOs) to create a biomineralized nanomaterial (GOx&HRP@ZIF-8/ASO), aiming to achieve efficient antibacterial effects (Zhang Y. et al., 2022). The results showed that the composites exhibited excellent antibacterial properties, with a concentration of only 16 μg/mL for MRSA bacteria after treatment. Additionally, the composites demonstrated superior biofilm destruction ability, with a bacteria removal efficiency of 88.2%, compared to simple ZIF-8 (32.85%) and ftsZ ASO (58.65%). This indicates that the production of reactive oxygen species (ROS) by biological cascade enzymes was fully utilized.

In a study conducted by Wang et al. (Zhang et al., 2023), dimethyloxallyl glycine (DMOG) was loaded into the ZIF-8 skeleton to create a drug-loading system aimed at promoting osteogenesis-angiogenesis coupling. Transmission electron microscopy (TEM) images revealed that the DMOG@ZIF-8 nanoparticles exhibited a crystal morphology similar to ZIF-8. X-ray photoelectron spectroscopy (XPS) analysis indicated that the coupling between DMOG and ZIF-8 was achieved through the binding of C=O and C-O bonds.

To assess the vascularization and bone regeneration effects of DMOG@ZIF-8 nanoparticles, the authors prepared implants containing DMOG@ZIF-8 using sodium alginate (Figure 4A). They further studied the osteogenic activity of DMOG@ZIF-8 by utilizing a rat defect model. Immunofluorescence staining was performed to detect signal transduction related to angiogenesis and osteogenesis during bone regeneration (Figures 4B, C). The results showed that the DMOG@ZIF-8 group exhibited higher intensity of BMP-2, OPN, OCN, CD31, HIF-1α, and VEGF-a compared to the other groups. This indicates that DMOG@ZIF-8 effectively regulated angiogenesis and promoted osteogenic ability. Furthermore, the newly formed bone was investigated (Figures 4D–J). It was evident that DMOG@ZIF-8 effectively promoted new bone formation, and the high expression of related osteogenic and angiogenic genes further confirmed this observation. In summary, DMOG@ZIF-8 demonstrated enhanced migration of human umbilical vein endothelial cells, secretion of angiogenesis-related proteins, and extracellular matrix mineralization, thereby promoting vascularized bone formation after implantation (Figure 4K).

For tissue defect produced by bone tumor, it was expected that nanoparticles have anti-tumor functions apart from the aforementioned functions. In this context, Luan et al. utilized ZIF-8 to absorb indocyanine green (IR820), and then functionalized with hyaluronic acid (hydroxyapatite) to composite nanoparticles with targeted functions (Zhang et al., 2018). Results showed the nanoparticles could effectively target tumors and inactivate tumor cells. Fang et al. used ZIF-8 nanoparticles to encapsulate autophagy inhibitor 3-methyladenine (3-MA) to slow-control its release before reaching the target (Chen et al., 2018). Cell tests revealed that 3-MA@ZIF-8 exhibited excellent antitumor efficacy and effectively inhibited the expression of autophagy-related markers (Beclin 1 and LC3).

The application of stimuli-responsive nanocarriers in drug delivery has become an interesting opportunity for optimizing tissue regeneration therapy (Mura et al., 2013). In a stimuli-responsive delivery system, the drugs loaded into nanoparticles can be released in response to specific stimuli such as pH, glucose, light, or temperature (Ganta et al., 2008). This allows the nanocarriers to specifically respond to pathological triggers present at selected target sites, making them a promising approach for tissue engineering. Among the various stimuli-responsive properties, pH responsiveness has been particularly considered as promising for tissue engineering, as both the pH at defect sites and in tumor environments are lower than that of normal tissue (Zhu and Chen, 2015; Qian et al., 2023a). By designing nanocarriers with pH-responsive properties, drug release can be specifically triggered in damaged tissue rather than normal tissue.

In a pH-responsive delivery system, ZIF-8 offers inherent advantages compared to stimuli-responsive nanocarriers synthesized through complex processes. ZIF-8 is relatively stable in aqueous solutions and its degradation rate increases as the environmental pH decreases, making it more suitable for treating tissue damage. Tyagi et al. (Kaur et al., 2017) utilized ZIF-8 to load 6-mercaptopurine (6-MP) and found that 6-MP@ZIF-8 exhibited significantly faster drug release in acidic pH compared to pH 7.4. Gai et al. (Sun et al., 2019) designed functional core-shell nanoparticles by encapsulating unstable d-α-Tocopherol succinate (α-TOS) within ZIF-8 and coating it with hyaluronic acid (hydroxyapatite). The results showed that the HA shell served as a tumor-targeted “guider,” connecting with tissue tumors through the CD44-mediated pathway. Subsequently, the decomposition of the ZIF-8 core released the loaded α-TOS in the acidic microenvironment of the tumor.

Tissue repair is a highly intricate process that requires coordinated events to ensure successful healing. In conditions like osteomyelitis, incomplete removal of bacterial infection at the defect site can lead to necrosis of newly formed bone tissue (Li et al., 2016). Therefore, it becomes crucial to develop a programmable delivery system that offers precise control over the timing and dosage of drug release in the patient’s body. Ideally, nanoparticles with programmable delivery functionality can improve therapeutic effectiveness by allowing control over the timing, duration, dose, and site-specific release of drugs in a predictable, repeatable, and on-demand manner. This programmability enables enhanced treatment outcomes and personalized medicine approaches.

A straightforward and effective method to encapsulate drugs in ZIF-8 is through chemical binding or physical adsorption. By utilizing this approach, controlled release of drugs can be achieved in a spatial and temporal manner, either by surface functionalizing ZIF-8 or by designing another functional material using ZIF-8 as a precursor. Ren et al. (Li et al., 2016) developed anti-tumor core-shell nanoparticles called ZDOS NPs, which had a dual function. The ZIF-8 core of the nanoparticles was loaded with DOX (doxorubicin), while the shell consisted of silicon-containing disulfide bonds. Under physiological conditions, ZDOS NPs remained stable. However, in the presence of endogenous glutathione in tumor cells, the disulfide bonds were ruptured, exposing the ZIF-8 core. This triggered the controlled release of DOX, enabling programmed drug delivery. Wang et al. (Tan et al., 2022) embedded silver nanoparticles and emodin (Phy) into the structure of ZIF-8 and modified it with hyaluronic acid (hydroxyapatite) to create composite particles with synergistic antimicrobial activity. The HA component of the nanoparticles underwent decomposition due to the secretion of hyaluronidase by bacterial growth, causing its accumulation around the bacteria. As the bacteria metabolized, the microenvironment underwent slight acidification, triggering the pH-responsive release of Phy and Ag.

Chu et al. (Pan et al., 2018) developed a novel drug delivery system where a nanometer-thick ZIF-8 film was grown in situ on the surface of carboxylated mesoporous silica (MSN-COOH) nanoparticles, as illustrated in Figure 5. In this design, the ZIF-8 membrane facilitated the transformation of the charge of MSN-COOH from negative to positive through electrostatic interactions, enabling effective loading of siRNA (small interfering RNA). The positively charged membrane enhanced cellular uptake of the nanoparticles and promoted their escape from lysosomes. Moreover, the ZIF-8 membrane decomposed in the acidic lysosomal environment, leading to the intracellular release of siRNA. Upon entering the cell, the ultra-thin ZIF-8 membrane would decompose in acidic lysosomes, triggering the release of both siRNA and drugs. These experiments demonstrated that the nanoparticles significantly enhanced the therapeutic effect on cancer cells with multiple drug resistance.

Recently, many studies have been conducted exploring ZIF-8 for its potential in drug delivery. However, conventional drug therapies often face challenges in clinical practice, such as uncontrolled release and drug resistance. To address these issues, the combination of photothermal therapy (PTT) and chemotherapy has emerged as a promising approach for achieving more efficient therapeutic effects in complex tissue repair scenarios. For instance, Yin et al. developed a targeted drug delivery system for osteosarcoma using polydopamine (pDA)-modified ZIF-8 nanoparticles loaded with methotrexate (MTX) (Yin et al., 2022). In this system, ZIF-8 served as a stable platform for drug loading and targeted delivery, while pDA modification prevented excessive drug release and imparted excellent photothermal effects and biocompatibility to the delivery system. Biological assays demonstrated that the pDA/MTX@ZIF-8 nanoparticles induced apoptotic cell death in MG63 cells through the controlled release of MTX. Moreover, the introduction of PTT effectively enhanced the anti-tumor effects and reduced the dosage of chemotherapy drugs. The results showcased the synergistic chemo-photothermal therapy effect of pDA/MTX@ZIF-8 nanoparticles (combination index CI = 0.346) and their exceptional biocompatibility, highlighting their potential for osteosarcoma therapy.

Another noteworthy study by Xiao et al. focused on the development of antibacterial agents with dual stimuli-responsive capabilities using ZIF-8 as a binder (Xiao et al., 2021). The researchers encapsulated vancomycin within ZIF-8, which was surface-modified with polydopamine. This approach enabled the combined effect of near-infrared (near-infrared) light-activated hyperthermia and the pH-responsive properties of ZIF-8. As a result, the system achieved efficient drug delivery, effectively eliminating planktonic bacteria and preventing biofilm formation, as shown in Figure 6. Furthermore, cell testing demonstrated that Van@ZIF-8@PDA exhibited minimal toxicity, thereby reducing the required antibiotic concentrations for bacterial eradication. The researchers also verified the excellent biocompatibility of the system in vivo using a mouse skin abscess model infected with Mu50. Overall, this work presents a promising strategy for combating antibiotic-resistant bacterial infections.

As well known, near-infrared light is commonly divided into two biologically transparent windows: the near-infrared I window (650–950 nm) and the near-infrared II window (1,000–1,350 nm) (Tsai et al., 2013). The near-infrared II window offers deeper tissue penetration due to reduced absorption and scattering effects. Therefore, utilizing the photothermal effect within the near-infrared II window is particularly meaningful for deep tissue repair. Deng et al. developed a yolk-shell structured drug carrier, Au@MOF, with remote-controlled and stimuli-responsive functions. The carrier consisted of star-shaped gold (Au star) as the photothermal yolk and biodegradable ZIF-8 as the shell (Deng et al., 2019). The chemotherapeutic drug, doxorubicin hydrochloride (DOX), was encapsulated within the cavity, enabling controlled release behavior through the degradation process of ZIF-8 in the mildly acidic tumor microenvironment. Upon 1,064 nm laser irradiation, the gold nanostar@ZIF-8 system effectively killed tumor cells through the synergistic effects of photothermal therapy and triggered drug release. Additionally, the strong absorbance of the system in the NIR region allowed for thermal imaging and photoacoustic imaging capabilities.

PDT is a non-invasive treatment where photosensitizers absorb energy from a specific light source, transferring it to surrounding oxygen molecules to generate ROS and eliminate abnormal cells. PDT combined with drug therapy offers a promising approach for addressing tissue repair issues caused by tumors or bacterial infections. Chen et al. developed a novel drug delivery system based on ZIF-8 for synergistic chemotherapy and PDT in endophthalmitis treatment (Chen et al., 2019). The system involved the in situ growth of silver (Ag) and subsequent modification with vancomycin/NH₂-polyethylene glycol (Van/NH₂-PEG) on the surface of ZIF-8 loaded with the photosensitizer ammonium methylbenzene blue (MB). In vitro bacterial tests demonstrated high efficacy in chemotherapy and photodynamic therapy against Staphylococcus aureus, Escherichia coli, and MRSA. Moreover, an in vivo mouse endophthalmitis model confirmed the biocompatibility and antibacterial properties of the composite nanomaterials. The study’s phototherapy synergistic chemotherapy approach, taking advantage of the inherent transparency of the eyes, holds promising potential for ophthalmic disease applications. Additionally, Yang et al. utilized ZIF-8 as a carrier to prepare hibiscus-like nanoparticles (6RF@ZIF-8) for the treatment of corneal cross-linking (CXL) using the common photosensitizer riboflavin-5-phosphate (RF) (Yang M. et al., 2022). The results demonstrated good compatibility and improved CXL effects compared to conventional protocols, with the added benefit of relieving postoperative eye pain and reducing the risk of infectious keratitis (Figure 7).

Considering the superiority of phototherapy, combining PTT and PDT in an appropriate way may bring desirable treatment outcomes. Tian et al. developed hybrid nanoparticles consisting of a porphyrin-based organic polymer (POP) coated on ZIF-8 (POP@ZIF-8) for cancer photodynamic and photothermal therapy (Tian et al., 2023). The pH-responsive properties of ZIF-8 enable the accurate delivery of the photosensitizer (porphyrin-based POP) to tumor areas, where it can effectively deactivate abnormal tumor cells through PDT. Simultaneously, the composite materials can convert light into local high heat, causing damage to tumor cells under laser irradiation and synergistically promoting the production of reactive oxygen species, thus enhancing the effectiveness of PDT. In cases where persistent pathogen infections delay the wound healing process and bring uncertain complications, Zhang et al. coencapsulated the phytochemical curcumin (Cur) and indocyanine green (ICG) into ZIF-8 for PDT/PDT sterilization (Zhang S. et al., 2022). The results demonstrated that the composite material exhibited efficient and rapid antibacterial performance through the synergistic effect of photothermal and photodynamic therapy, achieving a bactericidal rate of over 99%. Additionally, the material showed good compatibility, contributing to the rapid recovery of infected wound sites with minimal biological burden.